Pharmaceutical Policy Analysis – a European Perspective on Pricing and Reimbursement in Challenging Times

PHARMACEUTICAL POLICY ANALYSIS – A EUROPEAN PERSPECTIVE ON PRICING AND REIMBURSEMENT IN CHALLENGING TIMES

Christine Leopold The research presented in this PhD thesis was conducted under the umbrella of the Utrecht World Health Organization (WHO) Collaborating Centre for Pharmaceutical Policy and Regulation, which is based at the Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands. The Collaborating Centre aims to develop new methods for independent pharmaceutical policy research, evidence-based policy analysis and conceptual innovation in the area of policy making and evaluation in general.

The research in this thesis was performed in collaboration with the Gesundheit Österreich GmbH / Austrian Health Institute / WHO Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policy, Vienna, Austria.

Leopold, C. Pharmaceutical Policy Analysis – A European perspective on pricing and reimbursement in challenging times Thesis Utrecht University – with ref. – with summary in Dutch and German ISBN: 978-94-6182-363-2 Printed by: Off Page, www.offpage.nl Copyright © 2014 by C. Leopold. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior permission of the author. PHARMACEUTICAL POLICY ANALYSIS – A EUROPEAN PERSPECTIVE ON PRICING AND REIMBURSEMENT IN CHALLENGING TIMES

Prijzen en vergoeding van geneesmiddelen in een economische recessie - farmaceutisch beleid in perspectief (met een samenvatting in het Nederlands)

Analyse arzneimittelpolitischer Maßnahmen – ein Blick auf Europa in wirtschaftlich schwierigen Zeiten (mit einer Zusammenfassung in deutscher Sprache)

Proefschrift

ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op woensdag 8 januari 2014 des ochtends te 10.30 uur

door

Christine Leopold

geboren op 29 september 1979 te Wenen, Oostenrijk Promotores: Prof. dr. H.G.M. Leufkens Prof. dr. R.O. Laing

Co-promotores: Dr. A.K. Mantel-Teeuwisse Dr. S. Vogler TABLE OF CONTENTS

Chapter 1 General introduction 7

Chapter 2 External price referencing and its impact on medicine prices 21 2.1 Differences in external price referencing in Europe 23 - A descriptive overview 2.2 Impact of external price referencing on medicine prices 43 – a price comparison among 14 European countries 2.3 Is Europe still heading to a common price level for on-patent 59 medicines? An exploratory study among 15 Western European countries

Chapter 3 Re-evaluation and adjustment of pharmaceutical policies 75 in times of economic recession 3.1 Impact of the recession on the pharmaceutical policy 77 environment and medicines sales in eight European countries 3.2 Impact of pharmaceutical policy interventions on utilization 99 of antipsychotic medicines in Finland and Portugal: interrupted time series analyses

Chapter 4 Personalized medicine as a challenge for policy makers 115 4.1 Personalized medicine as a challenge for public pricing 117 and reimbursement authorities– a survey among 27 European countries (including Iceland and Norway) on the example of trastuzumab

Chapter 5 General discussion 135

Chapter 6 Summary, Samenvatting, and Zusammenfassung 153 6.1 Summary 155 6.2 Samenvatting 163 6.3 Zusammenfassung 171

Chapter 7 Addendum 179 7.1 Acknowledgements 181 7.2 List of co-authors 185 7.3 List of publications 189 7.4 About the author 195

CHAPTER

General introduction 1

1 General introduction 9 Thisthesis bodyisa ofwork belonging seriesato ofpharmaceutical policy analysis projects Although an increasing number of descriptions of national pharmaceutical systems were The The pharmaceutical policy environment is dynamic as new medicines are being developed Figure 1 [22-25]. The focus of this thesis is to understand pharmaceutical policies through lensthe of analyzing European pricing and reimbursement policies and their impacts. ofpublic authorities [20,21] became key references for research on pricing and reimbursement policies. However, as the pharmaceutical policy landscape is impact analysesrapidly are constantly needed.evolving, research and undertaken under the umbrella of the Utrecht WHO Collaborating Centre for Pharmaceutical Policy and Regulation, all focusing on different aspects of the policy cycle depicted in published in recent years to address the need for country specific information,evaluations ofanalyses the and impact of national pharmaceutical pricing and reimbursement policiesstill are rare [4-8]. Besides peer-reviewed articles, as reportsthe Organization by for Economic international Co-operation organizationsand Development such (OECD) [9-16], Health theOrganization World (WHO) [17], the European Commission [18-19] and networks of European at at the starting point and innovation; at of the research regulatory and policy making level; at the level of outcomes or finallyat the level of measuring the impact on public health, as illustrated in Figure 1. Policy analysis examines the intended and unintended impacts of policies or policy changes on various outcomes such as medicine prices, pharmaceutical expenditure, medicine population. a of rates mortality as such health public overall on eventually and utilization innovation [3]. Therefore, the question for policy makers is, given that resources will always be too too be always will resources that given is, makers policy for question the Therefore, [3]. innovation should policy pharmaceutical a of aspects which time, same the at problems all address to limited they prioritize to obtain the best public health for the lowest cost [4]. To ensure a sustainable environment governments are required to regularly monitor policies, implement new ones and readjust existing polices. For this reason pharmaceutical policy levels: different at analysis changes policy and policies aims implemented these of performance at the and effects assessing the However, policy However, making is also shaped by the diverse interests and power of other stakeholders [2]. industry payers, patients and pharmacists, regulators, prescribers, as such system the in and differentmedical Tensionsneeds are especiallyarise. noticeable with respect to pricing and equitable maintain necessaryto as view may plans care health what medicines; of reimbursement access to medicines, industry may view as inimical to research and development (R&D) and Member States, policy makers are taking their decisions within a framework of legal regulations at national and European level. They have to relate to the political and social country, context while of at their the same time consider European and international developments. Within a national pharmaceutical system policy makers have many different policychoices, for example policies targeting at regulating prices, reimbursement limits and rational use of medicines. BACKGROUND stakeholders, different many with framework a in embedded are policies pharmaceutical National differentlevels of legal requirements and different national policy objectives such as ensuring public affordability of health care while rewarding innovation [1,2]. In European Union (EU)

: In Europe reimbursable medicines medicines reimbursable Europe In : Regulation / policy making Research / innovationResearch / al Policy and Regulation, Utrecht Institute for Source: WHO Collaborating Centre for Pharmaceutical Policy and

