Availability of medicines in the European Union: results from the EURO-Medicines project.

SPECIAL ARTICLE P. Folino-Gallo áT. Walley áJ.C. Frolich áA. Carvajal I.R. Edwards Availability of medicines in the European Union: results from the EURO-Medicines project Received: 3 May 2001 / Accepted in revised form: 26 June 2001 / Published online: 2 August 2001 ÓSpringer-Verlag 2001 Abstract Objective: There is at present no comprehensive directory of medicines available in European countries. Such a directory would be valuable to policy analysts, clinicians, regulatory agencies, pharmaceutical companies and consumer groups. The aim of this project was to compile such a directory of all medicines marketed in each of the European Union member countries. Methods: Lists of medicines for each country, compiled from several national sources, classi®ed by AnatomicalChemical-Therapeutic (ATC) code. Census date was late 1998. Results: A comprehensive directory was created using data from 14 of the 15 European Union countries. Numbers of trade names and of active ingredients varied widely, from Germany with 18,554 and 1973, respectively, to Denmark with 1915 and 1016, respectively. In individual therapeutic areas, there were variations in the numbers of active ingredients available: the least variation between countries was in antineoplastic medicines (ATC code L, maximum number available in any country 101, minimum 60) and wider variation in alimentary (ATC code A, maximum 256, minimum 103) or cardiovascular (ATC code C, maximum 269, minimum 112). Only 7% of all the active ingredients were available in all the countries studied. The Scandinavian countries had the greatest proportion of active ingredients (60%) available in all other countries. Each country had a number of active ingredients available only in that country ± Italy had the largest number of these. Conclusions: The directory illustrates the wide variations in the availability of medicines across the European Union. The range of drugs available in each country represents dierences in regulatory and market policies, as well as cultural and historic dierences. This directory lends itself to many further analyses. Keywords Medicines áEurope áRegulation Introduction The development of centralised drug licensing in the European Union is an example of the harmonisation of European institutions [1, 2]. This follows from a system of individual national licensing agencies acting independently that has not entirely disappeared but which is far less important than before. A result of this previous system is that many older drugs are available in only one or some of the European states but not in others, or that the doses and indications may vary between countries. Other discrepancies have existed and continue to exist in the patterns of drug use with relatively few drugs being widely used in more than one country [3, 4], in expenditure on medication and in drug prices. Some of the most widely used medicines in some countries have even been withdrawn or were never licensed in others. There is rarely any scienti®c rationale for these discrepancies. A system of improved communication between national and pan-European regulatory agencies and the pharmaceutical industry was proposed in the early 1990s [5], particularly with regard to regulatory activity, pharmacovigilance and medicinal product authorisations. The general public was to have access to this information. Part of this was a directory of medicines, Eur J Clin Pharmacol (2001) 57: 441±446 DOI 10.1007/s002280100345 P. Folino-Gallo (&) Task Manager EURO-Medicines project, Institute of Hygiene, Largo F. Vito, 1, 00168 Rome, Italy E-mail: [email protected] Tel.: +39-06-30154396 Fax: +39-06-35019535 T. Walley Department of Pharmacology and Therapeutics, University of Liverpool, UK J.C. Frolich Department of Clinical Pharmacology, Hannover Medical School, Germany A. Carvajal Department of Pharmacoepidemiology, University of Valladolid, Spain I.R. Edwards WHO Adverse Drug Reaction Monitoring Centre, Uppsala, Sweden the European Product Index (EPI), itself a by-product of the European Community Pharmaceutical Information project [6]. The aims of this project were to ensure market transparency [7], support pharmacovigilance and provide technical information by creating a repertory of drugs available in the European Union. Early trials suggested that the system would be of great value, but various diculties have meant that the EPI has never been developed. European regulatory agencies depend on a drug dictionary produced by the