Research Report For reprint orders, please contact reprints@expert-review s.com Comparing policies to enhance prescribing eficiency in Europe through increasing generic utilization: changes seen and global implications Expert Rev. Pharmacoeconomics Outcomes Res. 10(6), 707–722 (2010). Brian Godman†, William Shrank, Morten Andersen, Christian Berg, Iain Bishop, Thomas Burkhardt, Kristina Garuoliene, Harald Herholz, Roberta Joppi, Marija Kalaba, Ott Laius, Diane McGinn, Vita Samaluk, Catherine Sermet, Ulrich Schwabe, Inês Teixeira, Lesley Tilson, F Cankat Tulunay, Vera VlahovićPalčevski, Kamila Wendykowska, Björn Wettermark, Corinne Zara and Lars L Gustafsson † Author for correspondence: Institute for Pharmacological Research ‘Mario Negri’, Via Giuseppe La Masa 19, 20156 Milan, Italy Tel.: +39 023 901 4314 Fax: +39 023 546 277 godman@marionegri.it Aim: the aim of this article was to evaluate the inluence of different demand-side measures to enhance the prescribing of generics in ambulatory care based on cross-national comparisons. Methods: an observational retrospective study was conducted using administrative databases from across Europe, documenting changes in reimbursed utilization and expenditure of different proton pump inhibitors (PPIs) and statins between 2001 and 2007, alongside different reforms to enhance prescribing eficiency. Utilization was converted to deined daily doses (DDDs) and expenditures were converted to euros. Demand-side measures were collated under the ‘4 Es’ – education, engineering, economics and enforcement – to enable comparisons on the nature and intensity of reforms between countries. Results: there were considerable differences in the utilization of generics and patent-protected PPIs and statins among Western European countries. Decreased utilization of omeprazole and simvastatin, alongside increased utilization of esomeprazole, atorvastatin and rosuvastatin, was seen in countries with limited demand-side measures to counteract commercial pressures. Prescribing restrictions, or a combination of education, prescribing targets and inancial incentives, had the greatest inluence on enhancing the utilization of omeprazole and simvastatin. For example, there was a threefold reduction in the utilization of atorvastatin in Austria following prescribing restrictions. Multiple demand-side interventions generally had a greater inluence than single interventions, with the impact appearing additive. Multiple interventions coupled with initiatives to lower prices of generics considerably enhanced prescribing eficiency. Conclusion: this cross-national study has demonstrated considerable variation in the utilization and expenditure of PPIs and statins across Europe, providing opportunities to further improve prescribing eficiency. The ‘4 Es’ do provide an understandable methodology to document and compare the inluence of different demand-side measures, with the inluence varying by their extent and intensity. Further reforms are essential given current inancial pressures. Consequently, further research will concentrate on the potential to develop a scoring system to help predict the possible impact of different demand-side measures on future utilization patterns. KEYWORDS : cross-national studies • demand-side reforms • generic drugs • generic substitution • prescribing eficiency For a full list of afiliations, please see the back page Drug therapy is an important treatment option in the management of patients in ambulatory c a re. T he focu s on pha rmac eut ic a l expenditures is increasing with expenditures having risen rapidly in the 1990s and early 2000s at between 4 and 13% per annum [1–7,101] . This rate is typically faster than that of other components of healthcare [5,6–10] , www.expert-reviews.com 10.1586/ERP.10.72 resulting in pharmaceutical expenditures in ambulatory care now being the largest or equal largest expenditure component in this segment among European countries [1,2,4,10–12] . European governments, health authorities and health insurance agencies have implemented a variety of reforms and initiatives to moderate this unsustainable growth. These include policies © 2010 Expert Reviews Ltd ISSN 1473-7167 707 Research Report Godman, Shrank, Andersen et al. surrounding generics including those that impact on prices (supply-side measures) as well as utilization (demand-side measures). Supply-side reforms include measures to [2–4,10,13,101] : • Engineer lower prices for multiple source products helped in many European countries by patients having to cover the costs themselves for a more expensive brand than the reference molecule in addition to any standard co-payment for the dispensed product; Drug utilization research Public health concepts for medicines Health systems research regarding medicines • Engineer low prices for interchangeable products within a class; • Lower the prices generally of existing medicines through compulsory price cuts. Figure 1. Relationship of drug utilization research with public health and health systems research ields. Alongside this, measures to rapidly reimburse generics once they receive marketing authorization through demonstrating the same qualitative and quantitative composition, as well as bioavailability, as the originator substance and their pricing policy are in line with current directives [13] . However, this is not always the case with appreciable delays occurring in some countries. The pricing policies for generics and originators (original-brand product once multiple sources are available) in Europe have recently been extensively described by us and others [13–19] . These aspects will therefore not be elaborated further. Reimbursed prices, especially for high-volume generic drugs, are low in Sweden and the UK. This is helped by compulsory generic substitutions in Sweden [9,13] , and high international Table 1. Country characteristics in 2008 unless stated. Characteristics AT DE EE FR GB HR IE IT LT NO PO PT RS SE SI TR Population (millions) 8.3 82.1 1.3 61.8 60.5 4.4 4.3 58.9 3.3 4.8 38.1 10.6 NR 9.2 2.03 74.8 % of GDP on healthcare 10.5 10.5 6.1 11.2 8.7 7.5 8.7 9.1 5.9 8.5 7.0 9.9† NR 9.4 8.1 6.0‡ 1.4 % of GDP on pharmaceuticals and other medical nondurables 1.6 1.3 1.8 NR NR 1.5 1.7 NR 0.7 1.6 2.2† NR 1.2 NR NR 1.1 1.4 1.0 1.5 NR NR NR NR 1.2 0.6 0.9 NR NR 0.9 1.2 NR ü ü % of GDP on prescription drugs ü Taxation-based system ü Health insurance-based system ü ü ü Pricing policy for MA generics MF MA MA Reference pricing – class VP ü ü MF MA RJT ü ü ü MA MA MA ü AC ü ü PP MF ü ü ü MA ü ü MA MF SP Only PPIs MA PP ü † 2006. 