Even though marketing authorization is harmonized in is through Europe harmonized authorization Even though marketing Usage / outcomes Public healthPublic / therapeutic needs Cost-containment and ensuring of sustainable public funds public sustainable of ensuring and Cost-containment Access to medicines: Access to medicines: to pricing and reimbursement of medicines to guarantee public funding of needed medicines. In the the In medicines. needed of funding public guarantee to medicines of reimbursement and pricing to forcing recession, economic an from suffering been have countries European several years five last [29-31]. healthcare including sectors many in spending public cut to countries these of many 10 influence the prices in other countries due to policies such as external price referencing [28]. referencing price external as such policies to due countries other in prices the influence – partially or fully either – for paid are market) the on medicines of majority the for account (which Hence, institutions. insurance health social or services health national as such payers party third by respect with framework policy pharmaceutical their adjusting continuously are countries European the implementation the of implementation the to access European in Medicine Agency discrepancies (EMA) [27], and efficacy and EU safety legislation on quality, marketing medicine’s a of basis the on authorization which process, reimbursement and pricing the during delays include Reasons appear. still medicines behavior or strategic of companies documentation or by insufficient can by be authorities caused of after the companies is on decision as and taken, pricing reimbursement prices in one country ranges from 9.4% in New Zealand to 16.6% in Canada in 2011 [26]. These variations in pharmaceutical pharmaceutical in variations These [26]. 2011 in Canada in 16.6% to Zealand New in 9.4% from ranges a within acting are They makers. policy national by made decisions by explained be can expenditure ensuring and resources public available of limits the within medicines to access granting of triangle within pillars three the of Each innovation. rewarding time same the at and funding wealth in as such sustainability situations national take to need who makers policy for challenges creates triangle this account: into developments historical and cultural as well as climate political the country, a of AND IN EUROPE of for proportion accounted a total In expenditure the considerable last decades pharmaceutical expenditure care health total of percentages These worldwide. and Europe in spending care health varied to a great extent among countries ranging from 6.8% in Norway to 28.5% in Greece and in Hungary in 33.4% from other examples 2011; of high outside income countries showed Europe Figure 1. Pharmaceutical Policy Analysis. Regulation, Utrecht Institute for Pharmaceutical Sciences, Utrecht University THE PHARMACEUTICAL POLICY LANDSCAPE GLOBALLY Pharmaceutical Sciences, Utrecht University Pharmaceutical Sciences, Utrecht Source: Source: WHO Collaborating Centre for Pharmaceutic

1 General introduction 1 General introduction 11 a commitment [38]. A national medicine policy shall aim to ensure access The pharmaceutical industry is an important player in European countries, countries, European in player important an is industry pharmaceutical The To To account for the described challenges within the triangle and the market failures the Besides these challenges, two additional factors play an important role in the complex During the last decades European countries implemented a variety of pricing and reimbursementandpricing of variety implementedcountriesa Europeandecades last the During policies, primarily to improve a more rationalto target use both and the affordabilityprice ofof medicines.a medicine In(supply order side) and prescribed volume of a medicine effective use of medicines by health professionals and consumers) [38]. PHARMACEUTICAL POLICY ANALYSIS THROUGH THE LENS OF PRICING AND REIMBURSEMENT set by the government for the pharmaceutical sector, and identifiesattainingthem.providesItframework a within thewhich activitiesthe pharmaceuticaltheof mainsector strategies for can be coordinated. It covers both the public and the private sectors, and involves all the main actors in the pharmaceutical field’ (equitable availability and affordability of essential medicines), quality (the quality, safety and efficacy of all medicines), and rational use (thepromotion of therapeutically sound and cost- to over-consume because they do not directly bear the cost of consumption; underinvestmentand forfinally particular diseases the [35-37]. WHO has been encouraging countriesregulations and policies. to A national medicine developpolicy is defined by the a WHO as ‘ national to a goal medicineand a guide for policyaction. It expresses includingand prioritizes the medium- to long-term goals dispensersprescribetodispense or certain brandedmedicines insteadlowerof priced generics profits; increaseimperfectowntheirto competition patented monopolisticmedicines as a have position and product proliferation does not automatically induce competition; inelasticitydemand as medicinesof are not commodity products because the patient will pay whatever s/he haswhento s/he gets sick; market failures because moralofa hazard asconsumers inclinedare highly specialized treatment options, such as medicines which require prior genetic testing as is the case for personalized medicines, are now becoming more widely available [34]. Second, the common rules of a free market do not apply to the pharmaceutical market – as for health care in general – because information asymmetriesasymmetries and between market prescribers, failures dispensers exist: and information consumers efficacy regarding the and quality, value safety, for money of individual medicines, which could allow prescribers and obligation to guarantee public affordability of medicines. This becomes evident when it comes to comes it when evident becomes This medicines. of affordability public guarantee to obligation [32,33]. value added major provides that medicine a of price “premium” a granting of question the pharmaceutical policy environment. First, the demand for medicines is rising in Europe in the last years due to the demographic shift associated with the ageingpeople often sufferof from multiplethe diseasespopulation. demanding numerous medicines.Older In addition, more Reward for innovation: innovation: for Reward not only as a supplier innovation. for reward the in factors or critical be can policies reimbursement and Pricing employer. distributor of (new) medicines but also This as objective of knowledge reward economy for innovation can be potentially conflicting with the governments’ the [43]. However, an up-to-date description of the differences in EPR Besides regulating the ex-factory price, policy makers may also regulate distribution margins margins distribution regulate may policy also makers price, Besidesthe ex-factory regulating When regulating medicine prices which all EU Member States do at least for reimbursable In In many countries worldwide there is a distinction between the public sector where distribution margins – as one way to control public spending. Analyzing the impact of these price price these of impact the Analyzing spending. public control to way one as – margins distribution of medicines. affordability of accessibility affected it whether understand important is to cuts 12 for for wholesalers and pharmacies. While the wholesale majority mark-ups, all EU of Member States EU regulate pharmacy margins, Member usually in States the form apply of regressive schemes or linear statutory mark-ups. Finally, European policy makers may apply value-added taxes (VAT) to medicines at very different rates and sometimes even differentiating reimbursable between and non-reimbursable medicines During [44,45]. the recent economic recession many countries implemented price cuts – either targeting at the ex-factory price level or at the practice of using the price(s) of a medicine in one benchmarkor several or countries reference in orderprice to for derive the a purposes product of in a given country’setting or negotiation the price of methodologiesthe in Europe and the impact of this pricing policy on medicine prices as well as its possible implication on price convergence has not been studied before. the third party payer (= reimbursable medicines). Free or market-based pricing is only applied to party or medicines). payer market-based the (= Free third reimbursable medicines[17,20]. over-the-counter often are which medicines, non-reimbursable medicines many countries apply external price referencing (EPR) [20]. EPRWHO is Collaboratingdefined by Centrethe for Pharmaceutical Pricing and Reimbursement Policies as ‘ private sector, where free or market-based pricing of medicines is common [9,17,37]. In many high high many In [9,17,37]. common is medicines of pricing market-based or free where sector, private income European countries such as the EU Member States this distinction between public channels private and through supplied often are medicines Although clear. always not is sector private they are to a great extent publicly funded through extensive insurance coverage (either social health insurance or national health services, so-called third party payers). they Therefore, often of cost the at dispensed are that medicines for negations price or regulations price medicine have medicines, for example those on the essential medicines list, are purchased and distributed by the state – often free of charge, and the private sector where medicines are handled by private and low e.g. countries, these of Many pocket. out-of fully purchased be to required are and actors middle income countries like India, Pakistan, Egypt, South Africa and China, have a rather small meaning public that sector, patients have to buy the majority of medicines out-of-pocket in the authorization at the EU-level, designing a pharmaceutical pricing and reimbursementis still a policynational competence of each EU Member State, provided that each country complies with the rules such as the EU Transparency Directiveprovidecommona procedural framework forpricing and(Councilreimbursement decisions withregard Directive 89/105/EEC) which to time-lines and how decision should be communicated [41,42]. (demand side), policy makers can choose from a regulatingvariety prices of or reimbursementsupply limitsside of medicinesmeasures and includingdemand side measures aiming at limiting prescribing behaviors of doctors by implementing prescribing budgets [17,20,39,40]. Importanthighlightto inthis context isthat, incontrast harmonizedto processes ofmarketing

