ILAE Commission on the Burden of Epilepsy, Subcommission on the Economic Burden of Epilepsy: Final Report 1998–2001

The objective of the Subcommission on the Economic Burden of Epilepsy was to review methods and findings on the economics of epilepsy, building on the prior work of the International League Against Epilepsy (ILAE) Commission on the Economic Aspects of Epilepsy 1, 2. To achieve this objective, the Subcommission gathered experts involved in economic studies in epilepsy who conducted workshops and made panel presentations at international congresses, prepared papers discussing methodologic issues and findings of recent economic studies in epilepsy, and prepared this summary report. Members included neurologists, psychologists, and economists from seven different countries. With the guidance and support of the Commission on the Burden of Epilepsy, headed by Torbjorn Tomson and Birthe Pedersen, the Subcommission was able to meet several times over the 3-year period, 1998–2001, to achieve its objective. At the International Congress in Prague, Czech Republic, the Subcommission held a 1-day work session to review the subjects to be addressed by commissioned papers and discuss the Global Campaign demonstration projects. A public symposium was sponsored in which the following presentations were made by Subcommission members: Estimates of the cost of epilepsy: cross-country comparisons; Outcome measures for cost-effectiveness analysis; The cost-effectiveness of new drugs; Economic value of surgery in epilepsy; and Objectives of the Global Campaign demonstration projects. The Subcommission held additional meetings in Orlando, Florida, and in San Diego and Los Angeles, California, in connection with the American Epilepsy Society annual meetings, and in Florence, Italy, in connection with the European Epilepsy Congress, to discuss outlines of commissioned papers and plans for paper completion and publication. The Subcommission's final meeting was held at the Congress in Buenos Aires to review final papers and discuss the final report. A public symposium was sponsored in which the following presentations were made: Economic evaluation in epilepsy: an overview; Economic analysis alongside clinical trials: what are the issues?; Comparison of medical and surgical costs for epilepsy; and Application of economic analysis in practice. The Subcommission will publish an Epilepsia supplement, the Economic Aspects of Epilepsy, to include two papers reviewing the current literature (Overview of economic assessment in epilepsy, Current issues and findings in assessing the cost of epilepsy) and three papers addressing major topics in the economics of epilepsy (Cost-effectiveness of epilepsy therapy: how should treatment effects be measured?, Cost-effectiveness of alternative treatment modalities, and Use of economic information in epilepsy decisions). In this report the Subcommission summarizes the methods, issues, and findings of economic studies of epilepsy completed in the mid- to late-1990s and provides recommendations and guidelines for future research. More detailed discussions of the material presented here may be found in the papers to be published by Subcommission members in the Epilepsia supplement. Economic analysis in epilepsy is concerned with the production and allocative efficiency of prevention and treatment decisions, services, and systems 3. Where healthcare is viewed as an output, the focus is on identifying services that achieve optimal outcomes for the least cost (production efficiency), and where healthcare is viewed as an input in the production of health, the emphasis is on maximizing health through effective allocation of resources among healthcare and other health determinants (allocative efficiency). Cost-of-illness studies have documented the direct and indirect cost of epilepsy on individuals and society. This line of research addresses allocative efficiency by documenting the overall economic burden of the illness and asking if costs could be lower with the "right," or most valued, mix of outputs. Economic evaluation studies have focused primarily on determining the costs and benefits of choosing among different antiepileptic drugs (AEDs) for monotherapy and add-on therapy, and selecting among alternative medical regimens (i.e., surgery vs. drug therapy). Calculation of the cost of epilepsy involves applying standard cost-of-illness methods to estimate direct and indirect costs attributable to epilepsy 4. Direct cost reflects resources consumed when healthcare and other social services are used to prevent, diagnose, treat, or rehabilitate persons with epilepsy. Such cost may include hospital inpatient and outpatient services, care of physicians and other practitioners, drugs, rehabilitation services, and other nonmedical items such as home care, special equipment, and so on. Indirect cost is defined as lost productivity due to morbidity and mortality including unemployment, underemployment, and decreased household work. The term "cost" refers to the economic value of resources consumed or not produced because of an illness. The value of resources is measured in terms of their "opportunity costs": the value those resources would have generated in their next best alternative use. Charge data are sometimes used to estimate resource costs, but researchers agree that in the absence of information on the costs of production, actual payments better reflect their social value. Indirect cost involves estimating the present value of future earnings and/or imputed wages from household work that are lost when people are not able to work. Cost studies vary in terms of their time perspective and the population considered. Prevalence-based cost studies estimate the cost over a short period (usually a year) for all prevalent cases, regardless of the evolutionary stage of the disorder. The short-term nature of this type of study makes it most appropriate for estimating the cost saving of a new technology or program that has short-term benefits for all patients. Incidence-based studies, conversely, consider the cost of epilepsy for new cases from the time of diagnosis to a definite end point, such as cure or death. This perspective is more appropriate when evaluating the cost saving of interventions that prevent new cases, or prevent or ameliorate the future course of a disease. The incidence-based