2007. AT: Austria; DE: Germany; EE: Estonia; ES: Spain – Catalonia; FR: France; GB: Great Britain; HR: Croatia; IE: Republic of Ireland; IT: Italy; LT: Lithuania; NO: Norway; PO: Poland; PT: Portugal; RS: Serbia; SE: Sweden; SI: Slovenia; TR: Turkey. GDP: Gross domestic product; NR: Not recorded. Generic pricing: MA: Mixed approach – combining prescriptive pricing for the irst generic or generics followed by market forces; MF: Market forces – where measures are in place to lower prices through market forces; PP: Prescriptive pricing for generics – dictated by health authorities or health insurance agencies. Reference pricing – Class: AC: Being actively considered; RJT: Proposed but Rejected; SP: Applies to some product classes but not all; VP: Voluntary reference pricing. ‡ 708 Expert Rev. Pharmacoeconomics Outcomes Res. 10(6), (2010) Comparing policies to enhance prescribing eficiency in Europe nonproprietary name (INN) prescribing linked with the transparent pricing of generics in the UK [13,20,21] . Reimbursed prices for six high-volume generics in Sweden were between 4 and 13% of the originator prices prepatent loss, with generic simvastatin and generic risperidone being 2% of the originator price in the UK [3,9,20,22] . Despite various initiatives [13] , the prices of generics still vary by up to 36-fold across countries depending on the molecule [18] . Consequently, reducing reimbursed prices for generics in some European countries is one way to enhance prescribing eficiency. Equally, enhancing the prescribing and dispensing of generics will also help to improve prescribing eficiency. Demand-side measures include the following [2–4,9,13,20,23–31] : • Encouraging pharmacists to substitute, where appropriate, through incentives and other mechanisms; • Additional patient co-payments for more expensive molecules than the referenced price molecule; • Prescribing targets coupled with physician inancial incentives; • Budget devolution coupled with inancial incentives and penalties; • Benchmarking physician prescribing patterns against each other coupled with inancial penalties for excessive costs. Research Report Table 2. Details of the administrative databases and data providers (100% coverage of the population unless stated). Providers for the cross-national Databases study Austria Data Warehouse of the Federation of Austrian Social Insurance Institutions (98% of the population) Germany GAmSi database, that is, GKV-Arzneimittel Schnellinformation, which covers all prescriptions paid for by the Social Health Insurance Funds (approximately 90% of the population) Estonia Estonian Health Insurance Fund Spain – Catalonia DMART (Catalan Health Service) database (all patients in Catalonia) Data only available from 2003 onwards France Medic’am database (CNAM-TS database for salaried personnel covering 75% of the population) Great Britain – England Information Centre for Health and Social Care Great Britain – Scotland PIS from NHS National Services Scotland Corporate Warehouse Croatia Croatian Institute for Health Insurance Republic of Ireland HSE-PCRS (GMS population covering approximately 25–30% of the population with higher morbidity than the general population, relected in consuming approximately 65% of total pharmaceutical expenditure) Italy OsMed database Lithuania Electronic database of the National Health Insurance Fund Norway NorPD Expenditure data only available from 2004 onwards Poland National Health Fund database However, it is recognized that prescribing Portugal INFARMED (NHS) database (approximately 75% of is a complex process. This typically involves the population) physicians sifting information from a variRepublic of Serbia’s Health Insurance ety of sources, including pharmaceutical Serbia Fund database companies, as well as balancing a range of Apoteket AB (National Corporation of Swedish personal, social and logistical inluences Sweden Pharmacies – monopoly up to 1 January 2010) including habitual behaviors in addition to The National Institute of Public Health and Health medical and pharmaceutical considerations Slovenia Insurance Institute Prescription database [29,32–38] . This complexity is relected, for instance, by pharmaceutical companies hav- Turkey SGK – single national public payer purchasing approximately 95% of pharmaceutical expenditure ing spent over GB£850 million/year in the in Turkey UK alone in marketing activities in recent GMS: General Medical Services; HSE-PCRS: Health Service Executive – Primary Care Reimbursement Service; years to inluence prescribing, with similar NorPD: Norwegian Prescription Database; PIS: Prescribing Information System, SGK: Social rates in other countries [24,38,102] . Security Institution. There have also been initiatives to address concerns regarding the effectiveness and safety of generics when they prescribing and dispensing includes prohibiting substitution where arise. These include educational initiatives via physicians, pharmacists concerns are evident, for example, in Sweden, or alternatively, and the media, not granting reimbursement where concerns with the recommending the prescribing of brand names, for example, in quality of the generic exist, for example, in Austria, as well as the UK with, for instance, ciclosporin, lithium and mesalazine directing prescribing and dispensing [2,4,9,13,21,23,39,40] . Directing as well as long-acting morphine. Thankfully, concerns over the www.expert-reviews.com 709 Research Report Godman, Shrank, Andersen et al. Table 3. Prescribing indicators used to assess changes in prescribing eficiency. Class Indicator Rationale PPI Percentage of generic omeprazole versus all omeprazole in 2007 Extent of prescribing and dispensing of the generic versus originator drugs after patent loss Percentage of omeprazole (all) versus all PPIs principally between 2001 and 2007, and in 2007 versus prepatent loss utilization (Western European countries) Omeprazole was the irst PPI to lose its patent; consequently, the principal focus initially for health authority and health insurance company interventions to enhance PPI prescribing eficiency As a result, the focus of this study was on omeprazole rather than other PPIs, which lost their patents during the course of the study Percentage of esomeprazole versus all PPIs principally between 2001 and 2007, and in 2007 versus