1 General introduction 1 General introduction 13 in July 2013 1 a third party payer determines [43]. Studying the impact of the implementation of such a system on the use of All of the above mentioned policies are primarily relevant for reimbursable medicines Besides the focus on regulating prices as well as limiting reimbursement, countries also choose choose also countries reimbursement, limiting as well as prices regulating on focus the Besides Studies which analyze the impact of pharmaceutical policies usually focus on reimbursable EU-28 = EU-27 countries plus Croatia (since 1 July 2013).

1 compared to 8.5% in 2001; with the lowest rate of 4.8% in Austria compared to Greece (27.6%) and Spain (26.3%) having the highest rate in July 2013 [57]. In terms of gross domestic product (GDP) the EU-27 countries had a GDP growth rate of +3.2% negativedownain to growth -4.3%,of recovering[58].2007, TheseJulyin developmentswhereas2009+0.1% to in 2009 it went have forced EU Member States to implement containmeasures costs which might fornegatively impact accessibilitybudget and affordability. savings and policies to IMPACT OF ECONOMIC RECESSION ON PUBLIC AFFORDABILITY OF MEDICINE CONSUMPTION Since the crash of the housing market in USA at the end the of world 2007, has been struggling with an economic recession [55,56]. Europe has faced difficulties in recoveringfrom the crisis in 2007 and was confronted with an unemployment rate of up to 12.1% for EU-28 the scope of different funding bodies. Nowadays, policy makers arerecognizing theadjust needpricingto and reimbursement policies to face these new circumstances.a researchHence, gapthere in is the assessment of the pricing and reimbursement personalizedmechanisms medicines atapplied the interface offor the hospital and out-patient sector. dispensed in the out-patient sector. Reimbursementout-patientdispensedmedicinesthesector. ofindispensed hospital settings in differs from the out-patient setting – funding is mainly through hospital budgetshealthcare or regional budgets – and different pricing medicines, andsuchpersonalizedas medicines paymentdefined– the as treatment plan based molecularon policies are applied [52].screening Certain and prior genetic testing that define whichregime will be most effective in specific patients [53,54] – are often used at the interface of those two sectors. Hence, they fall under to to implement measures related to the rational use of prescribing, generic medicines. e.g. and dispensaries, other Most and pharmacies at prescribers target Especially of regulations these [49-51]. doctors demand for side budgets prescribing and guidelines prescriptions substitution, generic generic policies were among the many policy options which medicines. were on implemented or spending adjusted public by control to recession economic the during makers policy MemberStates. Oneofthe very commonly used cost-containment reimbursement policies isa therapeutic reference price system [46-48], which is defined as ‘ a maximum price (=reference price) to be reimbursed for certain pharmaceuticals in an ATC 4 or 5 group’ ATC medicines is an example of a policy outcome analysis (see Figure 1). medicines as the vast majority of medicines in Europe are whichincluded is in anational list positive of lists, medicines that may be prescribedAgain manyat differentthe expensepolicies ofwith respect the thirdto reimbursement party payer. are applied in the different EU

chapter 2.1 Chapter 3.2 . chapter 2.3 explores how national medicine prices may be affected analyses which pharmaceutical pricing and reimbursement Chapter 2.2 Chapter 3.1 Chapter 3 focuses on how countries re-evaluate and adjust national policies in times of Only a few studies have been published which looked at the impact of the recent financial In In times of economic recession policy makers are confronted with four main challenges: 1) evaluates the correlation with medicines presents a detailed sales evaluation of the inimpact of different eightpolicy measures on the European consumption of antipsychotic countries. medicines in Portugal and Finland during the time of the economic recession. 14 overall medicine price level in European countries and whetherconvergence across Europethese is addressed in policies lead to price economic recession. policies were implemented by countries during the time of the economic recession and THESIS OUTLINE AND OVERVIEW Chapter2 addresses the question as to how national pharmaceutical policies aim at controlling public pharmaceutical spending by regulatinggives a medicinedescriptive overview prices. of one In of the particular, most external pricecommonly referencing. used pricing policies in Europe: by policies such as external price referencing. The aspect of how national policies affect the andtheir impact on medicines prices and consumption in Europe. The underlying basis for this thesis is pricing and reimbursement policy data in European countries, which are analyzeddescriptive asin well as through statistical methods by evaluating the impact of these policies on medicine prices and consumption, especially during the economic recession. in pharmaceutical consumption or medicine prices is crucial for policy makers to understandwhether public affordability and accessibilityto medicines is still guaranteed. GOALS AND OBJECTIVES OF THIS THESIS The goal of this thesis is to understand pharmaceutical pricing and reimbursement policies healthcare services as they cannot afford to pay for the services or the out-of-pocket costs [59]. [59]. costs out-of-pocket the or services the for pay to afford cannot they as services healthcare crisis on global health and in particular on pharmaceutical consumption [60-64], showing that pharmaceutical consumption went down especially in the Baltic countries and that Europeancountries had to implement a variety of pricing andreduced reimbursementpublic policiesbudgets. inInvestigating response the to impact of these policy changes and the declines may require more, not fewer resources (to address the adverse health effects of unemployment), 3) unemployment), of effects health adverse the address (to resources fewer not more, require may financial if erode they system health the destabilize further may services essential to cuts arbitrary longer the in costs increasing provided, care of quality the and care to access equitable protection, term. In cutsto addition new acrossthe introducing inefficiencies, boardare to unlikely address the exacerbating potentially existing fiscalinefficiencies, and constraint; patients 4) especially – vulnerable groups such as older people or low-income people – may refrain from demanding predictability of public funding for health care services as sudden interruptions to of revenue public for funding public as care health services interruptions sudden predictability spending public to cuts 2) care, health of level previous the maintain to difficult it make can streams at come a typically time when a shock to system an health on made in economic health response