perspective is more difficult because it is based on a longitudinal analysis of individuals, taking into account the temporal aspects of epilepsy. There are two broad estimation approaches that are used in cost-of-illness research in epilepsy: bottom-up individual related and top-down service related. In the former, cost estimates of the number and type of healthcare and social services consumed by individual patients are derived from observational studies of patient samples, or, alternatively, based on hypothetical information provided by expert panels and related literature. This approach is preferred when more precise estimates of individual costs are required and when examination of the variation in cost across individuals is desired. In the top-down type of study, estimates are based on surveys of funds received by providers of care, and a portion is attributed to epilepsy. Top-down studies use standard methods (disease-specific diagnosis coding) to allocate funds for epilepsy. This approach is preferred for estimates of high-prevalence illnesses that are well represented in national surveys. It yields only a rough approximation of specific costs for individuals and is incompatible with the stratification of cost by patient or disease characteristics. Ideally, estimates of aggregate costs derived from the two approaches should be similar. In reality, however, this is not certain because each approach is based on a different set of assumptions. The accuracy of the top-down approach depends on the precision of the methods used to derive estimates of the payments received by providers for treating people with epilepsy and the completeness of the list of providers. The accuracy of the bottom-up approach depends on how well the sample represents the universe of patients with epilepsy who receive care. Economic evaluations in epilepsy examine the cost and consequences of alternative treatments 5. Studies of AEDs have examined the choice of treatment for patients with new-onset epilepsy and epilepsy that does not respond well to medical treatment. Economic assessments also have examined choices among treatments for epilepsy, such as surgery versus pharmacologic therapy. The economic evaluation of epilepsy treatment involves examining incremental differences in costs and benefits of alternative courses of treatment. A cost–benefit ratio is calculated for one treatment or service compared with another, where the denominator reflects the incremental gain in health and the numerator reflects the additional cost of achieving that health gain. All appropriate costs and savings of both treatments must be accounted for. Economic assessment models differ in terms of the measures used to express the effectiveness of treatment. Cost-effectiveness analysis, the most widely used evaluation model, requires that health benefit attributable to alternative treatments be expressed in clinical terms, such as the number of persons with ≥50% reduction in seizure frequency or the number who are seizure free. An alternative form of economic evaluation is cost–benefit analysis, in which the health benefits are expressed in monetary terms. Because of ethical and methodologic concerns with monetary measurement of health gains, few true cost–benefit analyses have been performed in health care. In some cases, treatments produce identical health outcomes. When this can be assumed, the aim of a study is to determine the relative cost of each treatment option. Such studies are described as cost-minimization analysis. This has been the most common type of analysis in evaluating new drug treatments in epilepsy. When the gain in health is expressed in terms of health-related quality of life, such as Quality-Adjusted Life Years (QALYs) or Healthy Year Equivalents (HYEs), the economic assessment model is described as cost–utility analysis. Cost-utility analysis has become the gold standard in economic assessment of healthcare because the outcome measure reflects both the morbidity and mortality effects of treatment from the viewpoint of the patient 6. To derive QALYs, the change in life expectancy attributable to a treatment is adjusted for different health states experienced by the patient and weighted according to the patient's preferences. The values of cost per QALY gained have been reported for a number of interventions and illnesses, allowing comparisons of the economic profiles of epilepsy treatments with treatments for other diseases. Bottom-up and top-down cost-of-illness studies published from 1994 to the present in major epilepsy and/or neurology journals from around the world were reviewed to identify methodologic issues in the field 7-21. In this review, we discuss issues with the lack of standardized approaches in the field, the use of methods that do not meet standards, and application questions for which there are not widespread agreement. Recommendations are developed as to how to resolve these issues. Studies of the cost of epilepsy define the epilepsy population differently. Different definitions of epilepsy lead to different estimates of the number of people for whom costs are counted, with more inclusive definitions leading to higher total costs and lower average costs. In general, cost studies have focused on epilepsy as a generic illness and have yet to conduct analyses by seizure type or syndrome. Prevalence studies are typically based on the recruitment of patients with "active" epilepsy (i.e., epilepsy with recurring seizures and/or under current treatment). As a consequence, prevalence studies tend to give biased cost estimates because, even when cases are drawn from general populations, they overrepresent people with problems requiring medical attention. A further overestimate of cost is then expected when referral patients are considered as prevalent cases. These same studies may underestimate cost because newly diagnosed patients, who represent the highest fraction of the cost of epilepsy, are less frequently represented. Because of the lower likelihood of upward bias, it is recommended that cost studies be conducted in newly diagnosed patients identified from the community and followed up prospectively. Retrospective studies and prevalence-based studies also should be conducted, but, when possible, should focus on general populations of persons with epilepsy and use case definitions that minimize upward bias in cost estimation. The more inclusive definition of single unprovoked seizure has been used in incidence-based studies to document the high healthcare cost associated with diagnosing a case and determining initial treatment. This definition leads to lower cost estimates for those patients without recurrence. When single-seizure cases are included, it is recommended that the cost of these cases be reported separately from those who ultimately receive an epilepsy diagnosis. Studies vary in terms of the cost items that are included. Most studies include the well-known epilepsy-related items of healthcare consumption [i.e., physicians' visits, hospitalizations, diagnostic investigations, laboratory tests, and treatments (AEDs, surgical procedures, etc.)]