General Essays
International Journal of Technology Assessment In Health Care, 8:4 (1992), 671-682. Copyright © 1992 Cambridge University Press. Printed in the U.S.A.
ISSUES IN THE CROSS-NATIONAL ASSESSMENT OF HEALTH TECHNOLOGY Michael F. Drummond University of York
Bernard S. Bloom University of Pennsylvania
Guy Carrin Universiteit Antwerpen
Alan L. Hillman H. Christina Hutchings University of Pennsylvania
Robin P. Knill-Jones University of Glasgow
Gerard de Pouvourville Ecole Polytechnique, Paris
Koen Torfs Universiteit Antwerpen
Abstract 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.
The individual studies upon which this paper is based were funded by G. D. Searle. This support is gratefully acknowledged; however, the authors are solely responsible for the views that are expressed. We are also grateful to those agencies in each country that provided data and to Harpreet Kohli and Linda Davies for their contribution to the U.K. study. Finally, we are grateful to the anonymous referees for the comments they made and to Vanessa Windass for typing the manuscript.
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There is growing international interest in evaluating the broad effects of health care. One component of health technology assessment is economic evaluation, in which the costs of interventions are compared with their consequences (9;25;26). Economic evaluations of health technologies have now been reported in most countries of the European Community (1;6), Asia and Australasia (13;23), Latin America (5), and Africa (24). This is also, of course, a burgeoning literature in North America. With the growing international literature in economic evaluation and the rapid international spread of new health technologies, there is a need to undertake, or at least interpret, economic evaluations on the international level. For example, health care decision makers, especially in those countries having limited resources for health technology assessment, may wish to reinterpret in their own setting the results of an economic evaluation that was done elsewhere. This approach is now common in the case of clinical trials. In addition, the health technology industry is increasingly organized on an international basis, and key business decisions may need to take note of the situation in more than one country. For example, the pharmaceutical industry is moving toward international price harmonization for its products, a process which is likely to be accelerated by the integrated internal market within the European Community (3). Also, the costs of developing specialized medical equipment, such as lasers, may be such that a large international market needs to be assured. Therefore, the international costeffectiveness of these products is of key interest to manufacturers and potential purchasers. Finally, other forms of health services research, such as controlled clinical trials, are often mounted on an international basis in order to recruit sufficient numbers of patients or to satisfy the needs of different national medical and regulatory agencies, which like to see evidence of efficacy in their own patients. If economic evaluation is to follow suit, the issues raised by cross-national research need to be explored. However, the extrapolation of the results of economic evaluations from one setting to another is not a straightforward matter. A number of factors that are pertinent to health technology are known to vary from country to country. For example, basic differences in the demography and epidemiology of disease may suggest that a given treatment is cost-effective in one population but not in another. Differences in general and relative price levels for health care resources (such as surgical time) also may affect the ranking of alternatives in an economic evaluation (14). Community attitudes about health care and industrial policy regarding health technology may affect the weighting that is placed on individual factors in an economic analysis. Also, differences in the distribution of health care resources and their availability may affect the potential of countries to benefit from certain technological advances. In addition, many characteristics of health care systems can affect the diffusion and use of health technology. Clinical practice and conventions are known to differ widely both within and between countries (18). The incentives to professionals, institutions and patients may also affect how technologies are used (7). Finally, differences in information systems, especially financial systems, may limit the conduct of evaluations or the extrapolation of results from one setting to another. The ways in which cross-national differences affect the cost-effectiveness of health technologies or their evaluations have never been studied systematically. This paper is the first to explore 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. This paper brings together the four previously completed analyses in order to assess what extra 672
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knowledge can be gained about the cross-national assessment of health technology. In particular, can economic evaluations be performed in a way that will facilitate extrapolation from one country to another? In some circumstances, can decision makers base their decision merely on the results of an analysis that was performed in another country? The four evaluations concerned the prophylactic use of misoprostol, a synthetic prostaglandin El analogue with cytoprotective and antisecretory properties. It has recently been shown to prevent nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers in symptomatic patients who are receiving long-term NSAID therapy for osteoarthritis (11). The prophylactic use of misoprostol has major economic consequences because of the large population of patients using NSAIDs. In the United States alone, 63.3 million prescriptions for NSAIDs were written in 1987, 17.7 million of which were for patients with osteoarthritis (15;19). Evaluations of misoprostol have been completed in Belgium, France, the United Kingdom, and the United States. The results of the original studies have been published elsewhere (2;12;17;20), and it is not our aim to justify in detail the methods that they used nor their results. Rather, the goal of this paper is to address the following issues using misoprostol as an example: • Is it possible to develop a common method for economic evaluation that is applicable to all countries? • To what extent does the availability of data limit or modify the chosen economic evaluation methodology? • To what extent do differences in clinical or health care practice affect the results of an economic evaluation? • To what extent do differences in relative price levels affect the results of an economic evaluation? • To what extent are economic evaluation results transportable or need to be interpreted differently in different countries? • Does cross-national research give a clear picture of the economic impact of the new technology, and what additional insights does it provide?
METHODS Decision Tree
The same decision-analytic approach was used by all four studies as a basis for the evaluation of the prophylactic use of misoprostol. Investigators from the four countries agreed, at the outset, on basic methods, analytic perspective, and techniques. These then were applied within each national context to allow for unique practice patterns in each country. The decision tree (Figure 1) indicates that patients on NSAIDs who have abdominal pain and are given misoprostol will either comply or not comply with therapy. Depending on whether the patients take the drug, a certain proportion will develop ulcers. Of those who develop ulcers, a proportion will be hospitalized, the remainder being treated in an ambulatory setting. Of the hospitalized patients, a certain proportion will have an operation, the remainder being treated medically. The branch of the tree for patients who do not receive prophylaxis is similar to that of the "no compliance" group. Efficacy of Misoprostol
Data on the efficacy of misoprostol were taken from a randomized, double-blind, placebo-controlled, multicenter clinical trial (11). It assessed the rate of gastric ulceraINTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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Outcome
Hospitalized
Ambulatory
Compliance No Ulcer
Prophylaxis with Misoprostol
Plus Vi Course Misoprostol
No Surgery
Ulcer
4
Plus Full Course Misoprostol
Surgery
-O
Hospitalized Ulcer
•o
No Compliance
No Surgery
Ambulatory
Plus Vi Course Misoprostol
No Ulcer
OA Patients on NSAIDS with Q Abdominal Pain
Surgery Hospitalized No Surgery
Ulcer Ambulatory No Prophylaxis
-o No Ulcer
Figure 1. Decision-analytic model of prophylactic use of misoprostol in patients with osteoarthritis and abdominal pain who are taking nonsteroidal anti-inflammatory drugs (NSAIDs). Adapted from Hillman and Bloom, Archives of Internal Medicine, 1989,149, 2061-65, copyright 1989, American Medical Association.