1 General introduction 1 General introduction 15 ) of this thesis contains a general discussion of the chapter 5 looks into how European pricing and reimbursement authorities deal chapter chapter 4.1 The concluding chapter ( In In Europe, there is an increasing use of personalized medicines which require prior genetic included both new and often expensive medicines as well as medical devices such as diagnostics. diagnostics. as such devicesmedical as well as medicines expensive often newbothand included benefits and limitations of research oninterventions. pharmaceutical In pricing specific, and reimbursement methodological policy describedpolicytheand challenges implications studyalloffindings presented. are areas Finally, futurefor of comparing medicinesresearch prices are identified which could improve access are and affordability of medicines. testing which entail new challenges to policy makers with respect to pricing and reimbursement. reimbursement. and pricing to respect with makers policy to newchallenges entail which testing In specific, with the increasing challenge of how to evaluate and assess these ‘treatment packages’ which . . http://www. http://ec.europa. http://www.oecd-ilibrary. . Accessed. April202013. Accessed 20 June 2013. 2013. June 20 Accessed : http://whocc.goeg.at/Publications/ : . . Vogler S, Habl C, Leopold C, Rosian-Schikuta I, S, de Habl Vogler C, C, Leopold Rosian-Schikuta Joncheere K, Lyager Thomsen T. Pharmaceutical Pricing and Consumer and Reimbursement Health DG Information (PPRI): Luxembourg. report. final Protection of the European Commission. 2007; from Available BooksReports Paris V, Docteur E. Pharmaceutical Pricing Reimbursementand PoliciesCanada. inHealthOECD 24. No.2006. WorkingPaper. Paris V, Docteur E. Pharmaceutical Pricing Reimbursementand Policies in Switzerland”, OECD 27. No. Health2007. WorkingPaper. Paris V, Docteur E. Pharmaceutical Pricing Reimbursementand Policies in Health31.2008.WorkingNo. Paper. Germany. OECD Kaplan W, Writz VJ, Mantel-Teuwisse A, Stolk P, Duthey B, Laing R. Priority Medicines Report for UpdateWorldEuropetheHealthand2013.World Organization. 2013. Available from: who.int/medicines/areas/priority_medicines/ MasterDocJune28_FINAL_Web.pdf.Accessed 20 August2013 European CommissionPharmaceutical sector DG Brussels,Available 2009. from: inquiry final Competition. eu/competition/sectors/pharmaceuticals/ report. inquiry/staff_working_paper_part1.pdfAccessed20May 2013. High Level Pharmaceutical Forum. HighPharmaceutical LevelForum 2005-2008. Conclusions and Recommendations. European Commission DG Health & Consumers 2008. Available from:http://ec.europa.eu/enterprise/sectors/ healthcare/competitiveness/pharmaceutical-forum/index_en.htm Paris V, Belloni Pricing. OECD A. Health Working Paper. Value 2013. No. in 63. Pharmaceutical Available from: org/social-issues-migration-health/value-in-pharmaceutical-pricing_5k43jc9v6knx-enAccessedAugust2013. 14 on Kaló Z, Docteur Pricing E, and Reimbursement MoïsePolicies in Slovakia. P. Pharmaceutical31. No. OECDHealth2007. Working Paper. Moïse P, Docteur E. Pharmaceutical Pricing and ReimbursementPolicies Mexico.in OECD Health 25.No. WorkingPaper.2007. Moïse P, Docteur E. Pharmaceutical Pricing and HealthReimbursementSweden.OECD Policiesin 28. No. 2007. WorkingPaper.

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63. 62.

CHAPTER

External price referencing and its impact on medicine prices 2

CHAPTER

Differences in external price referencing in Europe - A descriptive overview 2.1 Health Policy. 2012;104(1):50-60

Christine Leopold, Sabine Vogler, Aukje Mantel-Teeuwisse, Kees de Joncheere, Bert Leufkens, Richard Laing EPR is a widely used pricing policy in Europe and is still actively used as well as This study aimed to provide an up-to-date analysis as well provide as description aimedcomparative study This to

: Review of the country-specific PPRI (Pharmaceutical Pricing and Reimbursement Of 28 analysed European countries 24 applied EPR in 2010. The majority of countries

24 including discussions on possible limitations of these pricing methods. adjustedbynational authorities. However, we still see room for improvement byimplementing more detailed legislations in terms of thecountries in case revision a product is ofnot on the market. prices We also see and the need for by formal information identifying sharing (e.g. congresses dedicated alternative to pricing strategies and systems) with other public pricing authorities to learn about the different EPR methodologies as well as the national experiences. These congresses might also give room to better understand national pricing methods basket, whereas lower-income countries refer to lower-income countries. Taking the average price of all countries in the basket as the basis common to strategycalculate (n=8).the The national methodologyprice ofwas EPRthe hasmost changed over inthe past 10 yearsmost (n=19). European countries Conclusions: Methods Information) Pharma Profiles written byrepresentatives of the PPRI Network. The Profiles were analysed according to predefined criteria. Results: have statutory rules to implement EPR. Most reference baskets.countries Higher-income countrieshad tend to includeless higher-incomethan countries in 10 their countries in their ABSTRACT Objective: Europe. in (EPR) referencing price external pharmaceutical of characteristics national the of

Differences in external price referencing in Europe - A descriptive overview 2.1 Differences in external price referencing in Europe - A descriptive overview 2.1 25 [11]. [10]. Most research studies Mostin the fieldresearch of pharmaceutical policy analysispricing describe different Pharmaceutical price regulations can occur at various points along the distribution chain, In In the early nineties, most governments in Europe decided to implement a mix of different Another relevant aspect to consider is that market dynamics in the pharmaceutical markets National governments take different interests into consideration when shaping a national as well as volume regulations and analyse their impact on pharmaceutical expenditure (e.g. Mrazek Mrazek (e.g. expenditure pharmaceutical on impact their analyse and regulations volume as well as cuts/freezes. External price referencing refers to prices of otherprice countriesreferencing (or whereas also internalreferred to as national reference pricing) pricesis ofa medicinesmethod in to a countrycompare with the price of identical pharmaceutical or similarlevel or producteven with therapeutic equivalent treatment (not necessarily a medicine) in a country). Other measures have taken a regulatingprofits more or calculating“cost-effective” prices indirectusing pharmaco-economic analysis approach to regulating medicine prices by mix mix of pricing and volume-control polices [9]. Otherwise it would lead to a so called “pendulum adjust players market as diminish would effects cost-saving desired the that meaning effect”, from manufacturer to wholesaler to pharmacists and patient. indirect.directpricebeormay Measures directforpricesettingRegulations include negotiations, statutory of the ex-factory pricing – either through external price referencing or internal price comparisons - and price pharmaceutical pharmaceutical policies which aimed at containing public spending while stimulating research controlling either on focused policies These development. industrial and (R&D) development and medicine prices on and/or containing the prescribed volume of medicines or both. Until today, there is still no agreement as to which policies or However, time interventions has are shown that perceived it as is successful. crucial to regularly adjust these policies and to have a fair prescribers decide which medicine the patient should take). In addition supply is characterised by a market with imperfect competition (pharmaceutical companies and significantdistributors amount of markethave power). This situationa requires that the state intervenes eitherto promote competition or to implement regulations to prevent exploitation of sick patients who may be willing to pay excessive amounts for an unreasonable hope of cure [5-8]. industry policy, by offeringrelatively high ex-factory prices or other concessions intendedto incentivise or reward the domestic pharmaceutical industry [2-4]. characterised medicines is for demand products. consumer Market for markets other from differ by low price sensitivity (as reimbursable medicines are paid to Payers)and arelatively high level of asymmetric ainformation between patient and prescriber large (as extent by Third-Party affordable accessto medicines within their limited publicresources. pharmaceuticalpayersNotably,underpolicy. arepressure citizens from otherand stakeholders to promote public health and to ensure prompt access to the sameaffordable time medicalthere is treatment.also pressure At for some countries to serve the objectives of a national INTRODUCTION AllEuropean countries havedifferent national pharmaceutical systemshistoric,to due political, legal and economic developments but also due to the ways in iswhich fundedthe health[1]. care These system countries all face the same challenge of guaranteeing their populations [12]. , latest access The PPRI network