. Some studies also account for nonhealthcare items such as transportation cost, residential care, and unpaid care or services provided by patients' relatives. Few studies have attempted to account for the indirect cost of epilepsy, and methodologic differences in items included and estimation procedures make comparisons difficult. Studies should capture the most comprehensive set of cost items possible. When it is necessary to rank the cost measures that are included, studies should focus on those items that are most likely to have a significant effect on costs. Researchers should justify the items selected for study and indicate important items that are not addressed. Only costs associated with the resources consumed or lost due to the presence of the disease under study should be included. In general, the cost experienced by patients with epilepsy is an overestimate of the cost attributable to epilepsy unless the costs of comorbid conditions are identified and excluded. The identification and exclusion of these conditions is difficult when they cannot be differentiated from epilepsy or its complications as potential sources of cost to be valued. For example, in a patient with posttraumatic hemiparesis and epilepsy, the direct cost relative to the management of the motor disturbance may be easily separated from the cost for the management of epilepsy. By contrast, driving or occupational restrictions tend to be attributed to both conditions. As well, the degree to which the cost is attributable to the cognitive and/or behavioral problems associated with epilepsy, an epileptogenic condition, or its treatment is hardly defined. Methods for attributing costs to epilepsy compared with any associated (whether or not specifically correlated) clinical condition in patients vary across studies 22. Recommended methods for dealing with this issue include the case–control or clinical review approach 22, 23. The attribution problem is particularly challenging with respect to certain large cost items such as residential care and special education for people with epilepsy. In several studies, these costs have been attributed to epilepsy without consideration of the comorbidity, or other disability, that may be present in many patients and also may contribute to the need for the services. By contrast, the incremental cost attributable to epilepsy as a comorbid condition in institutionalized persons has been calculated and found to be significant. Epilepsy is a diverse and heterogeneous condition, and those studies assessing the economic impact of treatment 24-33 have faced three main challenges: (a) the choice of outcome measures that express health gains in terms of quality of life and patient utility, (b) the inclusion of appropriate cost that adequately reflects the breadth of resources arising from treatment, and (c) the use of estimation methods whose validity can be accurately assessed. Epilepsy treatment outcomes are typically described in terms of improvements in specific clinical indices, such as seizure frequency and/or severity. There is some dispute about which measure to use. The main argument for these measures is their relative ease of measurement and interpretation. It is unclear how well different clinical measures reflect quality-of-life (QOL) outcomes that are associated with the treatment of epilepsy. Trials of monotherapy show that ≤90% of patients treated with AEDs will experience adverse symptoms related to their medication. These side effects can vary from mild feelings of fatigue to life-threatening hypersensitivity reactions. AEDs also may have adverse psychological and/or cognitive effects. Treatments sometimes fail to achieve adequate seizure control to offset these adverse effects, leading patients to discontinue the treatment. The QOL outcomes of treatment are significant to patients and physicians, but are difficult to measure. A variety of generic and epilepsy-specific scales have been developed to describe different health states in epilepsy 34. There is no consensus on which is most appropriate for general use. Furthermore, to reflect the patient's preferences, the QOL scales must be weighted by the value people place on different health states. This requires deriving utilities for different health states, by using a rating scale, standard gamble, or time trade-off method. For example, the time trade-off method involves patients stating how much of their life expectancy with their current state of health they would be willing to give up to live the remaining years in excellent health. The resulting responses are converted into a health utility index ranging from 0 (worst response) to 1 (best response, unwilling to give up any time). The index can then be used to adjust expected years of survival in a given health state by the utility of that health state to derive QALYs or HYEs. Another requirement of any economic evaluation is an accurate and complete assessment of the net cost of a considered treatments both now and in the future. The net cost of a new therapy should include the acquisition cost of the treatment, the cost of resources used in the management of adverse side effects of treatment, the cost of therapeutic switching if the treatment fails, and the cost increases or saving from outcome differences, if such differences exist. Direct cost and saving arise in relation to the treatment of an illness. Cost analyses in cost-effectiveness studies should attempt to measure the long-term incremental differences in healthcare, social service, and patient and caregiver cost attributed to a given treatment