tion over a three-month period in patients with osteoarthritis who were receiving longterm NSAID therapy and having abdominal pain upon entry into the study. Patients were endoscoped upon entry and shown to be free of ulcers. Endoscopy then was repeated at monthly intervals to detect ulcers, which were defined as circumscribed breaks (0.3 cm or larger) in the gastric mucosa. A more conservative definition of ulcer (lesions of 0.5 cm or larger) also was adopted in the trial, and these data were also used in the evaluation. The incidence of gastric ulcers over three months was 21.7% for lesions 0.3 cm or larger and 12.3% for lesions 0.5 cm or larger. In contrast, in patients who were assigned to receive 200 meg of misoprostol four times per day, there was a gastric ulcer incidence of only 1.4% for lesions 0.3 cm or larger and 0.7% for lesions 0.5 cm or larger. One hundred micrograms of misoprostol four times per day also had a prophylactic effect, with a gastric ulcer incidence of 5.6% for lesions 0.3 cm or larger and 4.2% for lesions 0.5 cm or larger. Differences in incidence of ulceration, whether analyzed by an intention-to-treat approach or an evaluable-cohort approach, were statistically significant (p < .001). It is well known that results of controlled clinical trials are not easily reproducible in regular clinical practice and that it is important for health technology assessments to make allowances for this fact. Therefore, in the individual national economic evalu674
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ations, two adjustments were made. First, it was acknowledged that compliance with therapy is likely to be lower in regular practice than in the trial. Therefore, estimates of compliance for the different daily dosing regimens were obtained from an earlier study of NSAID therapy (16). Second, in regular practice, a certain proportion of ulcers (popularly known as "silent ulcers") will remain undetected and, therefore, not incur the costs of medical care. An allowance for undetected ulcers was therefore included as part of the assessment, based on the rates for silent duodenal ulcer reported in the literature (21;22). Health Service Utilization and Costs
All analyses considered the direct medical costs that are associated with therapy, regardless of whether these were borne by the government, other third-party payers, or by the patient. In each case, the study took the perspective of the payer. Given the differences in the four health care systems, the relative burden of cost on each party varied from setting to setting. However, in all cases, the relevant costs were those of misoprostol itself, ambulatory care by physicians or at hospital outpatient departments, and inpatient hospital care — including follow-up care. Estimates of ambulatory care resource utilization were obtained from structured interviews in each country with physicians, either individually or as part of a Delphi panel group. They were asked to specify the number of visits and types of investigations or therapy that would be required for symptomatic patients: (a) having an ulcer that eventually required hospitalization, (b) having an ulcer that was treated in an ambulatory setting, and (c) not having an ulcer. Utilization of resources in the hospital sector was obtained from routinely available statistics in the different countries. Available data differed slightly from country to country but included mainly the proportion of gastric ulcer patients who were hospitalized, the proportion of hospital patients who underwent surgery, and the lengths of inpatient stays for surgical and medical cases. Prices for resources were obtained either from routinely available statistics or by additional study. This was the aspect of the analysis that differed most by country. In Belgium, for example, Diagnosis Related Group (DRG) rates were available for hospitalized patients. In France and the United Kingdom, where hospital cost systems are not well developed, special hospital cost studies had to be mounted. In the United States, a Medicaid database was available for inpatient-service use for patients with gastric ulcer. These data were combined with those on average payments by Independence Blue Cross and Pennsylvania Blue Shield to estimate the costs of managing ulcer disease. Balance of Costs and Benefits
Costs of misoprostol prophylaxis were thus compared with those of no prophylaxis in each country in order to assess the extent to which additional costs for drugs over a three-month period were balanced by savings in investigations, visits, drug therapy for ulcer, and hospitalizations. The case-fatality rate for gastric ulcer also was recorded. However, the evaluation did not include a formal assessment of the incremental cost per life-year saved by misoprostol prophylaxis because of investigators' concern about the problems of extrapolating beyond the three-month period of the clinical trial. RESULTS
The main results of the study are shown in Tables 1-3. Details are available in the reports of the individual countries (2;12;17;20). Table 1 shows the use of resources and the INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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Belgium Ambulatory care of ulcer Physician (office) visits Outpatient (specialty clinic) visits Endoscopies X-rays H2 antagonist Total cost (in US dollars)* Care of "no ulcer" group Physician (office) visits
3 1.5 1.5 0
7 weeks 389 1.1 0 0.9 0
Outpatient (specialty clinic) visits
Endoscopies X-rays Antacids Total cost (in US dollars)* Cost of misoprostol (3 months)* (US$)
800 meg
France
U.K.
U.S.
6.4 2.7 1.5 0.7
3 0 1 1
2 0 2 0
6 weeks 256 2 0 0 0
4-5 weeks
6 weeks
24
48
132
129
6 weeks 540 3.4 0.1 0.5 0.2 6 weeks 71 134
12 weeks 901 2 0 0 0 0 80 180
* Costs are expressed in 1988 prices. Conversions to US dollars from other currencies are made by purchasing power parities (OECD, 1989). These remain relatively constant through time and are not affected by transient fluctuations in exchange rates. Table 2. Input Values: Hospital Care Belgium Percentage of ulcer patients hospitalized Percentage hospitalized patients receiving operation (other than endoscopy) Length of hospital stay (days) Operation No operation Total cost including follow-up care Surgical case (in US dollars)* Medical case (in US dollars)*
France
U.K.
U.S.
18.9
6.0
5.3
8.6
16.7
19.0
43.2
12.0
18 8
18 13
9 10
7 6
4165 1793
6503 2569
2533 1548
15,700 3450
* Costs are expressed in 1988 prices. Conversions to US dollars from other currencies are made by purchasing power parities.
expenditures for ambulatory care. Of the four countries, the United Kingdom has the greatest use of resources, perhaps reflecting its relatively well-developed primary care services. The table also shows that the published price of misoprostol is similar for the three European Community countries but is relatively higher in the United States. However, drug prices need to be interpreted with caution, as published prices may be subject to discounts in some settings. In addition, a higher price in a given country does not necessarily imply a lower value for the money. This point will be expanded later. Table 2 shows the use of resources and expenditures for hospital care. The four countries differ both in the percentage of ulcer patients who are hospitalized and the percentage who receive surgery. The length of hospital stay is shortest in the United States, but the cost of a surgical case is by far the highest. Table 3 shows expected net costs (savings) of three months of misoprostol prophylaxis. The most striking element is the similarity of overall results, particularly with the high-dose regimen. The main message is that despite differences among the coun676
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Cross-national TA Table 3. Expected Costs (Savings) per Patient for 3 Months of Misoprostol Prophylaxis (in US Dollars)*
High dose (800 meg daily, 60% complianccf) Ulcers 0.3 cm or larger (silent ulcer rate of 40%) Ulcers 0.5 cm or larger (silent ulcer rate of 40%) Low dose (400 meg daily, 72% compliancet) Ulcers 0.3 cm or larger (silent ulcer rate of 40%) Ulcers 0.5 cm or larger (silent ulcer rate of 40%)
Belgium
France
U.K.
U.S.