prepatent loss utilization (Western European countries) Only PPI to be patent protected (single source) during the study period among Western European countries Percentage of generic simvastatin versus all simvastatin in 2007 Extent of prescribing and dispensing of the generic versus originator drugs after patent loss Percentage of simvastatin (all) versus all statins principally between 2001 and 2007, and in 2007 versus prepatent loss utilization (Western European countries) Simvastatin was the irst major statin to lose its patent; consequently, the principal focus initially for health authority and health insurance company interventions to enhance statin prescribing eficiency As a result, the focus of this study was on simvastatin rather than other statins, which lost their patents during the course of the study Percentage of atorvastatin and rosuvastatin versus all statins principally between 2001 and 2007, and in 2007 versus prepatent loss utilization (Western European countries) Only statins to be patent protected (single source) during the study period among Western European countries Statins PPI: Proton pump inhibitor. effectiveness and/or safety of generics among physicians typically only occur in a minority of cases [5,9,41–44] . This situation is not helped by some originator companies questioning the quality of generics as part of their marketing efforts to reduce sales erosion post-patent loss [103] . Concurrent with this, there have been initiatives by European authorities to optimize the prescribing of new premium-priced drugs to further enhance prescribing eficiency. This is because expenditure on new drugs is seen as a major challenge to continued equitable and comprehensive healthcare in Europe [45] , exacerbated by the limited health gain with many new products versus current standards [2,4,46–48] . Maximizing prescribing eficiency for both new and existing drugs will help address the continual pressures on pharmaceutical budgets driven by demographic changes, rising patient expectations, stricter clinical targets, the continued launch of new innovative premium-priced drugs and the growth in individualized medicines [8,45,47,49] . European countries are already learning from each other [27] , which needs to continue to avoid prohibitive increases in either taxes or health insurance premiums in order to maintain comprehensive and equitable healthcare. Cross-national comparisons of drug utilization is one method for identifying possible measures that countries could introduce, as they help identify potential areas for improving prescribing eficiency through evaluating the consumption of medicines using standard methodologies and possible rationales for patterns observed (FIGURE 1) . They also enable analytical studies, linking datasets between countries and matching changes in utilization and expenditure patterns with reforms to guide future initiatives. 710 The objectives of this paper are: • First, to analyze changes in drug utilization and expenditure of high-volume ambulatory care drugs in recent years across Europe; • Second, to try and match the changes seen with ongoing demandside measures, collated into understandable subgroups in order to enhance comparisons; • Third, to identify possible future demand-side measures that European countries could instigate in addition to current measures to further enhance the utilization of generics. As a result, we would be able to add to the existing literature, as there are currently only a limited number of publications assessing the impact of different demand-side measures on future prescribing patterns apart from those concerning guideline production and dissemination, academic detailing or audits combined with feedback and inancial incentives [26,30,31,50,51] . This is not helped by health authorities and health insurance agencies typically instigating a range of measures simultaneously or in quick succession, making such analyses dificult. Methodology This was an observational uncontrolled retrospective study [52], involving an analysis of reimbursed prescriptions from administrative databases. This methodology was used as there was no opportunity for a controlled study with data analyzed retrospectively. In addition, health authorities and health insurance agencies typically instigate a number of measures simultaneously or in quick succession. These may also last over time, with some applying nationally while others Expert Rev. Pharmacoeconomics Outcomes Res. 10(6), (2010) Comparing policies to enhance prescribing eficiency in Europe vary in intensity between regions within a country. As a result, there was no opportunity to perform more sophisticated analytical studies. We acknowledge the limitations of the chosen study design. A total of 18 European countries and regions were included in the analysis: Austria, Croatia, Estonia, France, Germany, Italy, Lithuania, Norway, Portugal, Poland, the Republic of Ireland, Serbia, Slovenia, Spain (Catalonia), Sweden, Turkey and the UK (England and Scotland). The countries relect differences in geography, epidemiology, inancing of healthcare, available resources for healthcare including pharmaceuticals, approaches to the pricing of generics, originators and single-sourced products, as well as differences in measures to enhance the prescribing of generics (TABLE 1) [1,13,53,104] . A total of 9% of gross domestic product is currently spent on healthcare in Spain, with 1.8% spent on pharmaceuticals [104] . Catalonia was chosen to represent Spain in this study as it is one of the principal autonomous communities in Spain that has been active over a number of years, instigating a range of measures to enhance the prescribing of generics [10] . As stated, only administrative databases from health authorities of health insurance groups were used for the analyses (TABLE 2) to ensure consistency as well as relect the public health perspective Research Report of this paper. Using administrative databases also ensured that all reimbursed prescriptions were captured for the respective country populations as commercial sources can sometimes include only a sample of pharmacies or, alternatively, only data from wholesalers. The latter does not include any products sold directly from generic manufacturers to community pharmacies. Two classes of drugs were chosen for in-depth analysis of the potential inluence of different demand-side measures on ambulatory care prescribing. These were the