[8]. EPR is howeveris[8].policyEPR a http://ppri.goeg.at This study will provide policy makers and . 4 [9]. As a consequence price changes in one country influence 3 and South Africa 2 , Brazil 1 In In order to analyse and understand pricing policy trends in Europe, attention needs to be Only a few studies have described the detailed characteristics of one particularly widely 25 February 2011 Pharmaceutical Pricing and Reimbursement Information, available online Brazil refers to among other countries Portugal, Spain, France, Italy, and Greece United Kingdom, Belgium, Italy, Spain and Portugal South Africa refers to among other countries Spain; and Lebanon refer to among other countries France, Jordan refers to among other countries United Kingdom, France, Spain, Italy, Belgium, Greece and the Netherlands the and Greece Belgium, Italy, Spain, France, Kingdom, United countries other among to refers Jordan

4 26 responsible for pricing and reimbursement 1 2 3 for public authorities in pricing and reimbursement in Europe. networkWithincountry-specific reports,the PPRI Pharma Profiles,scope nationalon pricing reimbursement and of the PPRI systems of the European Member States as well as associated countries were approachpublished. This of collecting information is unique representativesof public asauthorities, such as Ministries theof Health or third party payers, who PPRIare Pharma Profiles were written by in Europe and will discuss whether this tool is still appropriate for all countries and in which ways. which in and countries all for appropriate still is tool this whether discuss will and Europe in MATERIALS AND METHODS The main source of data was information published by started the as an PPRIEU-funded projectnetwork. from 2005 until 2007 and continues as a sustainable network differencesand commonalities of EPR in all 27 European Union (EU) MemberStates plus Norway by describing and analysing the different methodologies taking into account the of EPR, distribution countries, the price calculation methodology geographic and any changes the reference in the EPR methodology over time. In this study only the out-patient sector is analysed and no comparison of impact on prices has been attempted. EPR tool policy pricing the on picture up-to-date an policy pharmaceutical of field the in scientists Jordan pricesinother countries worldwide. Stargardt showed inhisstudy thatmarginal a price change in Germany led to price changes in countries that have Germany in the country basket [13]. given to the different characteristics of each single pricing policy. many This countries use needs a combination to of methods. be The objective of done this study as was to examine the price benchmark/comparison). EPR is defined by theReimbursement European Information (PPRI) Pharmaceutical glossary as “the practice of Pricing using the price(s) of a medicine and in one or several countries in order to derive a benchmark or reference price for the purposes settingofnegotiatingor given country”productthepriceathe ofin that is applied by countries worldwide and often European countriescountries. are Examples taken of as countriesreference which use European country prices as reference prices are (2002) (2002) aimed in her study to review pharmaceutical pricing policies in Europe to understand the outcomes) actual of evidence and expenditures pharmaceutical on regulations of impact used pricing policy, namely external price referencing (EPR also referred to as international

Differences in external price referencing in Europe - A descriptive overview 2.1 Differences in external price referencing in Europe - A descriptive overview 2.1 27 the the ) for 2009. 5 Hungary for instance instance for Hungary

http://epp.eurostat.ec.europa.eu/portal/page/portal/ ; latest access 25 February 2011 Calculationmethod of the reference price (package size, frequency of updating of prices, what price level is taken: manufacturer, wholesale, pharmacy) Changes in the EPR methodologies over time Coverage of patent protected medicines or also including generics Existence of external price referencing National legal framework Composition of country basket Other countries use EPR within the reimbursement system by setting the price, which might be might which price, the setting by system reimbursement the within EPR use countries Other In order to best describe the EPR systems in Europe, the basic principles of the EPR system, As the PPRI Pharma Profilesreferred to the years 2007 and 2008, furtherresearch was health/introduction EUROSTAT EUROSTAT public health database, available online

5 determined at manufacturer, wholesale or pharmacy level (see also Table 1). Table also (see level pharmacy or wholesale manufacturer, at determined stated: The manufacturer price of a newly included preparation containing active ingredient(s) that is not yet reimbursed cannot be higher than the lowest of the existing manufacturer prices Greece, Spain, Portugal, Italy, in Germany, the countries in listed Ireland, the application (France, country). additional one and Austria Belgium, Slovakia, Republic,Czech Slovenia, Poland, price in other countries of the European Economic Area is only one criterion among many others, others, many among is one criterion only Area Economic of the European countries in other price when considered are that funds on available impact and costs, R&D volume, sales as expected such for pricing EPR that is the criterion stated sole Cyprus price. wholesale 1). the “reasonable” Table approving (see products (OTC) over-the-counter including products pharmaceutical imported all of RESULTS Existence of EPRprices, inmedicine the national EU andsetting NorwayDenmark, When Norway). plus (23 out of States the 27 EU Member in countries 2010. 24 in EPR was implemented EPR use not did Kingdom United and Sweden Germany, In Belgium, 1). Figure (see information or as supportive Finland, In criterion main as the applied either was EPR assessments. economic include criteria other criteria, pricing many of one just was EPR were ranked by gross domestic product (GDP) per capita as provided by EUROSTAT Then the average rank of all reference countriesbetweencapita rankandGDP/per the average rankofthe reference countries inthe inbasket was the basket was calculated. Correlation assessed using Kendall’s rank correlation tau (a measure for ranked data). • • • measureTo whether countries referenced other countries of similar economic level, countries which are the most commonly occurring elements, were taken for the analysis. The following principles were chosen: • • • required to obtain the most recent communication information with members of the available.PPRI network. The information This on EPR presented is was what done throughwas available as of November written 2010.