32
61
55
22
63
79
72
72
5
15
3
(40)
40
35
22
16
* Costs are expressed in 1988 prices. Conversions to US dollars from other currencies are made by purchasing power parities. t Compliance figures are taken from the study of NSAID-dosing regimens. It has also been assumed that 200 meg twice daily has the same effect as 100 meg four times daily, the regimen that was tested in the clinical trial.
tries' patterns of clinical practice and cost components, the cost-benefit result is broadly the same. In particular, the higher cost of the drug in the United States does not lead to a greater cost overall. DISCUSSION
The comparison and juxtaposition of the four countries' studies within this common framework gives additional insights for consideration of the individual studies themselves. If economic evaluations are ever to be conducted and interpreted on an international basis, the five issues that were identified earlier need to be addressed. These are discussed in turn. Development of a Common Methodology
The study showed that it was possible to develop a common methodology within the decision-analytic framework, although minor modifications to the decision tree were made in the individual countries' studies in order to account for local differences in clinical opinion about the importance of particular factors. (The analysis here uses the same decision tree in all of the countries, however, in order to facilitate comparisons of results.) In undertaking the economic evaluation, all four teams decided to concentrate on direct medical expenditures over three months of treatment, because the original clinical trial provided data for only that period. Although hospitalization for gastric ulcer carries with it a significant risk of fatality, in none of the countries did the researchers calculate cost per year of life saved for those situations where misoprostol led to a net cost. This decision reflects a growing level of agreement among economics researchers on the type of evaluation that is feasible given limited data. Problems of Data Availability
Data on ambulatory care were sparse or difficult to interpret in all of the countries. Even in the United States, where medical claims databases are available, the study team preferred to undertake structured interviews with physicians, as these were felt to be INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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more reliable. However, the improvement of ambulatory care data bases should be a priority if cross-national assessment of health technology is to progress. Routine statistics on hospital utilization were available for all four countries, although in France the small sample size made it necessary to base the analysis on all peptic ulcers rather than gastric ulcer only. (The small sample size also restricted the possibility of subgroup analysis in France.) In Belgium, DRG data were easier to obtain than ICD-9 diagnostic data, so cost data on all peptic ulcers were obtained, including esophageal ulcers. The biggest cross-national difference was in the availability of data on hospital costs. In countries such as the United Kingdom, where hospitals are given global budgets, cost data for the treatment of specific diagnoses are not generally available. Therefore, locally based cost studies are usually required. This situation is rapidly improving through the development of case-mix-related approaches such as DRGs. However, in using DRGs or any other case-mix-related data, it is important to consider whether these are based on costs or charges (10). In this study, the Belgian DRG data (for three hospitals) were based upon charges, both to patients and third-party payers, and not upon costs. These charges comprised a per diem rate for nursing and "hotel" costs, physicians' fees, and payments for laboratory tests, drugs, and minor resources. DRG rates that reflect charges would be relevant to an analysis from the perspective of the third-party payer but not necessarily relevant to one from the viewpoint of society as a whole. The impact of the different approaches that were used in estimating hospital costs was not critical in this study, as the results were relatively insensitive to these costs. However, more generally, the noncomparability of hospital financial systems is likely to be a serious impediment to cross-national studies. Therefore, to facilitate the extrapolation of results, it is important to also report the physical quantities of resources that are used (e.g., number of days of hospitalization, number and length of surgeries, etc.). Decision makers who want to reinterpret these data in their own setting can then examine their own local clinical practice and prices for resources. Influence of Practice Variations
There were cross-national differences regarding the definition of ulcer and dosage regimen. In some settings, a definition of lesions of 0.3 cm or greater was considered acceptable; in others it was considered important to report results for lesions that were greater than 0.5 cm. Also, in the United States, the 800-mcg daily dose was taken as the base case; however, in the United Kingdom, a 400-mcg daily dose was used, as it was considered to reflect more accurately regular clinical practice. In reality, the 400mcg dose may also be widely used in the United States, although labeling recommends dosing up to 800 meg daily. The issue of silent ulcers was considered important in all four countries. Therefore, a conservative approach was adopted, using a 60% compliance and 40% silent ulcer rate in the base case. It is particularly interesting to note the relatively high hospitalization rate for ulcers in Belgium and high surgery rates in the United Kingdom. The U. K. figures are explained partly by the much higher age of their patients (64 years old on average, compared with 42 years old in the United States). The rates also may be a result of the combination, in the British National Health Service (NHS), of a well-developed primary care sector and a resource-limited hospital sector. This situation means that ulcers are more likely to be managed for as long as possible by the family physician. This treatment in turn means that the disease may have progressed further by the time of admission, necessitating a higher level of surgical intervention. 678
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Differences in hospitalization rates and lengths of stay had little impact on the results in this study. However, this finding would not necessarily be the case for economic evaluations of other health technologies. Therefore, economic evaluation models that are developed on a cross-national level need to facilitate (as in this case) the incorporation of country-specific data that relate to different practice patterns. Interpretation of Results in Different Settings
Results for various combinations of data are given in Table 3. It is up to the decision maker to interpret the results depending on his or her perception of the national importance of each of those factors that generally affect the net cost/saving from the use of misoprostol. One important facet of interpretation relates to the slightly different perspectives of the main decision makers in the different countries. A key decision maker is the third-party payer. For example, in managed-care systems in the United States, it is clearly the case that savings in medical services accrue directly to the organization that decides whether to encourage misoprostol prophylaxis. In other settings, such as the United Kingdom, this is less clear cut. Although the central government is the third-party payer, budgets for family practitioners and hospitals are administered separately. Therefore, there is no direct financial incentive to the primary care physician to prescribe misoprostol prophylactically in order to save other costs, apart from his or her own time and trouble in investigating patients. Physicians may prescribe it because of the benefits to patients of being able to remain on NSAID therapy, however. Other key actors in the health care system who are responsible for a particular budget may take yet another view. For example, if fewer patients with ulcers are admitted to a hospital, much depends on the hospital's ability either to use the freed beds for other patients or close the beds and on the impact that these decisions have on costs and income. In the United States, a hospital that takes on additional or different cases would be reimbursed accordingly. By contrast, in the United Kingdom, a hospital operating under a fixed global budget might be in financial difficulty if other, more expensive, cases were admitted instead of ulcers. However, new proposals for the British NHS seek to rectify this situation through the development of contracts for clinical services, in which funding will follow the patient (4). Under all health care systems, hospitals may need time to rationalize services if they chose to reduce capacity, and hence costs, as a result of fewer patients with ulcers being admitted. Finally, the patient's perspective may also vary from setting to setting. The level of copayment for drugs differs among countries; this may affect compliance with therapy, particularly when (as in this case) the drug does not affect symptoms and is being used solely for its prophylactic effect. Given the variety of perspectives in different countries, a major implication is that the results of economic evaluations should be represented in a disaggregated way so that individual decision makers can interpret the costs and benefits from their particular viewpoints. Additional Insights from Cross-National Research