proton pump inhibitors (PPIs) – anatomical therapeutic chemical (ATC) group A02BC [105] – and the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) – ATC group C10AA [105] . They were chosen as they are both high-volume prescribing areas in ambulatory care. They also contain a mixture of generics, originators and single-sourced products in a class with single-sourced products marketed as major developments at premium prices, even though health authorities and health insurance agencies generally view these developments as minor at best for the majority of patients [24,53,102,106–111] . There may be some evidence suggesting greater effectiveness for very high doses of atorvastatin, but this should only apply to a minority of patients [54] . Lastly, PPIs and statins are typically Table 4. Dates when generic omeprazole and generic simvastatin were irst reimbursed in Western European countries. Country Year when generic omeprazole was dispensed and reimbursed Year when generic Baseline year for assessing utilization simvastatin was dispensed and patterns of PPIs reimbursed Baseline year for assessing utilization patterns of statins Comments Austria 2003 2002 2002 2001 – Germany 2002 2001 2003 2002 – Spain – Catalonia Available in 2003 2003 Available in 2003 2003 Data only available after 2003 for analysis France 2004 2003 2005 2004 – GB – England 2002 2001 2003 2002 – GB – Scotland 2002 2001 2003 2002 – Republic of Ireland 2002 2001 2003 2002 – Italy 2007 2006 2007 2006 2008 data compared with 2006 as generics only recently became available Norway Available in 2004 2004 Available in 2004 2004 Prescription expenditure data only available from 2004; consequently, start of data analysis Portugal Available in 2000 2000 2001 2000 Data only available from 2000, that is, after generic omeprazole was launched Sweden 2003 2002 2003 2002 – GB: Great Britain; PPI: Proton pump inhibitor. www.expert-reviews.com 711 Research Report Godman, Shrank, Andersen et al. Table 5. ‘4 E’ categorization of demand-side initiatives across Europe. 4 ‘E’ category Deinition Examples Education Programs that inluence prescribing through dissemination of material, which can be passive or active Simple distribution of printed treatment guidance Intensive strategies such as educational outreach visits and the monitoring of prescribing against agreed guidance or guidelines coupled with feedback Engineering Organizational or managerial interventions Price: volume agreements for existing drugs Disease management programs Prescribing targets, for example, the percentage of prescriptions for generic omeprazole versus all PPIs and percentage generic simvastatin versus all statins and goals for INN prescribing when this is not obligatory or enforced Economics Financial interventions (positive and negative) Patient co-payments for more-expensive drugs than the current reference molecule Positive and negative inancial incentives for physicians Devolved budgets to physicians Enforcement Regulations including those enforced by law Mandatory generic substitution in pharmacies Prescribing restrictions such as prior authorization schemes, for example, atorvastatin in Austria, or alternatively, prescribing restrictions with follow-up only where concerns arise, for example, in Norway and Sweden ‘4 Es’: Education, engineering, economics and enforcement; INN: International nonproprietary name; PPI: Proton pump inhibitor. Data taken from [26]. the subject of many country and/or regional initiatives to enhance eficiency. Utilization rates for the substances in each class were computed using deined daily doses (DDDs) [112] . The concepts of ATC classiication and DDDs were developed to facilitate comparisons in drug utilization between countries, especially where there are differences in pack sizes and available tablet strengths [55,56] . The ATC/DDD index from 2010 has been used in line with recommendations [57] . A number of prescribing indicators were selected to assess the inluence of the various demand-side reforms and initiatives on improving prescribing eficiency. These were based on current measures used by health authorities across Europe [9,10,20,102] . Their details and rationale are included in TABLE 3. Lovastatin was available in some European countries; however, its utilization was limited even in these countries, especially with the increasing utilization of simvastatin. Consequently, simvastatin was the major focus of health authority and health insurance company activity, and is the statin chosen in this study. As seen in TABLE 3, the analysis principally focused on the years between 2001 and 2007, as typically both generic omeprazole and generic simvastatin became available and were reimbursed during this time period in Western European countries (TABLE 4) . Only Western European countries were included in this particular analysis as generic omeprazole was either the only available PPI in former Central and Eastern European countries during some or all of the study period, or was available here earlier than in Western European countries. There was a similar situation with the statins, with generic simvastatin again being available earlier in Central and Eastern Europe than in Western European countries. In addition, generic atorvastatin also became available in Central and Eastern European countries during the study period. All these factors impact on the utilization patterns in former Central and Eastern European countries compared with those in Western European countries. 