World Health Organization (WHO) and on a commercial directory produced by a for-pro®t organisation. The former, although useful, does not contain dosage form and some other information. The latter is not available to other groups except at great expense. Identifying the discrepancies in availability of medicines can therefore be dicult, since at present there exists no directory of all medicines available in each European state. Such a directory would be of value to regulatory agencies, to those agencies negotiating drug prices, to manufacturers and those charged with promoting good prescribing. Other potential users of such a directory would be those with direct responsibility for patient care who need to identify the medicines a patient is using and consumers. To ®ll this gap, we undertook the ``EURO-Medicines'' project, funded by the Commission of the European Communities under the IV Research programme (Biomed 2-Area 6, Public Health). Its aims were to de®ne drugs available in member states and, using these data, to compare the performance of each member state in regulating its drug market. The objectives (tasks) of this project were threefold: ·Task 1 ± to undertake a comprehensive survey of all medicines marketed in each of the 15 European Union members ·Task 2 ± to examine selected medicines identi®ed from the list developed in task 1 as being available in most or all countries by reviewing the summary of product characteristics (SPC), since this represents the uses of the medicines approved in each state by the regulatory agencies ·Task 3 ± to list active ingredients withdrawn for reason of safety or ineectiveness from any of the countries identi®ed from ocial lists and from published data and to examine if these ingredients were still available in other countries This paper describes task 1. Methods Each medicine was to be classi®ed by the WHO Anatomical Therapeutic Chemical (ATC) code [8] and identi®ed by international non-proprietary name of its active ingredients. Other information to be recorded was the proprietary name (with details such as pharmaceutical form, strength and pack size), the marketing authorisation holder, the year of approval, whether reimbursed by the health service, prescription status (hospital only, prescription only, over-the-counter) and any special restrictions on its use (e.g. for opiates or other controlled drugs). Unbranded or generic medicines were treated in the same way with the exception of the proprietary name. Utilisation data and prices were also recorded when available. The census period for these lists was the second half of 1998. A number of methodological diculties were anticipated. We expected diculty in ®nding complete national databases of good quality, despite a European requirement to have such a list available in each state [9]. We therefore aimed to use a variety of agencies in each of the member states to compile a list of available medicines, largely national formularies and also data from Ministries of Health or other national organisations, public or commercial as necessary. We also expected the data from such diverse sources to be of varying quality, and for quality assurance and standardisation of the data we followed the European Prestandard ENV 12610 (Medical Informatics ± Medicinal Product Identi®cation) [10]. Further diculties were the de®nitions of what constituted a medicine. For licensed drugs, this is clear but for many over-thecounter (OTC) preparations, the distinction may be dicult. For OTC preparations such as vitamins, we decided to include a preparation only if we considered that it was clearly used therapeutically, and not as a simple food supplement, based on listing in the British National Formulary or similar source. Similarly, we decided to exclude herbal and homeopathic preparations where the range of products available varies enormously across Europe. We generally accepted the ATC code assignment on a national list where available, but for some countries it was necessary to undertake the assignment. The data were analysed using commonly available software (MS Excel 97 and Access 97). Results Data were received from a variety of sources. For only one country (Greece) was it not possible to obtain data. No source had all the information required, and the sources ranged from national lists provided by state agencies to prescribing databases, compendia of summaries of product characteristics, as well commercial directories of available medicines (Table 1). There are no data available at present on dermatological preparations in Portugal. The