n.a. n.a. n.a. n.a. n.a. n.a. 2010 2005 2005 2007 2009 2006 method 2011 plans plans 2011 no change no change no change no change 2005, 2010 2005, 2010 calculation 2000, 2010 2005, 2008, various times 2009, plans for 2011 for plans 2009,

n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. 2010 2005 2005 2005 2003 2007 Changes in EPR methods 2009 2009 2006 no change no change no change various times country basket abolishment of EPR in 2005 in EPR of abolishment abolishment of EPR in 2002 in EPR of abolishment

calculation not defined not defined 3 lowest price 3 lowest prices transport costs Ø of all countries Ø of all countries Ø of all countries Ø of all countries Ø of all countries Ø of all countries Ø of all countries the price +in EE LT Ø of the 3 countries http://ppri.goeg.at lowest price per basket lowest price per basket lowest price per basket lowest price per basket prices in reference countries reference in prices Prices “similar” to those in the RO, SE, DE, DK, SI, SK, CZ, HU, EE HU, CZ, SK, SI, DK, DE, SE, RO, Ø of the 4 lowest plus 3% to cover reference countries (DE, ES, UK) IT, with 95% of the average manufacturer manufacturer average the of 95% with 95% of the average of the 3 countries AT, EL, CY, LV, LI, LU, MT, NO, PT, PL, FR,PL, PT, NO, MT, LU, LI, LV, CY, EL, AT, of the prices in EEA countries according according countries EEA in prices the of Ø of the 6 lowest countries in the basket the in countries lowest 6 the of Ø Third lowest price and not higher than Checking of the price level and the range range the and level price the of Checking to this ranking: NL, BE, BG, ES IE, IS, UK, IT IT UK, IS, IE, ES BG, BE, NL, ranking: this to Declared manufacturer price is compared compared is price manufacturer Declared Calculation of reference price

ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory price basis pharmacy retail pharmacy retail pharmacy retail pharmacy purchase pharmacy purchase pharmacy purchase pharmacy purchase Pharmacy retail, ex factory ex retail, Pharmacy Source of GDP: EUROSTAT, http://epp.eurostat.ec.europa.eu/portal/page/portal/health/introduction EUROSTAT, GDP: of Source GDP = gross domestic product, HU = Hungary, IE = Ireland, IT = Italy, LT = Lithuania, LU = Luxembourg, LV = Latvia, MT = MT = Latvia, LV = Luxembourg, LU = Lithuania, LT = IT Italy, = IE Ireland, = HU Hungary, product, domestic = gross GDP = SI Sweden, = SE Portugal, = PT medicine, prescription-only = POM Poland, = PL Norway, = NO Netherlands, = NL Malta, Kingdom United = UK reimbursable, = reimb. Slovakia, = SK Slovenia, Source for abbreviations: http://publications.europa.eu/code/en/en-370100.htm Source about external referencing:

5 7 8 9 11 15 15 15 15 17 12 21 19 19 19 18 14 14 10 22 20 in basket Ø rank of countries 1 3 5 7 2 8 9 6 4 11 13 15 17 12 21 19 18 16 14 27 23 25 10 22 28 26 24 20 (GDP 2009) income rank

GDP Composition of basket 15300 17200 12200 22100 14300 19200 12900 15000 18900 23200 27400 27400 29300 24300 26500 19000 10900 25400 20700 29800 (2009) 26600 28400 24400 30800 28000 42000 64000 1 3

2 8 9 6 9 9 4 4 4 4 4 17 12 16 14 22 26 24 24 in basket not defined not defined # of countries

Differences in external price referencing in Europe - A descriptive overview 2.1 Differences in external price referencing in Europe - A descriptive overview 2.1

n.a. n.a. n.a. n.a. n.a. n.a. 2010 2005 2005 2007 2006 2009 method 2011 plans plans 2011 no change no change no change no change 2005, 2010 2005, 2010 calculation 2000, 2010 2005, 2008, various times 2009, plans for 2011 for plans 2009,

n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. 2010 2003 2005 2005 2005 2007 Changes in EPR methods 2006 2009 2009 no change no change no change various times country basket abolishment of EPR in 2005 in EPR of abolishment abolishment of EPR in 2002 in EPR of abolishment

calculation not defined not defined 3 lowest price 3 lowest prices transport costs Ø of all countries Ø of all countries Ø of all countries Ø of all countries Ø of all countries Ø of all countries Ø of all countries the price +in EE LT Ø of the 3 countries http://ppri.goeg.at lowest price per basket lowest price per basket lowest price per basket lowest price per basket prices in reference countries reference in prices Prices “similar” to those in the RO, SE, DE, DK, SI, SK, CZ, HU, EE HU, CZ, SK, SI, DK, DE, SE, RO, Ø of the 4 lowest plus 3% to cover reference countries (DE, ES, UK) IT, with 95% of the average manufacturer manufacturer average the of 95% with 95% of the average of the 3 countries AT, EL, CY, LV, LI, LU, MT, NO, PT, PL, FR, PL, PT, NO, MT, LU, LI, LV, CY, EL, AT, of the prices in EEA countries according according countries EEA in prices the of Ø of the 6 lowest countries in the basket the in countries lowest 6 the of Ø Third lowest price and not higher than Checking of the price level and the range range the and level price the of Checking to this ranking: NL, BE, BG, ES IE, IS, UK, IT IT UK, IS, IE, ES BG, BE, NL, ranking: this to Declared manufacturer price is compared compared is price manufacturer Declared Calculation of reference price

ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory ex factory price basis pharmacy retail pharmacy retail pharmacy retail pharmacy purchase pharmacy purchase pharmacy purchase pharmacy purchase Pharmacy retail, ex factory ex retail, Pharmacy Malta, NL = Netherlands, NO = Norway, PL = Poland, POM = prescription-only medicine, PT = Portugal, SE = Sweden, SI = SI Sweden, = SE Portugal, = PT medicine, prescription-only = POM Poland, = PL Norway, = NO Netherlands, = NL Malta, Kingdom United = UK reimbursable, = reimb. Slovakia, = SK Slovenia, Source for abbreviations: http://publications.europa.eu/code/en/en-370100.htm Source about external referencing: http://epp.eurostat.ec.europa.eu/portal/page/portal/health/introduction EUROSTAT, GDP: of Source GDP = gross domestic product, HU = Hungary, IE = Ireland, IT = Italy, LT = Lithuania, LU = Luxembourg, LV = Latvia, MT = MT = Latvia, LV = Luxembourg, LU = Lithuania, LT = IT Italy, = IE Ireland, = HU Hungary, product, domestic = gross GDP

5 7 8 9 11 15 15 15 15 17 21 12 19 19 19 18 14 14 10 22 20 in basket Ø rank of countries 1 3 5 7 2 8 9 6 4 11 13 15 17 12 21 19 18 16 14 27 23 25 10 22 28 26 24 20 (GDP 2009) income rank

GDP Composition of basket 15300 17200 12200 22100 14300 19200 12900 15000 18900 23200 27400 27400 29300 24300 26500 19000 10900 25400 20700 29800 (2009) 26600 28400 24400 30800 28000 42000 64000 1 3