The major finding of the cross-national study was that resource savings from misoprostol prophylaxis significantly offset the costs for most settings under most assumptions. Conservatively, the results at the high dose for ulcers that are 0.5 cm or larger indicate that the percentage of the cost of misoprostol that is offset by savings in other health care resources was 52, 39, 44, and 60 in Belgium, France, the United Kingdom, and the United States, respectively. The percentage of the cost that is offset was higher under the other assumptions, with a net saving being achieved in the United States for ulcers that are 0.3 cm or larger with the low dose. The similarity of results INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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in the four countries greatly increases our confidence that cross-national assessments of health technologies are both feasible and useful. This finding may also increase the confidence of other decision makers, in jurisdictions where misoprostol has not yet been evaluated, that similar results may pertain in their setting. Therefore, it may not be necessary to repeat all studies in all countries in order to inform decision making. However, it is clear from the study that wholesale extrapolation from one setting to another is not possible without adapting to the unique characteristics of each, such as relative cost differences and patterns of care. Therefore, further cross-national studies of this type are required. Nevertheless, a common decision-analytic model can be developed, to which local data readily can be applied. Indeed, given what is known about small area variations in clinical practice even within countries, more attention could be given to the problem of how the results of cost-effectiveness studies (which are typically undertaken in one place) can be generalized. Furthermore, knowledge of the sensitivity of economic results to key parameters can guide priorities for local study. For example, in this case it is clear that more attention should be placed on obtaining an accurate estimate of ambulatory care costs rather than hospital costs, to which the model is not sensitive. Also, the study indicates a need to determine at what size an ulcer becomes important clinically, as this affects the estimates significantly. The cross-national study also shed some light on the net value of the new technology in different countries. It was noted earlier that new drugs are increasingly being priced on an international basis in an attempt to reduce the incentives to wholesalers to import from one country to another and to reduce the concerns of policy makers in those countries with a relatively high price for drugs, in particular the United States and Germany. It is therefore particularly interesting to note that while the price of misoprostol was highest in the United States, the expected costs per patient of three months of prophylaxis were generally lowest because of the relatively higher costs of those resources that were saved. As health care decision makers continue to press for more value for money from health care interventions, it is likely that the prices of drugs will more closely reflect their economic value rather than the costs of their development (8). Therefore, the paradox, highlighted by this cross-national study, is that the value of a drug can differ from one setting to another, depending on the costs of other health care resources and of alternative treatments. This fact suggests either that a differential pricing policy can be defended analytically or that common international prices need to be based on an average economic value of the drug across a number of countries, as well as its cost of production. Overall, this study has shown 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 with little additional effort. Furthermore, if cross-national studies of other health care interventions also show that overall results are similar from place to place, it may not be necessary to repeat economic evaluations in every setting, thereby saving scarce evaluative resources. REFERENCES 1. Britton, M., Jonsson, E., Marke, L.-A., & Murray, V. Diagnosing suspected stroke: A costeffectiveness analysis. International Journal of Technology Assessment in Health Care, 1986, 2, 147-58.
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Cross-national TA 2. Carrin, G., & Torfs, K. Economic evaluation of the preventive use of misoprostol in osteoarthritic patients treated with NSAIDs: The case of Belgium. Antwerp: Discussion Paper, University of Antwerp, 1989. 3. Commission of the European Communities. The cost of non-Europe in the pharmaceutical industry. Research on the cost of non-Europe, basic findings; volume 15. Brussels: CEC, 1989. 4. Department of Health. Working for patients. London: Department of Health, 1989. 5. Dominguez Uga, M. A. Economic analysis of the vaccination strategies adopted in Brazil in 1982. PAHO Bulletin, 1988, 22(3), 250-68. 6. Drummond, M. F. (ed.). Economic appraisal of health technology in the European Community. Oxford: Oxford University Press, 1987. 7. Drummond, M. F. Financial incentives to change behaviour towards health technology. In B. Stocking, (ed.), Expensive health technologies; Regulatory and administrative mechanisms in Europe. Oxford: Oxford University Press, 1988, 66-78. 8. Drummond, M. F. The role of economic evaluation in the pricing of modern pharmaceutical products. Pharmaceutical Times, 1990, March, 38-42. 9. Drummond, M. F., Stoddart, G. L., & Torrance, G. W. Methods for the economic evaluation of health care programmes. Oxford: Oxford University Press, 1987. 10. Finkler, S. A. On the distinction between costs and charges. Annals of Internal Medicine, 1982, 96, 102-09. 11. Graham, D. Y., Agrawal, N. M., & Roth, S. H. Prevention of NSAID-induced gastric ulcer with the synthetic prostaglandin misoprostol: A multicentre, double-blind, placebo-controlled trial. Lancet, 1988, ii, 1277-80. 12. Hillman, A. L., & Bloom, B. S. Economic effects of prophylactic use of misoprostol to prevent gastric ulcer in patients taking nonsteroidal anti-inflammatory drugs. Archives of Internal Medicine, 1989, 149, 2061-65. 13. Horton, S., & Claquin, P. Cost-effectiveness and user characteristics of clinic-based services for the treatment of diarrhoea: A case study in Bangladesh. Social Science and Medicine, 1982, 17(11), 721-29. 14. Hull, R. D., Hirsh, J., Sackett, D. L., & Stoddart, G. L. Cost effectiveness of clinical diagnosis, venography and noninvasive testing in patients with symptomatic deep-vein thrombosis. New England Journal of Medicine, 1981, 304, 1561-67. 15. IMS. National drug and therapeutic index, 1987. Blue Bell, PA: IMS, 1988. 16. Jacobs, J., & Bloom, B. S. Compliance and cost in NSAID therapy. Hospital Therapeutics, 1987(suppl.), 32-39. 17. Knill-Jones, R., Drummond, M. F., Kohli, H., & Davies, L. M. Economic evaluation of gastric ulcer prophylaxis in patients receiving non-steroidal anti-inflammatory drugs. Postgraduate Medical Journal, 1990, 66, 639-46. 18. McPherson, K., Wennberg, J. E., Hovind, O., et al. Small area variation in the use of common surgical procedures: An international comparison of New England, England and Norway. New England Journal of Medicine, 1982, 307, 1310-14. 19. Pharmaceutical Data Services. PDSprescription audit. Scoftsdale, AZ: Pharmaceutical Data Services, 1988. 20. de Pouvourville, G. Use of misoprostol as a prophylactic treatment in gastric ulceration associated with non-steroidal anti-inflammatory drugs. Paris: Centre de Recherche en Gestion, ficole Polytechnique, 1990. 21. Soil, A. H., & Isenberg, J. I. Duodenal ulcer diseases. In M. H. Sleisenger and J. S. Fordtran, (eds.), Gastrointestinal disease: pathophysiology, diagnosis and management, 3rded. Philadelphia, PA: W. B. Saunders Co., 1983. 22. Sontag, S., Graham, D. Y., Belsito, A., et al. Cimetidine, cigarette smoking and recurrence of duodenal ulcer. New England Journal of Medicine, 1984, 311, 689-93. 23. Veale, A. M. O. Screening for phenylketonuria. In H. Bickel, R. Guthrie, and G. Ham-
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merson (eds.), Neonatal screening for inborn errors of metabolism. Heidelberg: SpringerVerlag, 1980. 24. Wang-Ombe, J. K. Economic evaluation in primary health care: The case of Western Kenya Community Health Care Project. Social Science and Medicine, 1988, 18(5), 375-85. 25. Warner, K. E., & Luce, B. R. Cost-effectiveness and cost-benefit analysis in health care. Ann Arbor, MI: Health Administration Press, 1982. 26. Weinstein, M. C, & Stason, W. B. Foundations of cost-effectiveness analysis for health and medical practices. New England Journal of Medicine, 1977, 296, 716-21.