data on trade names for Austria, Belgium and Germany include not only the proprietary name but also the formulation and strength; these data are therefore not directly comparable to the data for the other countries which include only the proprietary name. Numbers of medicines available The numbers of medicines available varied widely among countries, with Germany having the largest number of both active ingredients (by ATC codes) and trade names and the Scandinavian countries the least (Table 2). The average ratio between trade names and active ingredients is higher in Germany than in other countries. Details by ATC code (1st level) are shown in Table 3. Similarities and discrepancies between countries The similarities and discrepancies between countries were further explored. Table 4 shows what percentage of the ingredients licensed in each country is available in the other countries, for those countries for which complete data are available. More than 60% of the ingre442 dients licensed in the Scandinavian countries are available in all the other states. The extreme ®gures are for Germany and Sweden: 83% of the active ingredients licensed in Sweden are available in Germany, but only 42% of the ingredients approved in Germany are available in Sweden. Table 1 Data sources used by country Austria Austria Codex Belgium Internal list from the Belgian Pharmaceutical Association Gecommentarieerd Geneesmiddelen-Repertorium. Heymans Instituut Compendium des Medicaments Denmark Laegemiddelstyrelsen. Apotekssforbeholdte Farmaceutiske Specialiteter, Specialitets Takst Laegemiddelkataloget Finland Internal list from the Laakelaitos Lakemedelsverket (National Agency for Medicines) France Dictionnaire Vidal French Translation of the ATC code by CNHIM ± Centre National Hospitalier d'Information sur le Me Âdicament Germany Internal ®le from Bundesvereinigung Deutscher Apothekerverbande, der Bundesapothekerkammer und des Deutschen Apothekerverbandes Rote Liste FachInfo Fachinformationsverzeichnis Deutschland Ireland Internal list from the Irish Medicines Agency Internal list from Irish Pharmaceutical Association MIMS (Ireland) ± Monthly Index of Medical Specialities, Dec. 1998 Summary of Product Characteristics Compendium 1997±1998 (Irish Pharmaceutical Healthcare Association) Italy Informatore Farmaceutico. Edizione per il medico Supplemento ordinario alla Gazzetta Uciale della Repubblica Italiana REFI ± Repertorio Farmaceutico Italiano Luxembourg Ministere de la Sante. Division de la Pharmacie et des Medicaments. Liste des medicaments admis a la vente dans le Grand-Duche Âde Luxembourg Netherlands Internal list from the Z-Index Association Lijst van Farmaceutische Producten. College ter beoorderling van geneesmiddelen Portugal Lista de medicamentos sujeitos e nao sujeitos a receita me Âdica Lista o®cial dos medicamentos comparticionados pelo Servico Nacional de SauÁ de Spain CEF. Catalogo de Especialidades Farmace Âuticas Base de datos de Medicamentos ECOM (Base de Datos de la Direccio Án General de Farmacia y Productos Sanitarios) Sweden Internal list from the Lakemedelsverket (Medical Product Agency) FASS. Lakemedel i Sverige UK Internal list from the UK Medicines Control Agency Prescription Pricing Authority BNF ± British National Formulary, Sept. 1998 ABPI Compendium of Data Sheet and Summaries of Product Characteristics 1997±1998 Table 2 Numbers of active ingredients and trade names by each country and ratio of trade names to active ingredients. ATC Anatomical-TherapeuticChemical Country Number of active ingredients (ATC codes) Number of trade names Mean number of trade names per active ingredient Austria a 1727 8643 5.01 Belgium a 1483 6118 4.13 Denmark 1016 1915 1.88 Finland 1130 2282 2.02 France 1514 4089 2.70 Germany a 1974 18,554 9.40 Ireland 1352 3751 2.77 Italy 1693 5070 2.99 Luxembourg 1537 3204 2.08 Netherlands 1290 3359 2.74 Portugal 1398 4355 3.12 Spain 1338 4100 3.06 Sweden 1041 1954 1.88 UK 1366 3635 2.66 a For Austria, Belgium and Germany, the ``trade name'' includes not just the proprietary name but also the preparation form and strength. The ®gures for trade name in these countries is therefore not directly comparable with those in other countries 443 Only 7% of all the active ingredients are available in all the participating countries. The percentage diers among ATC classes: high for antineoplastic agents, systemic hormones (both 18%) and antiinfective agents (12%), low for dermatological agents, antiparasitic agents and various (1% each or less) and nootropics (none mutually available). Number of