712 Reimbursed expenditures, principally from 2001 to 2007, were also captured for each product and class along with changes in utilization to try and assess the inluence of the various reforms and initiatives on overall prescribing eficiency from a public health/payer perspective. The only exceptions were Austria, Germany and Norway, where it was dificult to separate reimbursed from total expenditure. We acknowledge that there are differences in co-payments, pharmacy and wholesaler remunerations as well as value-added tax (VAT) between European countries. In addition, we are aware that community pharmacists may receive discounts and rebates directly from generic manufacturers to preferentially dispense their generics, and in some countries, there is appreciable dispensing of parallel imported products. However, reimbursed expenditure relects the recorded situation among the health authorities and health insurance agencies. Reimbursed expenditures were initially calculated in the local currencies and were subsequently converted to euros in 2007 to facilitate comparisons: €1 = GB£0.734 and SEK9.25 (2007). There was no allowance for inlation as typically generic prices were compared with prepatent loss prices by the various authorities [13] . In addition, the prices of generics do not generally rise and may also be subjected to price cuts; however, this is not always the case [13,113]. Details of the various supply- and demand-side reforms in each selected European country were collated with the help of the considerable expertise of the co-authors, from published papers, web-based publications or internal documents known to the coauthors. Details of the reforms were subsequently re-validated with the co-authors to add robustness to the analyses. A narrative review of identiied papers was subsequently conducted by one of the co-authors (Brian Godman). The various demand-side measures have been collated under the ‘4 Es’ methodology – that is, education, engineering, economics and enforcement – to simplify comparisons between countries (TABLE 5), Expert Rev. Pharmacoeconomics Outcomes Res. 10(6), (2010) Comparing policies to enhance prescribing eficiency in Europe given the extensive range of measures that have been introduced across Europe. This approach has been used in other settings and adapted to healthcare [9,10,20,26,58] . Finally, there has been no analysis of the initial rationale behind the appropriateness of prescribing either a PPI or statin, as this would require access to patient databases and would detract from the main focus of the paper, which is the identiication of potential measures to further enhance prescribing eficiency once physicians have decided to prescribe either a PPI or lipid-lowering drug. However, these issues have been discussed in individual country publications [10,20,58] . Results Research Report Table 6. Summary of the different demand-side reforms and initiatives among European countries categorized under the ‘4 E’s. Country DE/states ES/Catalonia ü ü FR† ü GB – England ‡ GB – Scotland LT ü ü EE IT/regions Engineering ü AT IE Education ü ü ü ü Economics Enforcement ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü ü The various European countries have HR implemented a range of different demand- NO ü ü side reforms to try and enhance prescribing PO ü ü ü eficiency generally and for the PPIs and ü ü ü ü PT statins (TABLE 6) . Details of general measures ü RS Selected drugs to enhance prescribing eficiency and their intensity, as well as speciic measures for SE ü ü ü ü the PPIs and statins, are summarized in SI ü ü Selected drugs SUPPLEMENTARY TABLE 1 [114] . ü TR FIGURE 2 depicts the utilization of generic † Contrats d’amélioration des pratiques individuelles (CAPI) in France for prescribing targets linked with omeprazole versus all omeprazole, and incentives was only introduced in 2009 [2]. generic simvastatin versus all statins, in ‡Differences between England and Scotland are principally in terms of drug budget devolution/accountability (see SUPPLEMENTARY TABLE 1) [114]. 2007 in selected Western European coun- AT: Austria; DE: Germany; EE: Estonia; ES: Spain – Catalonia; FR: France; GB: Great Britain; HR: Croatia; IE: tries. As stated, reimbursed prices for both Republic of Ireland; IT: Italy; LT: Lithuania; NO: Norway; PO: Poland; PT: Portugal; RS: Serbia; SE: Sweden; generics and originators are typically the SI: Slovenia; TR: Turkey. same across Europe, with patients being required to fund the also lower in 2007, at 42% of all statins versus 55% in 2004. additional costs themselves for a more expensive product [13] . TABLE 7 documents the changes in the utilization patterns of the FIGURE 3 depicts the changes in utilization for omeprazole and PPIs and statins in selected Western European countries brought esomeprazole as a percentage of all PPI utilization in 2007 versus about by the various demand-side initiatives (TABLE 5 & SUPPLEMENTARY utilization rates seen just prior to patent loss of omeprazole (TABLE 2) TABLE 1), combined with initiatives to lower generic prices in each unless stated. The various demand-side measures inluencing the country [13] , and their impact on overall eficiency. Only half utilization patterns for omeprazole and esomeprazole are docu- the countries have been documented for illustrative purposes. The various reforms in Italy (SUPPLEMENTARY TABLE 1) [114] led to reimmented in TABLE 1 [114]. SUPPLEMENTARY TABLE 2 [114] documents the actual changes in utilization patterns for omeprazole and esomeprazole bursed expenditure for the PPIs in 2008 decreasing by 24% versus as a percentage of all PPI utilization on a DDD basis over time 2006, despite a 35% increase in volumes. Reimbursed expenditure for the statins fell by 11% during the same period, despite a similar among Western European countries. 35% increase in volume. FIGURE 4 depicts the changes in utilization for simvastatin, atorIn Turkey, with currently only limited demand-side measures vastatin and rosuva statin as a percentage of all statin utilization in 2007 versus utilization rates seen just prior to patent loss (SUPPLEMENTARY TABLE 1) [114] , differences in utilization and expenditure of simvastatin (TABLE 2) unless stated. The various demand-side of PPIs and statins in 2009 versus 2007 were as follows: measures inluencing the utilization are again documented in • PPIs: PPI utilization increased by 26% while reimbursed expenSUPPLEMENTARY TABLE 1 [114] . SUPPLEMENTARY TABLE 3 [114] documents the diture increased by 61% through a 5.5-fold increase in the utilichanges in utilization patterns for simvastatin, atorvastatin and zation of esomeprazole (from 2 to 7% of total PPI utilization), rosuvastatin as a percentage of all statin utilization on a DDD while omeprazole utilization decreased from 10 to 5% of total basis over time among the Western European countries. PPI utilization; In France, there has been greater utilization of pravastatin than simvastatin. The combined utilization of simvastatin and • Statins: statin utilization increased by 6% while expenditure increased by 41%, with greater utilization of atorvastatin (76% prava statin, which lost its patent shortly after simvastatin, was www.expert-reviews.com 713 Research Report 100 Godman, Shrank, Andersen et al. Discussion including likely future developments over the next 5 years in Europe The irst comprehensive list of DDDs was