versus its comparator. Acceptable approaches to cost measurement vary by the degree of precision required. The most accurate is microcosting, and involves specific enumeration and summation of payments for inputs (i.e., personnel, facility, supplies) used in providing healthcare and social services that are consumed in the treatment of a patient. Because input data are generally not available, gross costing methods are typically used in empiric cost studies in which payment for more global units of service (i.e., the average payment for a physician visit or a day in the hospital) are documented. To date, the most common method for cost-effectiveness analysis in epilepsy studies is hypothetical modeling of outcomes from different treatments, services involved in treatment, treatment of side effects, and treatment switching. This involves combining data from different sources (i.e., other cost studies, clinical trials, and expert panels). The advantage of this approach is the feasibility of estimating a broad set of cost and outcome issues over a long period. As assumptions accumulate and qualitative and quantitative data are combined, the validity of the estimates using this approach become less defensible. Lacking in the literature are prospective evaluations of the cost and outcomes of treatments combining rigorously designed cost studies with the clinical trials of the treatments in question. Such efforts have begun, and more should be completed. This approach offers to eliminate many of the problems of modeling. Alternatively, more naturalistic studies need to be conducted by using medical claims data to obtain actual data for cost estimates. Such studies can also provide information on effectiveness, although efforts must be made to control for confounding factors and selection bias. Such trials and observational studies are time consuming and expensive to perform. Consequently, it also is necessary for economic modeling in treatment assessment to be improved, particularly with respect to the use of qualitative methods and sensitivity analysis. It is essential that when assumptions are made, the methods by which they are derived be stated explicitly. Where possible, formal methods of arriving at such estimates should be used. Qualitative research methods such as consensus techniques and Delphi panel techniques can be used to establish the opinions of physicians expert in treating epilepsy. These methods are designed to maximize the possible amount of generalization of results obtained from small panels. It is also necessary to test the potential importance of errors in assumptions using sensitivity analysis. The form of sensitivity analysis adopted should be stated clearly. Univariate sensitivity analysis involves sequentially testing the impact of changes in single variables on the study findings. Individual parameters are varied across a range that is either based on available evidence or according to a formally derived estimate. Multivariate sensitivity analysis involves testing more than one assumption at a for each to be may be used. can be to for cost-effectiveness has been made in the economic burden of epilepsy and evaluating the economic effects of new A range of estimates of the direct cost of epilepsy in different are available for and the determinants of variation in cost across patients is It would be to if the differences in average cost among are due to in terms of cost or healthcare resource use. Another may be related to the by of which has been to have a significant effect on More estimates of direct costs must be developed to To the cost variation across individuals, a general model of the determinants of variation in and cost should be developed that the relative importance of clinical such as and seizure frequency and as compared with social and economic such as and a clinical it may be expected that clinical factors should most of the In recent variation in healthcare and cost, to clinical has been in a number of disease The importance of these factors in epilepsy has not been in the literature. there is much work to be in the of estimates of the indirect cost of epilepsy. differences those who the method of measurement and those who would use the method should be measures of indirect cost must be defined and surveys conducted of general populations of people with epilepsy to estimate each measure. and specific measures of health states in epilepsy that are appropriate for general use in cost-effectiveness studies must be research is to determine the of people for different health states. Lacking in the economic evaluation literature are prospective evaluations of the cost and outcomes of treatments combining rigorously designed cost studies with the clinical trials of the treatments in question. A number of studies have begun, and more must be completed. Alternatively, more naturalistic studies should be conducted by using medical claims data to obtain actual data for cost estimates. Such studies also can provide information on effectiveness, although they must control for confounding factors and selection bias. Economic modeling in treatment assessment must be improved, particularly with respect to the use of qualitative methods and sensitivity analysis. It is essential that when assumptions are made, the methods by which they are derived be stated explicitly. Where possible, formal methods of arriving at such estimates should be used. economic studies should be conducted in with less developed or newly and for populations with to Cost and cost-effectiveness studies need to questions of in those countries. treatments, treatment and diagnostic and/or therapeutic procedures may be Different measures of cost should be identified and assessed. guidelines and on methodologic issues in the application of economic analysis in could be addressed by future It is the of this Subcommission that the work that has been on the economic aspects of epilepsy will in both the developed and of the The methods used to conduct these studies must and become more standardized so that comparisons across studies epilepsy can be made, and the costs of epilepsy can be compared with those of other and conditions. The of health services and must be to document adequately the economic burden of epilepsy and to alternative for its prevention and

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