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International Journal of Technology Assessment In Health Care, 8:4 (1992), 671-682. Copyright © 1992 Cambridge University Press. Printed in the U.S.A.
ISSUES IN THE CROSS-NATIONAL ASSESSMENT OF HEALTH TECHNOLOGY Michael F. Drummond University of York
Bernard S. Bloom University of Pennsylvania
Guy Carrin Universiteit Antwerpen
Alan L. Hillman H. Christina Hutchings University of Pennsylvania
Robin P. Knill-Jones University of Glasgow
Gerard de Pouvourville Ecole Polytechnique, Paris
Koen Torfs Universiteit Antwerpen
Abstract 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.
The individual studies upon which this paper is based were funded by G. D. Searle. This support is gratefully acknowledged; however, the authors are solely responsible for the views that are expressed. We are also grateful to those agencies in each country that provided data and to Harpreet Kohli and Linda Davies for their contribution to the U.K. study. Finally, we are grateful to the anonymous referees for the comments they made and to Vanessa Windass for typing the manuscript.
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There is growing international interest in evaluating the broad effects of health care. One component of health technology assessment is economic evaluation, in which the costs of interventions are compared with their consequences (9;25;26). Economic evaluations of health technologies have now been reported in most countries of the European Community (1;6), Asia and Australasia (13;23), Latin America (5), and Africa (24). This is also, of course, a burgeoning literature in North America. With the growing international literature in economic evaluation and the rapid international spread of new health technologies, there is a need to undertake, or at least interpret, economic evaluations on the international level. For example, health care decision makers, especially in those countries having limited resources for health technology assessment, may wish to reinterpret in their own setting the results of an economic evaluation that was done elsewhere. This approach is now common in the case of clinical trials. In addition, the health technology industry is increasingly organized on an international basis, and key business decisions may need to take note of the situation in more than one country. For example, the pharmaceutical industry is moving toward international price harmonization for its products, a process which is likely to be accelerated by the integrated internal market within the European Community (3). Also, the costs of developing specialized medical equipment, such as lasers, may be such that a large international market needs to be assured. Therefore, the international costeffectiveness of these products is of key interest to manufacturers and potential purchasers. Finally, other forms of health services research, such as controlled clinical trials, are often mounted on an international basis in order to recruit sufficient numbers of patients or to satisfy the needs of different national medical and regulatory agencies, which like to see evidence of efficacy in their own patients. If economic evaluation is to follow suit, the issues raised by cross-national research need to be explored. However, the extrapolation of the results of economic evaluations from one setting to another is not a straightforward matter. A number of factors that are pertinent to health technology are known to vary from country to country. For example, basic differences in the demography and epidemiology of disease may suggest that a given treatment is cost-effective in one population but not in another. Differences in general and relative price levels for health care resources (such as surgical time) also may affect the ranking of alternatives in an economic evaluation (14). Community attitudes about health care and industrial policy regarding health technology may affect the weighting that is placed on individual factors in an economic analysis. Also, differences in the distribution of health care resources and their availability may affect the potential of countries to benefit from certain technological advances. In addition, many characteristics of health care systems can affect the diffusion and use of health technology. Clinical practice and conventions are known to differ widely both within and between countries (18). The incentives to professionals, institutions and patients may also affect how technologies are used (7). Finally, differences in information systems, especially financial systems, may limit the conduct of evaluations or the extrapolation of results from one setting to another. The ways in which cross-national differences affect the cost-effectiveness of health technologies or their evaluations have never been studied systematically. This paper is the first to explore 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. This paper brings together the four previously completed analyses in order to assess what extra 672
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knowledge can be gained about the cross-national assessment of health technology. In particular, can economic evaluations be performed in a way that will facilitate extrapolation from one country to another? In some circumstances, can decision makers base their decision merely on the results of an analysis that was performed in another country? The four evaluations concerned the prophylactic use of misoprostol, a synthetic prostaglandin El analogue with cytoprotective and antisecretory properties. It has recently been shown to prevent nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers in symptomatic patients who are receiving long-term NSAID therapy for osteoarthritis (11). The prophylactic use of misoprostol has major economic consequences because of the large population of patients using NSAIDs. In the United States alone, 63.3 million prescriptions for NSAIDs were written in 1987, 17.7 million of which were for patients with osteoarthritis (15;19). Evaluations of misoprostol have been completed in Belgium, France, the United Kingdom, and the United States. The results of the original studies have been published elsewhere (2;12;17;20), and it is not our aim to justify in detail the methods that they used nor their results. Rather, the goal of this paper is to address the following issues using misoprostol as an example: • Is it possible to develop a common method for economic evaluation that is applicable to all countries? • To what extent does the availability of data limit or modify the chosen economic evaluation methodology? • To what extent do differences in clinical or health care practice affect the results of an economic evaluation? • To what extent do differences in relative price levels affect the results of an economic evaluation? • To what extent are economic evaluation results transportable or need to be interpreted differently in different countries? • Does cross-national research give a clear picture of the economic impact of the new technology, and what additional insights does it provide?
METHODS Decision Tree
The same decision-analytic approach was used by all four studies as a basis for the evaluation of the prophylactic use of misoprostol. Investigators from the four countries agreed, at the outset, on basic methods, analytic perspective, and techniques. These then were applied within each national context to allow for unique practice patterns in each country. The decision tree (Figure 1) indicates that patients on NSAIDs who have abdominal pain and are given misoprostol will either comply or not comply with therapy. Depending on whether the patients take the drug, a certain proportion will develop ulcers. Of those who develop ulcers, a proportion will be hospitalized, the remainder being treated in an ambulatory setting. Of the hospitalized patients, a certain proportion will have an operation, the remainder being treated medically. The branch of the tree for patients who do not receive prophylaxis is similar to that of the "no compliance" group. Efficacy of Misoprostol
Data on the efficacy of misoprostol were taken from a randomized, double-blind, placebo-controlled, multicenter clinical trial (11). It assessed the rate of gastric ulceraINTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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Outcome
Hospitalized
Ambulatory
Compliance No Ulcer
Prophylaxis with Misoprostol
Plus Vi Course Misoprostol
No Surgery
Ulcer
4
Plus Full Course Misoprostol
Surgery
-O
Hospitalized Ulcer
•o
No Compliance
No Surgery
Ambulatory
Plus Vi Course Misoprostol
No Ulcer
OA Patients on NSAIDS with Q Abdominal Pain
Surgery Hospitalized No Surgery
Ulcer Ambulatory No Prophylaxis
-o No Ulcer
Figure 1. Decision-analytic model of prophylactic use of misoprostol in patients with osteoarthritis and abdominal pain who are taking nonsteroidal anti-inflammatory drugs (NSAIDs). Adapted from Hillman and Bloom, Archives of Internal Medicine, 1989,149, 2061-65, copyright 1989, American Medical Association.