published in Norway in 1975 and has developed since then. As a result, 80 DDDs are now the internationally accepted methodology for comparing 70 drug utilization across countries, espe60 cially where there are different packs and tablet strengths between countries 50 [57,59,60,112] . Consequently, the ATC/DDD methodology was employed in these two 40 cross-national comparisons. The plethora of demand-side initiatives 30 (TABLE 6 AND SUPPLEMENTARY TABLE 1) [114] appears to have resulted in considerable utiliza20 tion of generic drugs versus the respec10 tive originators, with utilization rates of over 80% typically being achieved for 0 the generic drugs (FIGUR E 2) . The major GB GB AT DE ES FR IE NO PT SE exception among the Western European Eng Scot countries is the Republic of Ireland, with Country currently limited measures to enhance the prescribing of generics even in this selected Omeprazole Simvastatin population. This will change with the planned introduction of reference pricing Figure 2. Utilization of generic omeprazole versus all omeprazole and generic for the molecule in 2011 [12] . However, it simvastatin versus all simvastatin in 2007 in selected European countries is dificult at this stage to fully predict the (deined daily dose basis). outcome. AT: Austria; DE: Germany; ES: Spain; FR: France; GB Eng: England; GB Scot: Scotland; IE: Republic of Ireland; NO: Norway; PT: Portugal; SE: Sweden. The different demand-side measures, Reproduced from [13] . their extent and intensity collated under the ‘4 Es’ (SUPPLEMENTARY TABLE 1) [114] do appear of total statin utilization in 2007 rising to 84% in 2009), and to lead to considerable differences in the utilization of omeprazole simvastatin utilization decreasing from 9% of the total statin and simvastatin, as well as single-sourced PPIs (e.g., esomeprazole) utilization to 5% during this period. and statins (e.g., rosuvastatin and atorvastatin), among Western TABLE 8 documents the impact of the various reforms (TABLE 6 & European countries over time (SUPPLEMENTARY TABLES 2 & 3) [114] , and in SUPPLEMENTARY TABLE 1) [114] on PPI and statin prescribing eficiency 2007 versus patterns seen before the patent loss of either omeprazole amongst former Central and Eastern European countries in recent or simvastatin (FIGURES 3 & 4) . years. As previously discussed, generic PPIs and statins, includWe consider that despite the study design limitations, prescribing ing generic atorvastatin, were typically available earlier in these restrictions (enforcement) as a single entity appear to appreciably countries, making comparisons dificult with Western European inluence utilization. This is depicted by the considerable reduccountries. tion in the utilization of atorvastatin and rosuvastatin in Austria, In Poland in 2007 versus 2001, there was nearly a twofold dif- Germany and Norway in 2007 versus prepatent loss rates (FIGURE 4, ference in the rate of increase in the utilization of PPIs versus the SUPPLEMENTARY TABLES 1 & 3) [114] compared with increased utilization increase in expenditure. At the same time, there was a 4.5-fold of these single-sourced statins France, the Republic of Ireland, difference between the rate of increase in the utilization of statins Portugal and Turkey, where there are currently fewer demand-side versus that seen for expenditure. reforms to counteract pharmaceutical company marketing presThe situation in Serbia is complicated by generic PPIs and sures (SUPPLEMENTARY TABLE 1) [114] . However, it is dificult to substantiate statins having been on the market before comprehensive data- this within the study design. This is starting to change in France sets became available in 2005. The various policies led to over- with the introduction of prescribing targets such as the percentage all expenditure for the PPIs only increasing 1.7-fold between of prescriptions for generic PPIs and statins linked with inancial 2005 and 2009, while utilization increased 2.1-fold. Reimbursed incentives [2] . expenditure for the statins increased sixfold during this period The nature of the enforcement (SUPPLEMENTARY TABLE 1) [114] also while utilization increased 6.5-fold. appears to impact on subsequent utilization patterns with a % utilization for the molecule 90 714 Expert Rev. Pharmacoeconomics Outcomes Res. 10(6), (2010) Comparing policies to enhance prescribing eficiency in Europe Research Report 90 80 % utilization versus all PPIs DDD basis 70 60 50 40 30 20 10 0 AT DE ES† FR GB Eng GB Scot IE IT‡ NO§ PT¶ SE Country Omeprazole PL Omeprazole 2007 Esomeprazole PL Esomeprazole 2007 Figure 3. Utilization patterns on a DDDs basis in 2007 for omeprazole and esomeprazole versus prepatent loss of omeprazole (unless stated) among Western European countries. † Baseline = 2003; Catalonia = Spain. ‡ 2006 vs 2008. § Baseline = 2004. ¶ Baseline = 2000. DDD: Deined daily dose; PL: Before patent loss. AT: Austria; DE: Germany; ES: Spain; FR: France; GB Eng: England; GB Scot: Scotland; IE: Republic of Ireland; IT: Italy; NO: Norway; PT: Portugal; SE: Sweden. seemingly greater fall in the utilization of atorvastatin and simvastatin following prescribing restrictions in Austria compared with Norway when factoring in baseline levels for the utilization of atorvastatin and rosuvastatin (FIGURE 4) . This phenomenon will be explored further in future papers. www.expert-reviews.com The combination of education, engineering and economics also appreciably inluences the future utilization of multiple versus patent-protected products within a class. This can be seen when comparing the changes in PPI (omeprazole and esomeprazole) and statin (simvastatin, atorvastatin and rosuvastatin) utilization 715 Research Report Godman, Shrank, Andersen et al. 90 80 % utilization versus all statins DDD basis 70 60 50 40 30 20 10 0 AT DE ES† FR GB Eng GB Scot IE IT‡ NO§ PT SE Country Simvastatin PL Simvastatin 2007 Atorvastatin + Rosuvastatin PL Atorvastatin + Rosuvastatin 2007 Figure 4. Utilization of simvastatin, atorvastatin and rosuvastatin prior to the availability of generic simvastatin and in 2007 on a DDD basis in Western European countries. † Baseline = 2003; Spain is Catalonia. ‡ 2006 vs 2008. § Baseline = 2004. DDD: Deined daily dose; PL: Before patent loss. AT: Austria; DE: Germany; ES: Spain; FR: France; GB Eng: England; GB Scot: Scotland; IE: Republic of Ireland; IT: Italy; NO: Norway; PT: Portugal: SE: Sweden. in Sweden and the UK (England and