2 8 9 6 9 9 4 4 4 4 4 17 12 16 14 22 26 24 24 in basket not defined not defined # of countries

POM POM POM POM POM Scope all medicines all medicines all medicines all medicines reimb. Medicines reimb. Medicines reimb. Medicines reimb. Medicines reimb. Medicines reimb. Medicines reimb. Medicines reimb. Medicines reimb. Medicines reimb. Medicines reimb. Medicines reimb. Medicines imported medicines innovative medicine innovative medicine Existence of EPR main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion main criterion EPR not applied EPR not applied EPR not applied EPR not applied Overview on EPR methodology adoption depth of EPR supportive information supportive information CZ:this methodology is only applicable for pricing; for reimbursement prices of all other EU Member States are checked and the lowest price per basket is taken DE:since 2011 EPRisused assupportive information forinnovative medicines forthe price review afterone year. sinceMT: 2011 EPR is applied. AT = Austria, BE = Belgium, BG = DK = Denmark, Bulgaria, EE = c. EL Estonia, = Greece, = EPR = ES price external referencing, country, = CY Spain, FI = = Finland, FR = France, Cyprus, CZ = Czech Republic, DE = Germany, C. UK ES FI FR HU IE IT LT LU LV MT NL NO PL PT RO SE SI SK AT BE BG CY CZ DE DK EE EL Table 1.Table http://ppri.goeg.at March. Source: th . Map of external price referencing in Europe, 2010. 1 On the other hand, Portugal is an example of a country, which defined detailed rules asto AccordingsomePPRItoNetwork members mightitalsotrue be forsomecountries thatthe Belgium, the Czech Republic, Greece and Luxembourg applied EPR to all medicines 30 how to apply EPR in the Decree-Law 14 65/2007, Nr. national law may define a detailed EPR methodology, which might not always be fully appliedduetolacking information (e.g.no availability of prices in some countries). National legislation might be modified by further legallyrelevant documents. In most EU Member States, EPR was based on statutory regulations or legislated pricing rules. These statutory rules may define the different characteristicsroom for interpretations. of Ireland, EPRa country in with thedetail tradition orto regulate mayits policies leave through agreements, has no laws or decrees Pharmaceutical for Healthcare EPR. Association Howeverand the Association the of agreementsPharmaceutical Manufacturers between of Ireland contain the the formal rules to be Irish applied. on the market. Other countries used EPR only for reimbursable,specific prescription-only categories medicines or innovative of medicines medicines, as was the case in France. such as Legal framework Figure

Differences in external price referencing in Europe - A descriptive overview 2.1 Differences in external price referencing in Europe - A descriptive overview 2.1 31 Kendall’s rank correlation Tau: 0.556263 (p-value= 0.0005331). AT = Austria, BE = = Austria, AT (p-value= 0.556263 0.0005331). Tau: correlation rank Kendall’s As shown in Figure 2, there is a relationship between GDP per capita rank and the average As shown in Table 2 there was great variation in the number of countries included in the ES = Spain, FI = Finland, FR = France, HU = Hungary, IE = Ireland, IT = Italy, LT = Lithuania, LU = Luxembourg, LV = Latvia, = LV Luxembourg, = LU Lithuania, = LT Italy, = IT Ireland, = IE Hungary, = HU France, = FR Finland, = FI Spain, = ES UK Slovakia, = SK Slovenia, = SI Sweden, = SE Portugal, = PT Poland, = PL Norway, = NO Netherlands, = NL Malta, = MT http://publications.europa.eu/code/en/en-370100.htm) abbreviations: for (Source Kingdom. United = Figure Figure 2. Kendall`s rank correlation tau: correlation between GDP per capita rank and the average rank of the basket.in the countries reference Greece, = EL Denmark, = DK Estonia, = EE CZ Cyprus, = CY BG Czech Republic, = Bulgaria, Belgium, = Germany, = DE (n=13),FranceUnited(n=11)Kingdomcountriesandthe(n=11)were frequently most referenced. rank of the reference countries in the basket (Kendall’s rank correlation tau: 0.556263, p-value = 0.0005331). But within this analysis it is clear that outlier countries exist such as Poland which has a low-income rank and refers to higher-income countries. Lower-income countries refer reference country basket. The most common methodology in Europe wasten countriesto in havethe basket;less six countriesthan defined between 10-20 countries in their basket and fourcountries (Austria, Belgium, Malta and Slovakia) had more than 20 countries in the basket. Italy had not specified the countries that it was usingsetting prices. as Slovakia EPR had isthe maximum only number aof countries supportive in the tool reference basket when (n=26) andLuxembourg hadtheminimum numberreference ofcountries (n=1). Germany (n=13), Spain Composition of country baskets European countries generally tend to comparability geographic and/or choose proximity. European countries with similar economic However, However, other However the frequency of reviewing [14]. , latest access 20 June 2011 June 20 access latest , http://legemiddelverket.no/upload/50116/Revurderingsrekkefølge on which it is made transparent in advance when prices of the different Price comparison is based on the price in the local currency, converted 6 Prices of medicines change over time, which needed to be taken into account when As summarised in Table 1 the most commonly used pricing method within EPR was to take Norwegian Medicine Agency, available online online available Agency, Medicine Norwegian %202011%20-%20nettutgave%20korrigert.xls

6 32 Price Service) to check the prices on a random basis prices differs among countries, e.g. Portugalreviews its prices on a quarterly basis and Norway published a schedule products according to their anatomical therapeutic chemical (ATC) class are reviewed; othercountries like Hungary do not regularly review their prices. for them to report price changes to public authorities, which resulted in adjustingused within thethe EPR system.prices In addition, public pricing authorities (in most countries either the Pharmaceutical Department within the Ministry of Health or third party payers)prices checkedwhich were the reported in the application by manufacturers, putting a substantial burden on pricing authorities. Austrian Social Insurance legislation, for example, provides for a public healthinstitution which runsmedicinesa price service allMemberofEU States (Pharmaceutical Romania took the lowest price per basket. It was reported by PPRI most network cases,members Greece that hadin the lowest price per basket. Germany mostand referenced to, followedSpain by France wereand the Unitedthe Kingdom (see countriesalso 2).Table applying EPR. The majority of countries had some kind of agreements with manufacturers countries decided to be vague when defining the definingmethodology countrieswhenvaguethe be decided calculating for France,to price. the forinstance, stated that the price should be consistent with prices ofcomparators, which leaves room for case-by-case negotiations between authorities and manufacturers. the average of the country basket. Bulgaria, Greece and Norwaythree definedlowest thecountries average ofas the their reference price, whereas Hungary, Luxembourg, Poland and Calculation of the reference price Some countries defined very detailed methodologies about calculating thereference price e.g. NorwayParities. Power Purchasing to refer to whether or use to rate exchange specifyingwhich by for instance stated: “ to Norwegian Krones. The mean exchange rate of the last six whole months, as presentedthe Central by Bank of Norway, is used as the basis for the comparison of prices”. precise rules how to carry out price comparisons, in particular how to proceed similarif pharmaceuticalsidentical or were not on the market in the reference countries and how to adjustfor different countries. Countries which do not legally define alternative countriesnon-availability inof case of the medicine might see the limitations ofcould happen thatexternal none of the referenceprice countries have areferencing price for that medicine.as it toother lower-wealth countries, more wealthy countries frequently define high-income states as reference countries. As mentioned earlier, most countries the compositionhave of statutorythe reference regulationscountries; howeveron only a few countries specify alternativecountries in case of non-availability of a medicine. For example, Cyprus and Portugal had