tion over a three-month period in patients with osteoarthritis who were receiving longterm NSAID therapy and having abdominal pain upon entry into the study. Patients were endoscoped upon entry and shown to be free of ulcers. Endoscopy then was repeated at monthly intervals to detect ulcers, which were defined as circumscribed breaks (0.3 cm or larger) in the gastric mucosa. A more conservative definition of ulcer (lesions of 0.5 cm or larger) also was adopted in the trial, and these data were also used in the evaluation. The incidence of gastric ulcers over three months was 21.7% for lesions 0.3 cm or larger and 12.3% for lesions 0.5 cm or larger. In contrast, in patients who were assigned to receive 200 meg of misoprostol four times per day, there was a gastric ulcer incidence of only 1.4% for lesions 0.3 cm or larger and 0.7% for lesions 0.5 cm or larger. One hundred micrograms of misoprostol four times per day also had a prophylactic effect, with a gastric ulcer incidence of 5.6% for lesions 0.3 cm or larger and 4.2% for lesions 0.5 cm or larger. Differences in incidence of ulceration, whether analyzed by an intention-to-treat approach or an evaluable-cohort approach, were statistically significant (p < .001). It is well known that results of controlled clinical trials are not easily reproducible in regular clinical practice and that it is important for health technology assessments to make allowances for this fact. Therefore, in the individual national economic evalu674
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ations, two adjustments were made. First, it was acknowledged that compliance with therapy is likely to be lower in regular practice than in the trial. Therefore, estimates of compliance for the different daily dosing regimens were obtained from an earlier study of NSAID therapy (16). Second, in regular practice, a certain proportion of ulcers (popularly known as "silent ulcers") will remain undetected and, therefore, not incur the costs of medical care. An allowance for undetected ulcers was therefore included as part of the assessment, based on the rates for silent duodenal ulcer reported in the literature (21;22). Health Service Utilization and Costs
All analyses considered the direct medical costs that are associated with therapy, regardless of whether these were borne by the government, other third-party payers, or by the patient. In each case, the study took the perspective of the payer. Given the differences in the four health care systems, the relative burden of cost on each party varied from setting to setting. However, in all cases, the relevant costs were those of misoprostol itself, ambulatory care by physicians or at hospital outpatient departments, and inpatient hospital care — including follow-up care. Estimates of ambulatory care resource utilization were obtained from structured interviews in each country with physicians, either individually or as part of a Delphi panel group. They were asked to specify the number of visits and types of investigations or therapy that would be required for symptomatic patients: (a) having an ulcer that eventually required hospitalization, (b) having an ulcer that was treated in an ambulatory setting, and (c) not having an ulcer. Utilization of resources in the hospital sector was obtained from routinely available statistics in the different countries. Available data differed slightly from country to country but included mainly the proportion of gastric ulcer patients who were hospitalized, the proportion of hospital patients who underwent surgery, and the lengths of inpatient stays for surgical and medical cases. Prices for resources were obtained either from routinely available statistics or by additional study. This was the aspect of the analysis that differed most by country. In Belgium, for example, Diagnosis Related Group (DRG) rates were available for hospitalized patients. In France and the United Kingdom, where hospital cost systems are not well developed, special hospital cost studies had to be mounted. In the United States, a Medicaid database was available for inpatient-service use for patients with gastric ulcer. These data were combined with those on average payments by Independence Blue Cross and Pennsylvania Blue Shield to estimate the costs of managing ulcer disease. Balance of Costs and Benefits
Costs of misoprostol prophylaxis were thus compared with those of no prophylaxis in each country in order to assess the extent to which additional costs for drugs over a three-month period were balanced by savings in investigations, visits, drug therapy for ulcer, and hospitalizations. The case-fatality rate for gastric ulcer also was recorded. However, the evaluation did not include a formal assessment of the incremental cost per life-year saved by misoprostol prophylaxis because of investigators' concern about the problems of extrapolating beyond the three-month period of the clinical trial. RESULTS
The main results of the study are shown in Tables 1-3. Details are available in the reports of the individual countries (2;12;17;20). Table 1 shows the use of resources and the INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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Belgium Ambulatory care of ulcer Physician (office) visits Outpatient (specialty clinic) visits Endoscopies X-rays H2 antagonist Total cost (in US dollars)* Care of "no ulcer" group Physician (office) visits
3 1.5 1.5 0
7 weeks 389 1.1 0 0.9 0
Outpatient (specialty clinic) visits
Endoscopies X-rays Antacids Total cost (in US dollars)* Cost of misoprostol (3 months)* (US$)
800 meg
France
U.K.
U.S.
6.4 2.7 1.5 0.7
3 0 1 1
2 0 2 0
6 weeks 256 2 0 0 0
4-5 weeks
6 weeks
24
48
132
129
6 weeks 540 3.4 0.1 0.5 0.2 6 weeks 71 134
12 weeks 901 2 0 0 0 0 80 180
* Costs are expressed in 1988 prices. Conversions to US dollars from other currencies are made by purchasing power parities (OECD, 1989). These remain relatively constant through time and are not affected by transient fluctuations in exchange rates. Table 2. Input Values: Hospital Care Belgium Percentage of ulcer patients hospitalized Percentage hospitalized patients receiving operation (other than endoscopy) Length of hospital stay (days) Operation No operation Total cost including follow-up care Surgical case (in US dollars)* Medical case (in US dollars)*
France
U.K.
U.S.
18.9
6.0
5.3
8.6
16.7
19.0
43.2
12.0
18 8
18 13
9 10
7 6
4165 1793
6503 2569
2533 1548
15,700 3450
* Costs are expressed in 1988 prices. Conversions to US dollars from other currencies are made by purchasing power parities.
expenditures for ambulatory care. Of the four countries, the United Kingdom has the greatest use of resources, perhaps reflecting its relatively well-developed primary care services. The table also shows that the published price of misoprostol is similar for the three European Community countries but is relatively higher in the United States. However, drug prices need to be interpreted with caution, as published prices may be subject to discounts in some settings. In addition, a higher price in a given country does not necessarily imply a lower value for the money. This point will be expanded later. Table 2 shows the use of resources and expenditures for hospital care. The four countries differ both in the percentage of ulcer patients who are hospitalized and the percentage who receive surgery. The length of hospital stay is shortest in the United States, but the cost of a surgical case is by far the highest. Table 3 shows expected net costs (savings) of three months of misoprostol prophylaxis. The most striking element is the similarity of overall results, particularly with the high-dose regimen. The main message is that despite differences among the coun676
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Cross-national TA Table 3. Expected Costs (Savings) per Patient for 3 Months of Misoprostol Prophylaxis (in US Dollars)*
High dose (800 meg daily, 60% complianccf) Ulcers 0.3 cm or larger (silent ulcer rate of 40%) Ulcers 0.5 cm or larger (silent ulcer rate of 40%) Low dose (400 meg daily, 72% compliancet) Ulcers 0.3 cm or larger (silent ulcer rate of 40%) Ulcers 0.5 cm or larger (silent ulcer rate of 40%)
Belgium
France
U.K.
U.S.