exclusively available medicines In each country, there is a small number of active ingredients exclusive to that country. Table 5 shows the number of drugs exclusively available in only one country for some ATC groups for those countries for which data are available. Speci®c therapeutic areas The data allow more speci®c examination of individual therapeutic areas. For instance, the numbers of active principles and available preparations in each of the major classes of cardiovascular or neurological medicines can be compared in each country. Table 6 shows the range of drugs within a particular class within each country, i.e. beta blockers, ACE inhibitors, peripheral vasodilators or nootropics (e.g. piracetam). Discussion We developed a directory of medicines available in the European Union at a single point in time. This directory lends itself to many analyses of which this paper presents only a small number. More detailed examination of this database will be of value to a range of bodies as suggested above. This database is available now to interested parties (regulatory bodies and academic research) and we intend to make it more widely available on a website (www.euromedicines.org). Its updating and maintenance as medicines are licensed and withdrawn would considerably enhance the value of this data source, and we intend to undertake this work periodically. Country A B C D G H J L M N P R S V Total Austria 217 101 231 158 105 38 173 82 89 217 15 137 86 77 1727 Belgium 191 75 166 132 98 26 147 69 63 210 22 128 104 51 1483 Denmark 103 62 119 81 62 22 96 60 53 162 19 70 56 51 1016 Finland 130 60 118 78 72 20 116 73 60 144 11 75 66 107 1130 France 197 82 172 135 104 33 151 79 68 198 42 135 79 39 1514 Germany 256 124 269 184 119 40 178 101 91 258 28 141 116 82 1974 Ireland 219 75 138 141 64 31 125 68 60 192 15 103 70 51 1352 Italy 216 90 198 156 109 35 178 75 92 203 22 136 118 65 1693 Luxembourg 183 83 202 130 90 27 156 80 67 222 23 127 96 51 1537 Netherlands 148 75 164 93 81 28 124 82 47 184 22 84 78 78 1290 Portugal a 199 82 212 ± 90 31 157 66 93 176 26 130 96 40 1398 Spain 171 73 142 146 72 30 147 64 71 183 13 118 80 27 1338 Sweden 124 73 112 63 64 23 126 74 49 137 18 70 52 52 1041 UK 162 51 190 107 82 30 173 79 58 207 28 113 73 13 1366 a Data on dermatologicals for Portugal not available Table 3 Total number of active ingredients by ATC code 1st level, by country. Aalimentary tract and metabolism, Bblood and bloodforming organs, Ccardiovascular system, Ddermatologicals, Ggenitourinary system and sex hormones, Hsystemic hormonal preparations, excluding sex hormones and insulins, Janti-infectives for systemic use, Lanti-neoplastic and immunomodulating agents, Mmusculoskeletal system, Nnervous system, Panti-parasitic products, insecticides and repellents, Rrespiratory system, Ssensory organs, Vvarious Table 4 Similarities between countries in terms of availability of active ingredients. The percentage of drugs [Anatomic-TherapeuticChemical (ATC) code] available in country 1 also available in country 2 Country 2®Austria Belgium Denmark Finland Germany Ireland Italy Luxembourg Netherlands Spain Sweden UK ¯Country 1 Austria 100 59 49 51 81 51 60 63 57 53 48 54 Belgium 72 100 55 54 79 60 67 82 66 61 52 60 Denmark 81 73 100 75 84 67 69 76 76 65 73 71 Finland 78 67 70 100 79 61 68 71 69 60 70 67 Germany 68 54 43 44 100 47 54 59 50 49 42 49 Ireland 65 63 53 51 72 100 58 64 59 55 50 66 Italy 62 56 43 45 66 46 100 58 50 54 42 50 Luxembourg 71 75 52 52 79 56 63 100 60 58 49 57 Netherlands 80 76 65 63 84 65 69 75 100 63 61 69 Spain 69 65 51 51 75 55 68 66 58 100 48 59 Sweden 79 71 74 76 83 65 69 73 72 62 100 70 UK 6862 55 55 73 656264625853100 444 The range of drugs available in each country represents dierences in regulatory and market policies, as well as cultural and historic dierences [2]. This is not to necessarily imply that a decision in one country is better than another but to raise questions that require explanation. In the UK, for instance, the government has encouraged generic prescribing that in turn promotes the production of more preparations of widely used medicines, often unbranded, that are less expensive than the major-branded forms. Such generic or unbranded forms are not well documented in standard reference sources but were all included in our directory. There may also be dierences in medical culture and diagnosis, for instance the wide dierences in rates of prescribing with higher rates in Mediterranean countries and lower in Scandinavia [2, 11] or a diagnosis of systemic hypotension in Germany which is