Scotland), where all three approaches are combined, with France, Portugal, the Republic of Ireland (FIGURE 4, SUPPLEMENTARY TABLES 1–3) [114] and Turkey. The 716 differences in the observed utilization patterns for the different statins between England and Scotland (FIGURES 3 & 4) may well relect differences in economic intensity (SUPPLEMENTARY TABLE 1) [114] . Expert Rev. Pharmacoeconomics Outcomes Res. 10(6), (2010) Comparing policies to enhance prescribing eficiency in Europe Research Report Table 7. Inluence of supply and demand measures on prescribing eficiency between 2001 and 2007 among selected Western European countries. Country Class Utilization 2007 vs 2001 Expenditure 2007 vs 2001 €/1000 inhabitants/year in 2007 Austria PPI ↑ 3.6-fold ↑ 2.1-fold €19,299 Statins ↑ 2.4-fold ↓ 3% €9555 Germany PPI ↑ 3.2-fold ↑ 1.4-fold €13,864 Statins ↑ 2.1-fold ↓ 54% €6833 France† PPI ↑ 2.1-fold ↑ 38% €15,194 Statins ↑ 72% ↑ 19% €14,896 Great Britain – England PPI ↑ 2.3-fold ↓ 38% €6186 Statins ↑ 5.1-fold ↑ 20% €13,439 Republic of Ireland PPI ↑ 2.4-fold ↑ 2.6-fold Over €60,000 Statins ↑ 7.1-fold ↑ 4.9-fold Over €60,000 PPI ↑ 42% ↓ 48% €5832 Statins ↑ 2.5-fold ↓ 51% €5192 Sweden † In France there can be co-pays up to 35% for each class (SUPPLEMENTARY TABLE 1). In the Republic of Ireland, the General Medical Services population is highly selected with greater morbidity than the general population. PPI: Proton pump inhibitor. This again will be explored further in future papers. Overall, this accelerated the prescribing of generic simvastatin [58] . This is also combination of intensive demand-side measures together with seen when comparing the differences in subsequent utilization of measures to lower generic prices does enhance PPI and statin pre- omeprazole and esomeprazole in Austria, where there is currently scribing eficiency (TABLE 7), as seen when comparing expenditure no prior authorization for the PPIs (SUPPLEMENTARY TABLE 1) [114] , with (€/1000 inhabitants/year) for the PPIs and statins in England changes in the utilization of simvastatin, atorvastatin and rosuvasand Sweden in 2007 and the statins in Austria and Germany tatin following the availability of generic omeprazole and simvaswith those of countries with fewer demand-side measures (TABLE 7 tatin, respectively (FIGURES 3 & 4, SUPPLEMENTARY TABLES 2 & 3) [114] , with both & SUPPLEMENTARY TABLE 1) [114] . In Turkey, expenditures for both the being subject to educational and economic measures. In Sweden, the PPIs and statins rose at a faster rate than utilization despite recent regions (counties) have introduced prescribing targets and inancial measures to lower generic prices [13], facilitated by currently lim- incentives in addition to educational activities to further enhance the ited demand-side initiatives (SUPPLEMENTARY TABLE 1) [114] . This dem- prescribing of generic PPIs and statins [9,61] . Recently, the national onstrates that increased prescribing eficiency can be achieved by reimbursement agency in Sweden (TLV) introduced prescribing combining initiatives to lower generic prices where possible with restrictions for atorvastatin [108] . This should further enhance the those to enhance generic utilization. We acknowledge this may prescribing of generic simvastatin, mirroring the situation when the well be dificult in practice given the complexities of changing TLV introduced prescribing restrictions for angiotensin receptor physician prescribing behavior. Prescribing eficiencies have also been Table 8. Impact of supply- and demand-side measures on prescribing seen among former Central and Eastern eficiency of PPIs and statins in former Central and former Eastern European countries, especially among European countries. the statins in Croatia and Poland (TABLE 8) , Class Increase in utilization Increase in helped by reference-price initiatives among Country expenditure both classes with typically only a limited 2.5-fold 1.5-fold number of demand-side measures in opera- EE (2007 vs 2004) PPI tion (SUPPLEMENTARY TABLE 1) [114] . However, the Statins 1.8-fold 18% extent of the prescribing eficiencies seen HR (2007 vs 2000) PPI 4.4-fold 2.9-fold in practice has been compromised by the Statins 8.3-fold 3.2-fold availability of generic omeprazole and simv32.2-fold 14.7-fold astatin, particularly before 2000 and 2001. LT (2007 vs 2000) PPI The impact of the various demand-side Statins 6.1-fold 1.9-fold initiatives in Western European countries SI (2007 vs 2001) PPI 4.1-fold 2.8-fold also appears to be additive. The prescribStatins 2.7-fold 26% ing restrictions introduced for atorvastatin EE: Estonia; HR: Croatia; LT: Lithuania; PPI: Proton pump inhibitor; SI: Slovenia. in Austria (SUPPLEMENTARY TABLE 1) [114] further www.expert-reviews.com 717 Research Report Godman, Shrank, Andersen et al. blockers (ARBs) [62] in addition to existing demand-side measures. This substantiates the indings in previous publications regarding the additive impact of demand-side measures [63,64] . It also endorses current health authority and health insurance company activities to introduce a range of measures over time. However, care may be needed if enforcement is undertaken without necessarily considering the impact on the utilization and expenditure of products in related classes. For example, the reimbursement change with atorvastatin in Germany (SUPPLEMENTARY TABLE 1) [114] resulted initially in appreciable expenditure for ezetimibe alone or in combination, as no originator companies were promoting statins (€192 million vs €480.5 million for the statins in 2007) [53] . This situation is now changing through further demand-side initiatives (SUPPLEMENTARY TABLE 1) [114] in view of the concerns with the effectiveness of ezetimibe in practice [53] . There has also been appreciable utilization and expenditure of ezetimibe in France (€139.6 million in 2008 among the salaried population; 8% of statin and ezetimibe utilization) with the propensity of French physicians to prescribe new drugs versus those in England (3% of total utilization of statins and ezetimibe) and Sweden (3% of total utilization of statins and ezetimibe), which further demonstrates the inluence of multiple interventions in helping counteract pharmaceutical company marketing activities. As discussed, we accept that there are limitations with the study design. In addition to those described, there has been no link between indications and actual doses prescribed in order to calculate