32
61
55
22
63
79
72
72
5
15
3
(40)
40
35
22
16
* Costs are expressed in 1988 prices. Conversions to US dollars from other currencies are made by purchasing power parities. t Compliance figures are taken from the study of NSAID-dosing regimens. It has also been assumed that 200 meg twice daily has the same effect as 100 meg four times daily, the regimen that was tested in the clinical trial.
tries' patterns of clinical practice and cost components, the cost-benefit result is broadly the same. In particular, the higher cost of the drug in the United States does not lead to a greater cost overall. DISCUSSION
The comparison and juxtaposition of the four countries' studies within this common framework gives additional insights for consideration of the individual studies themselves. If economic evaluations are ever to be conducted and interpreted on an international basis, the five issues that were identified earlier need to be addressed. These are discussed in turn. Development of a Common Methodology
The study showed that it was possible to develop a common methodology within the decision-analytic framework, although minor modifications to the decision tree were made in the individual countries' studies in order to account for local differences in clinical opinion about the importance of particular factors. (The analysis here uses the same decision tree in all of the countries, however, in order to facilitate comparisons of results.) In undertaking the economic evaluation, all four teams decided to concentrate on direct medical expenditures over three months of treatment, because the original clinical trial provided data for only that period. Although hospitalization for gastric ulcer carries with it a significant risk of fatality, in none of the countries did the researchers calculate cost per year of life saved for those situations where misoprostol led to a net cost. This decision reflects a growing level of agreement among economics researchers on the type of evaluation that is feasible given limited data. Problems of Data Availability
Data on ambulatory care were sparse or difficult to interpret in all of the countries. Even in the United States, where medical claims databases are available, the study team preferred to undertake structured interviews with physicians, as these were felt to be INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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more reliable. However, the improvement of ambulatory care data bases should be a priority if cross-national assessment of health technology is to progress. Routine statistics on hospital utilization were available for all four countries, although in France the small sample size made it necessary to base the analysis on all peptic ulcers rather than gastric ulcer only. (The small sample size also restricted the possibility of subgroup analysis in France.) In Belgium, DRG data were easier to obtain than ICD-9 diagnostic data, so cost data on all peptic ulcers were obtained, including esophageal ulcers. The biggest cross-national difference was in the availability of data on hospital costs. In countries such as the United Kingdom, where hospitals are given global budgets, cost data for the treatment of specific diagnoses are not generally available. Therefore, locally based cost studies are usually required. This situation is rapidly improving through the development of case-mix-related approaches such as DRGs. However, in using DRGs or any other case-mix-related data, it is important to consider whether these are based on costs or charges (10). In this study, the Belgian DRG data (for three hospitals) were based upon charges, both to patients and third-party payers, and not upon costs. These charges comprised a per diem rate for nursing and "hotel" costs, physicians' fees, and payments for laboratory tests, drugs, and minor resources. DRG rates that reflect charges would be relevant to an analysis from the perspective of the third-party payer but not necessarily relevant to one from the viewpoint of society as a whole. The impact of the different approaches that were used in estimating hospital costs was not critical in this study, as the results were relatively insensitive to these costs. However, more generally, the noncomparability of hospital financial systems is likely to be a serious impediment to cross-national studies. Therefore, to facilitate the extrapolation of results, it is important to also report the physical quantities of resources that are used (e.g., number of days of hospitalization, number and length of surgeries, etc.). Decision makers who want to reinterpret these data in their own setting can then examine their own local clinical practice and prices for resources. Influence of Practice Variations
There were cross-national differences regarding the definition of ulcer and dosage regimen. In some settings, a definition of lesions of 0.3 cm or greater was considered acceptable; in others it was considered important to report results for lesions that were greater than 0.5 cm. Also, in the United States, the 800-mcg daily dose was taken as the base case; however, in the United Kingdom, a 400-mcg daily dose was used, as it was considered to reflect more accurately regular clinical practice. In reality, the 400mcg dose may also be widely used in the United States, although labeling recommends dosing up to 800 meg daily. The issue of silent ulcers was considered important in all four countries. Therefore, a conservative approach was adopted, using a 60% compliance and 40% silent ulcer rate in the base case. It is particularly interesting to note the relatively high hospitalization rate for ulcers in Belgium and high surgery rates in the United Kingdom. The U. K. figures are explained partly by the much higher age of their patients (64 years old on average, compared with 42 years old in the United States). The rates also may be a result of the combination, in the British National Health Service (NHS), of a well-developed primary care sector and a resource-limited hospital sector. This situation means that ulcers are more likely to be managed for as long as possible by the family physician. This treatment in turn means that the disease may have progressed further by the time of admission, necessitating a higher level of surgical intervention. 678
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Differences in hospitalization rates and lengths of stay had little impact on the results in this study. However, this finding would not necessarily be the case for economic evaluations of other health technologies. Therefore, economic evaluation models that are developed on a cross-national level need to facilitate (as in this case) the incorporation of country-specific data that relate to different practice patterns. Interpretation of Results in Different Settings
Results for various combinations of data are given in Table 3. It is up to the decision maker to interpret the results depending on his or her perception of the national importance of each of those factors that generally affect the net cost/saving from the use of misoprostol. One important facet of interpretation relates to the slightly different perspectives of the main decision makers in the different countries. A key decision maker is the third-party payer. For example, in managed-care systems in the United States, it is clearly the case that savings in medical services accrue directly to the organization that decides whether to encourage misoprostol prophylaxis. In other settings, such as the United Kingdom, this is less clear cut. Although the central government is the third-party payer, budgets for family practitioners and hospitals are administered separately. Therefore, there is no direct financial incentive to the primary care physician to prescribe misoprostol prophylactically in order to save other costs, apart from his or her own time and trouble in investigating patients. Physicians may prescribe it because of the benefits to patients of being able to remain on NSAID therapy, however. Other key actors in the health care system who are responsible for a particular budget may take yet another view. For example, if fewer patients with ulcers are admitted to a hospital, much depends on the hospital's ability either to use the freed beds for other patients or close the beds and on the impact that these decisions have on costs and income. In the United States, a hospital that takes on additional or different cases would be reimbursed accordingly. By contrast, in the United Kingdom, a hospital operating under a fixed global budget might be in financial difficulty if other, more expensive, cases were admitted instead of ulcers. However, new proposals for the British NHS seek to rectify this situation through the development of contracts for clinical services, in which funding will follow the patient (4). Under all health care systems, hospitals may need time to rationalize services if they chose to reduce capacity, and hence costs, as a result of fewer patients with ulcers being admitted. Finally, the patient's perspective may also vary from setting to setting. The level of copayment for drugs differs among countries; this may affect compliance with therapy, particularly when (as in this case) the drug does not affect symptoms and is being used solely for its prophylactic effect. Given the variety of perspectives in different countries, a major implication is that the results of economic evaluations should be represented in a disaggregated way so that individual decision makers can interpret the costs and benefits from their particular viewpoints. Additional Insights from Cross-National Research