rarely made in the UK [2]. Garattini [3, 4] attributes the diering patterns of use of medicines in major European markets to the in¯uence of promotion by national pharmaceutical companies, the lack of adequate training of physicians in clinical pharmacology and the lack of reliable comparative clinical data to allow clinicians to distinguish between more expensive `me-too' drugs and their prototypes. This has resulted in the past in 20% of expenditure in Italy or France going for drugs considered to be of little or no proven therapeutic bene®t [12, 13]. Both countries have since taken drastic action to redress this situation, but discrepancies still exist [14]. The discrepancies in the market originate at least in part with discrepancies in the medicines available in each country. These discrepancies may take a number of forms. Medicines may be licensed in some countries but not in others, as shown in this article. Others may be withdrawn for safety reasons from some countries, but may be among the best-selling and most widely used drugs in other countries (e.g. dipyrone was withdrawn in many countries but is widely used in Spain). There may also be dierences in the indications for older drugs across national boundaries (e.g. trimetazidine is used for angina in France and for Meniere's disease in Denmark). It is dicult to keep track of new products, indications, contraindications and adverse drug reactions within one country, but with such wide variations in medicines licensed and the terms of the licence, the increasing movement of patients or health care profesCountry A02B C G H J01 J05 L M01 N R03A R03C Austria 1 11 1 3 0 0 2 4 10 1 2 Belgium 0 3 3 0 1 0 0 0 7 0 0 Germany 0 17 5 5 3 0 5 5 14 2 3 Denmark 0 0 1 1 0 0 1 0 1 0 0 Finland 2 1 2 0 0 0 1 0 3 0 0 France 0 10 8 4 4 0 0 2 19 0 0 Italy 2 30 9 4 9 1 3 4 25 2 3 Luxembourg 0 4 2 0 2 0 2 1 10 0 0 Netherlands 0 2 0 0 1 0 2 0 1 0 0 Portugal 2 9 3 0 2 0 0 2 7 0 0 Spain 0 8 3 2 10 0 2 4 13 0 0 Sweden 0 1 1 1 2 0 1 0 4 0 0 UK 1 19 5 2 6 0 1 0 13 2 2 Table 5 Active ingredients exclusively available in one country [selected Anatomic-Therapeutic-Chemical (ATC) groups]. A02B drugs for treatement of peptic ulcers, Ccardiovascular system, Ggenitourinary system and sex hormones, Hsystemic hormonal preparations, excluding sex hormones and insulins, J01 antibacterials for systemic use, J05 antivirals for systemic use, Lantineoplastic and immunomodulating agents, M01 antiin¯ammatory and antirheumatic products, Nnervous system, R03A adrenergics, inhalants, R03C adrenergics for systemic use Table 6 Number of trade names/active ingredients [Anatomical-Therapeutic-Chemical (ATC) codes] in four selected therapeutic groups. ACE angiotensin-converting enzyme Country Beta-blocking agents, C07A ACE inhibitors, plain, C09AA Peripheral vasodilators, C04 Psychostimulants and nootropics, N06BX Austria 54/21 29/13 44/23 10/3 Belgium 28/17 11/9 12/10 7/3 Denmark 39/15 22/10 2/2 0/0 Finland 38/16 26/12 6/3 1/1 France 27/17 15/10 38/17 12/7 Germany 94/21 56/13 96/24 58/7 Ireland 32/14 14/9 9/8 2/2 Italy 25/15 29/13 50/17 48/11 Luxembourg 34/20 15/12 34/16 15/7 Netherlands 92/18 20/10 21/8 6/2 Portugal 41/17 48/12 51/22 52/9 Spain 26/13 58/10 22/10 25/8 Sweden 24/13 15/9 4/4 1/1 UK 39/15 14/10 11/9 2/1 445 sionals across national boundaries will cause many problems. The lack of a comprehensive database of available products compounds this. The diculties of creating this database were greater than initially anticipated. An important weakness in our data is the lack of uniformity between countries in the assignment of ATC code, particularly for the active ingredients with more or many ATC codes. To explore this problem, a comparative analysis of ATC assignment in European countries has been planned in co-operation with the WHO-Oslo Centre. Another weakness in the data is the diculties of de®ning numbers of OTC or general-sales-list preparations, and this may explain a small amount of the variation in number of preparations between countries. Some countries had only an incomplete or even no national list available from government sources, despite a European Union (EU) directive [9]. The EU recognises the need for product information of the type in our database. An initiative of the European Medicines Evaluation Agency, the Medicines Information Network for Europe [15], is attempting to improve market transparency within the EU by harmonising the product information available in the EU. Its aims are to make available all SPCs and any Patient Information Lea¯ets in all EU ocial languages in an