prescribed daily doses (PDD) [65] . This is particularly important for the statins given the recent guidance advocating higher doses [66–68] . We also acknowledge that we did not include over-the-counter (OTC) or hospital sales when assessing utilization. However, we were more concerned with changes in utilization patterns in ambulatory care than absolute utilization levels. We are aware that there can be differences in utilization igures between information management system (IMS) and administrative databases, especially where there are high co-payments and/ or signiicant prescribing restrictions for the class [69] . We have seen this in practice [Kristina National Health Insurance Fund, Vilnius, Lithuania, Pers. Comm.] , building on previous studies with statins [69] . However, this should only have a limited impact when assessing changes in utilization patterns. Despite these limitations, we believe we have added to the paper by Ostoni and colleagues [50] by showing that different demand-side measures can be used in addition to academic detailing, benchmarking and auditing to further inluence prescribing. We have also seen countries learning from each other with, for example, the introduction of prescribing targets and inancial incentives in France and Spain (Catalonia), as well as the introduction of prescribing restrictions for atorvastatin and ARBs in Sweden following the challenge when reference pricing was introduced for single-source PPIs [3,9,24] , which is still being debated in the courts. Switching programs and prior authorization schemes for the statins are also being successfully introduced in Primary Care Trusts in the UK in line with national guidance [20] . Despite the outcome from the various initiatives to date (SUPPLEMENTARY TABLE 1) [114] , further measures are essential. The next stage of the research will be to try and develop a robust scoring system that can help predict the outcome of different demand-side intervention strategies alone or in combination at discrete time points following the availability of generics in a class. These will build on existing measures as well as on the tremendous variation currently seen following the different demand-side measures and their intensities among Western European countries (FIGURES 3 & 4, SUPPLEMENTARY TABLES 1–3) [114] . This should also help to address the shortcomings in the current literature highlighted by Ostoni and colleagues [50] . In conclusion, a number of demand-side initiatives have been introduced across Europe to try and limit the growth in pharmaceutical expenditure. These can be categorized under the ‘4 Es’, with different measures and their intensities appearing to have a considerable inluence on utilization patterns and overall prescribing eficiency. Multiple interventions appear to have a greater inluence than single interventions, building on previous indings. Further measures are essential, mandating European countries to continue learning from each other. This also includes successfully addressing tactics used by pharmaceutical companies to delay the entry of generics [103] , which is to the detriment of all key stakeholder groups as it compromises the funding of new innovative drugs. Acknowledgements The authors would like to acknowledge the help of INFARMED for the provision of NHS data for Portugal, and the NHS Information Centre in Leeds, Key issues • Supply- and demand-side reforms surrounding generics can play a key role with increasing prescribing eficiency for ambulatory care drugs. Both measures are essential to maximize eficiency. • Increased utilization of premium-priced single-sourced proton pump inhibitors and statins is seen in countries where there are currently limited demand-side reforms to counteract commercial pressures, for example, in France, Portugal, the Republic of Ireland and Turkey. Increased utilization of generic omeprazole and simvastatin, along with reductions or only limited increased utilization of esomeprazole or atorvastatin and rosuvastatin combined, is seen in countries with multiple demand-side measures. • The impact of the interventions appears to be additive with multiple demand-side interventions having a greater inluence with changing utilization than single measures, with the exception of prescribing restrictions (enforcement). This led to appreciable improvements in prescribing eficiency when coupled with initiatives to obtain low prices for generics. However, this is dificult to substantiate given the limitations of the study design. • Further reforms are essential across Europe to increase prescribing eficiency to avoid prohibitive increases in either taxation or health insurance premiums to continue funding comprehensive and equitable healthcare. Countries are learning from each other but this will need to accelerate. 718 Expert Rev. Pharmacoeconomics Outcomes Res. 10(6), (2010) Comparing policies to enhance prescribing eficiency in Europe UK, for the provision of the data for England. They also acknowledge Fredrik Granath from the Karolinska Institutet, Stockholm, Sweden, for his helpful advice regarding statistical analyses. This study was in part supported by grants from the Karolinska Institutet. 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Supplementary Tables www.expert-reviews.com/toc/erp/10/6 20156 Milan, Italy Tel.: +39 023 901 4314 Fax: +39 023 546 277 godman@marionegri.it and Prescribing Research Group, University of Liverpool Management School, Liverpool, UK and Karolinska Institutet, Karolinska University, Hospital Huddinge, Stockholm, Sweden Slovenia Afiliations • Brian Godman Institute for Pharmacological Research ‘Mario Negri’, Via Giuseppe La Masa 19, 721 Research Report Godman, Shrank, Andersen et al. Health Evaluation & Research, National Association of Pharmacies (ANF), Lisbon, Portugal • • Lesley Tilson National Centre of Pharmacoeconomics in Ireland, Dublin, Ireland F Cankat Tulunay Medical School of Ankara University, Ankara, Turkey 722 • Vera Vlahović-Palčevski University Hospital, Rijeka, Croatia • Kamila Wendykowska HTA Consulting, Cracow, Poland • Björn Wettermark Karolinska Institutet, Karolinska University Hospital, Solna, Sweden and Medical Knowledge Centre, Stockholm County Council, Sweden • Corinne Zara Barcelona Health Region, Catalan Health Service, Barcelona, Spain • Lars L Gustafsson Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden Expert Rev. Pharmacoeconomics Outcomes Res. 10(6), (2010)