The major finding of the cross-national study was that resource savings from misoprostol prophylaxis significantly offset the costs for most settings under most assumptions. Conservatively, the results at the high dose for ulcers that are 0.5 cm or larger indicate that the percentage of the cost of misoprostol that is offset by savings in other health care resources was 52, 39, 44, and 60 in Belgium, France, the United Kingdom, and the United States, respectively. The percentage of the cost that is offset was higher under the other assumptions, with a net saving being achieved in the United States for ulcers that are 0.3 cm or larger with the low dose. The similarity of results INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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in the four countries greatly increases our confidence that cross-national assessments of health technologies are both feasible and useful. This finding may also increase the confidence of other decision makers, in jurisdictions where misoprostol has not yet been evaluated, that similar results may pertain in their setting. Therefore, it may not be necessary to repeat all studies in all countries in order to inform decision making. However, it is clear from the study that wholesale extrapolation from one setting to another is not possible without adapting to the unique characteristics of each, such as relative cost differences and patterns of care. Therefore, further cross-national studies of this type are required. Nevertheless, a common decision-analytic model can be developed, to which local data readily can be applied. Indeed, given what is known about small area variations in clinical practice even within countries, more attention could be given to the problem of how the results of cost-effectiveness studies (which are typically undertaken in one place) can be generalized. Furthermore, knowledge of the sensitivity of economic results to key parameters can guide priorities for local study. For example, in this case it is clear that more attention should be placed on obtaining an accurate estimate of ambulatory care costs rather than hospital costs, to which the model is not sensitive. Also, the study indicates a need to determine at what size an ulcer becomes important clinically, as this affects the estimates significantly. The cross-national study also shed some light on the net value of the new technology in different countries. It was noted earlier that new drugs are increasingly being priced on an international basis in an attempt to reduce the incentives to wholesalers to import from one country to another and to reduce the concerns of policy makers in those countries with a relatively high price for drugs, in particular the United States and Germany. It is therefore particularly interesting to note that while the price of misoprostol was highest in the United States, the expected costs per patient of three months of prophylaxis were generally lowest because of the relatively higher costs of those resources that were saved. As health care decision makers continue to press for more value for money from health care interventions, it is likely that the prices of drugs will more closely reflect their economic value rather than the costs of their development (8). Therefore, the paradox, highlighted by this cross-national study, is that the value of a drug can differ from one setting to another, depending on the costs of other health care resources and of alternative treatments. This fact suggests either that a differential pricing policy can be defended analytically or that common international prices need to be based on an average economic value of the drug across a number of countries, as well as its cost of production. Overall, this study has shown 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 with little additional effort. Furthermore, if cross-national studies of other health care interventions also show that overall results are similar from place to place, it may not be necessary to repeat economic evaluations in every setting, thereby saving scarce evaluative resources. REFERENCES 1. Britton, M., Jonsson, E., Marke, L.-A., & Murray, V. Diagnosing suspected stroke: A costeffectiveness analysis. International Journal of Technology Assessment in Health Care, 1986, 2, 147-58.
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Cross-national TA 2. Carrin, G., & Torfs, K. Economic evaluation of the preventive use of misoprostol in osteoarthritic patients treated with NSAIDs: The case of Belgium. Antwerp: Discussion Paper, University of Antwerp, 1989. 3. Commission of the European Communities. The cost of non-Europe in the pharmaceutical industry. Research on the cost of non-Europe, basic findings; volume 15. Brussels: CEC, 1989. 4. Department of Health. Working for patients. London: Department of Health, 1989. 5. Dominguez Uga, M. A. Economic analysis of the vaccination strategies adopted in Brazil in 1982. PAHO Bulletin, 1988, 22(3), 250-68. 6. Drummond, M. F. (ed.). Economic appraisal of health technology in the European Community. Oxford: Oxford University Press, 1987. 7. Drummond, M. F. Financial incentives to change behaviour towards health technology. In B. Stocking, (ed.), Expensive health technologies; Regulatory and administrative mechanisms in Europe. Oxford: Oxford University Press, 1988, 66-78. 8. Drummond, M. F. The role of economic evaluation in the pricing of modern pharmaceutical products. Pharmaceutical Times, 1990, March, 38-42. 9. Drummond, M. F., Stoddart, G. L., & Torrance, G. W. Methods for the economic evaluation of health care programmes. Oxford: Oxford University Press, 1987. 10. Finkler, S. A. On the distinction between costs and charges. Annals of Internal Medicine, 1982, 96, 102-09. 11. Graham, D. Y., Agrawal, N. M., & Roth, S. H. Prevention of NSAID-induced gastric ulcer with the synthetic prostaglandin misoprostol: A multicentre, double-blind, placebo-controlled trial. Lancet, 1988, ii, 1277-80. 12. Hillman, A. L., & Bloom, B. S. Economic effects of prophylactic use of misoprostol to prevent gastric ulcer in patients taking nonsteroidal anti-inflammatory drugs. Archives of Internal Medicine, 1989, 149, 2061-65. 13. Horton, S., & Claquin, P. Cost-effectiveness and user characteristics of clinic-based services for the treatment of diarrhoea: A case study in Bangladesh. Social Science and Medicine, 1982, 17(11), 721-29. 14. Hull, R. D., Hirsh, J., Sackett, D. L., & Stoddart, G. L. Cost effectiveness of clinical diagnosis, venography and noninvasive testing in patients with symptomatic deep-vein thrombosis. New England Journal of Medicine, 1981, 304, 1561-67. 15. IMS. National drug and therapeutic index, 1987. Blue Bell, PA: IMS, 1988. 16. Jacobs, J., & Bloom, B. S. Compliance and cost in NSAID therapy. Hospital Therapeutics, 1987(suppl.), 32-39. 17. Knill-Jones, R., Drummond, M. F., Kohli, H., & Davies, L. M. Economic evaluation of gastric ulcer prophylaxis in patients receiving non-steroidal anti-inflammatory drugs. Postgraduate Medical Journal, 1990, 66, 639-46. 18. McPherson, K., Wennberg, J. E., Hovind, O., et al. Small area variation in the use of common surgical procedures: An international comparison of New England, England and Norway. New England Journal of Medicine, 1982, 307, 1310-14. 19. Pharmaceutical Data Services. PDSprescription audit. Scoftsdale, AZ: Pharmaceutical Data Services, 1988. 20. de Pouvourville, G. Use of misoprostol as a prophylactic treatment in gastric ulceration associated with non-steroidal anti-inflammatory drugs. Paris: Centre de Recherche en Gestion, ficole Polytechnique, 1990. 21. Soil, A. H., & Isenberg, J. I. Duodenal ulcer diseases. In M. H. Sleisenger and J. S. Fordtran, (eds.), Gastrointestinal disease: pathophysiology, diagnosis and management, 3rded. Philadelphia, PA: W. B. Saunders Co., 1983. 22. Sontag, S., Graham, D. Y., Belsito, A., et al. Cimetidine, cigarette smoking and recurrence of duodenal ulcer. New England Journal of Medicine, 1984, 311, 689-93. 23. Veale, A. M. O. Screening for phenylketonuria. In H. Bickel, R. Guthrie, and G. Ham-
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merson (eds.), Neonatal screening for inborn errors of metabolism. Heidelberg: SpringerVerlag, 1980. 24. Wang-Ombe, J. K. Economic evaluation in primary health care: The case of Western Kenya Community Health Care Project. Social Science and Medicine, 1988, 18(5), 375-85. 25. Warner, K. E., & Luce, B. R. Cost-effectiveness and cost-benefit analysis in health care. Ann Arbor, MI: Health Administration Press, 1982. 26. Weinstein, M. C, & Stason, W. B. Foundations of cost-effectiveness analysis for health and medical practices. New England Journal of Medicine, 1977, 296, 716-21.
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