electronic database, regularly updated. It does not attempt to harmonise medical practice, nor to move too quickly to a single European pharmaceutical market [16]. A pilot project is to be undertaken by the European Joint Research Centre between 2000±2002, initially only for those products approved by the European Commission under the centralised and mutual recognition procedures. It will be some years before any results are seen. Its content and coverage dier from that in our database. As mentioned earlier, a previous attempt to establish a directory similar to EURO-Medicines as part of the European Union Drug Regulatory Agencies Network was unsuccessful. A further advantage of our database is that it was developed in parallel with another database covering most of the countries of central and eastern Europe preparing to join the EU in another project funded by the European Commission (CEE-Medicines, Folino P). This will allow EURO-Medicines to be rapidly expanded to keep pace with the future expansion of the EU. The advantages of such databases extend beyond supporting clinicians and promoting harmonisation of information and availability of medicines. Better knowledge of the current situation in other countries can be the foundation for new policy decisions constructed in the best interest of the patient. Such databases are therefore of interest to both European and national policy makers as well as to regulatory agencies, the WHO, consumer groups and pharmaceutical industry associations. Our database may allow countries to identify and address concerns about availability of medicines or to identify where and how they can improve their work, especially where benchmarking against other states suggests that patients are being exposed to dangerous or ineective therapies. This may lead to a substantial improvement in the quality of care and therapeutic outcome and a signi®cant improvement in the eciency of the health systems. Acknowledgements This project was funded by the European Union (Scienti®c Research-DG) under Biomed 2. We would like to thank the national agencies and professional organisations that provided their data. Our thanks to Kees DeJoncheere from the WHO Regional Oce for Europe in Copenhagen and Marit Ronning from the WHO Collaborating Centre for Drug Statistic Methodology in Oslo for their help and suggestions in analysing and interpreting the data. Academic researchers wishing to have access to this database should contact Dr. P. Folino. References 1. Jeerys DB, Jones KH (1995) EMEA and the new pharmaceutical procedures for Europe. European Medicines Evaluation Agency. Eur J Clin Pharmacol 47:471±476 2. Taylor D (1992) Prescribing in Europe±forces for change. BMJ 304:239±242 3. Garattini S, Garattini L (1993) Pharmaceutical prescriptions in four European countries. Lancet 342:1191±1192 4. Garattini S (1998) The drug market in four European countries. Pharmacoeconomics 14[Suppl 1]:69±79 5. Anonymous (1993) Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products. Ocial Journal, Brussels, L 214:1±21 6. ECPHIN Website http://ecphin.etomep.net/Ecphin/E_inform.html accessed 23/12/99 7. Anonymous (1989) Council Directive 89/105/EEC of 21 December 1988 relating to the transparency of measures regulating the prices of medicinal products for human use and their inclusion in the scope of national health insurance systems. Ocial Journal, Brussels, L 040:8±11 8. WHO Collaborating Centre for Drug Statistics Methodology (2000) Guidelines for ATC classi®cation and DDD assignment. WHO, Oslo 9. Anonymous (1992) Council Directive 92/26/EEC of 31 March 1992 concerning the classi®cation for the supply of medicinal products for human use. Ocial Journal, Brussels, L 113:5±7 10. European Committee for Standardisation. (1997) European Prestandard ENV 12610: Medical informatics ± medicinal product identi®cation. Brussels 11. OECD Health Policy Unit (2000) OECD Health data 2000. Paris 12. Durand-Zaleski I, Colin C, Blum-Boisgard C (1997) An attempt to save money by using mandatory practice guidelines in France. BMJ 315:943±946 13. Garattini S (1995) Cultural shift in Italy's drug policy. Lancet 346:5±6 14. Garattini S, Garattini L (1998) Discrepancy remains in pharmaceutical prescriptions in four European countries. BMJ 317:947 15. Meeting report of the workshop on Medicines Information Network for Europe EMEA, 10th July 1998. From EMEA website accessed 13th December 1999 16. Kanavos P (1998) Single European currency and Monetary Union. Macroeconomic implications for pharmaceutical spending. Pharmacoeconomics. 13:9±20 446