Differences in external price referencing in Europe - A descriptive overview 2.1

Differences in external price referencing in Europe - A descriptive overview

2.1

(Source for abbreviations: http://publications.europa.eu/code/en/en-370100.htm) abbreviations: for (Source PT = Portugal, SE = Sweden, SI = Slovenia, SK = Slovakia, UK = United Kingdom Kingdom United = UK Slovakia, = SK Slovenia, = SI Sweden, = SE Portugal, = PT

33 FI = Finland, FR = France, HU = Hungary, IE = Ireland, IS = Iceland, IT = Italy, LT = Lithuania, LU = Luxembourg, LV = Latvia, MT = Malta, NL = Netherlands, NO = Norway, PL = Poland, Poland, = PL Norway, = NO Netherlands, = NL Malta, = MT Latvia, = LV Luxembourg, = LU Lithuania, = LT Italy, = IT Iceland, = IS Ireland, = IE Hungary, = HU France, = FR Finland, = FI

AT = Austria, BE = Belgium, BG = Bulgaria, c. = country, CH = Switzerland, CY = Cyprus, CZ = Czech Republic, DE = Germany, DK = Denmark, EE = Estonia, EL = Greece, ES = Spain, Spain, = ES Greece, = EL Estonia, = EE Denmark, = DK Germany, = DE Republic, Czech = CZ Cyprus, = CY Switzerland, = CH country, = c. Bulgaria, = BG Belgium, = BE Austria, = AT

CZ: this methodology is only applicable for pricing; for reimbursement prices of all other EU Member States are checked and the lowest price per basket is taken. is basket per price lowest the and checked are States Member EU other all of prices reimbursement for pricing; for applicable only is methodology this CZ:

Alternative countries: BE, DE, DK, ES, IT, PT IT, ES, DK, DE, BE, countries: Alternative

frequency frequency

10 11 Reference 10 9 1 8 3 7 6 10 11 8 10 12 6 13 11 7 7 13 10 5 3 12 8 6 8 3

SK 26

SL 3

RO 12

PT 4

PL 17 CH

NO 9

NL 4

MT 12

LV 2

LU 1 origin of c.

LT 6

IT Not spec. Not

IE 9

HU 14 c add. 1

FR 4

FI 16 IS

ES Countries of Euro zone Euro of Countries

EL 22

EE 4 origin of c.

CZ 8

CY 4

BG 9 Russia

BE 24

AT 24

C. CZ CY BG BE AT ES EL EE DK DE LT IT IE HU FR FI NO NL MT LV LU SL SE RO PT PL Additional c. Additional UK SK Nr. Of c. Of Nr.

Countries in the basket the in Countries

Table 2. 2. Table Overview of country baskets in Europe, 2010 Europe, in baskets country of Overview [15].

[17]. [16]. While some countries define if define countries some While On contrary, On within contrary, the methodology of internal price prices referencing of Planned changes for 2011 were stated by Italy, the Netherlands and Latvia. Italy was exploring the the exploring was Italy Latvia. and Netherlands the Italy, by stated were 2011 for changes Planned Conversely, Malta has implemented EPR for new medicines in 2010. It was decided to includedecidedwasto Conversely,It implementedMaltamedicines newhas 2010.for EPR in Interesting to Interesting note was that two countries, Denmark and Sweden, stopped using EPR during In case countries have changed the country basket, it was observed that the number of possibility to apply EPR for generics and Latvia was negotiating to expand the countries included in in included countries the expand to negotiating was Latvia and generics for EPR apply to the possibility especially system, EPR their evaluating of process the in are Netherlands The basket. country the 1995/1996 in implementation the since reviewed been not has it as basket, country 34 12countries in the reference basket and totake the average price. In addition, Greece changed its EPR methodology from three countries in the reference basket to 22 European countries. In 2010, Germany, a country that traditionally has free pricing at ex-factory price level, decided in 2010 to use EPR as one of many criteria in case price negotiations would fail this time. Up to 2002 Denmark, however, only used EPR to set the reimbursement price in the out- the in price reimbursement the set to EPR used only however, Denmark, 2002 to Up time. this patient sector. Nevertheless, Denmark decided in 2009 – by agreement with the industry – to conversations personal to According sector. hospital the in medicines new for only EPR introduce with Swedish PPRI representatives the change in their country was due to achieving more cost- policies. cost-effectiveness as such strategies pricing other implementing by savings reimbursement system to all EU countries and before only to 8 countries), Greece (since 2010 change from three countries to 22 countries in the basket), in Irelandthe basket(now andnine before countries2006 are there were only five countries) andfromeight Slovakiareference countries to all changedother EU countries). inFor the remaining 2009 countries no exact information on the change in methodology was available. of the country basket, which was done by at least methodtwelve (eleven countries).countries, or the price calculation countries included in the basket was increased. This was the case in Austria (in 2005 increased the basket from 14 to 24 countries), in the Czech Republic (since 2009 price referencing in the the product is compared on a unit level (meaning e.g. per tablet, per dose) others don’t. Norway for for Norway don’t. others dose) per tablet, per e.g. (meaning level unit a on compared is product the package small a as consider they what methodology EPR the within rules exact defined has example injections for e.g. rules the to exemptions clear as well as units) (>30 large a or units) (<30 Changes in EPR methodologies over time overyears,lasttheten1, countriesAs shownTable in decided change toeither compositionthe referencing in referencing with combination internal price is referencing used by 18 countries, only internal is price referencing used in four and countries only EPR in six price internal However, countries. price a within price often reference used for the is setting reimbursement exclusively referencing EPR whereas system; is also used for prices setting of all in products the Czech market (Belgium, Republic, Greece and Luxembourg) or for innovative medicines comparison. of (France unit the define and to importance of is it Spain). methodologies For both External versus internal price referencing The methodology of EPR requires that countries compare prices of the same brand product in countries. different price 5 4 – at External a or level. either within ATC are compared the ATC country same medicine

Differences in external price referencing in Europe - A descriptive overview 2.1 Differences in external price referencing in Europe - A descriptive overview 2.1 35 [19]. [22]. In addition, [18]. He acknowledged that EPR has been a Seiter (2010) from the World Bank who has suggested that Filko stated that due to the policy change of EPR in Slovakia in 2009, [20]. Over the last couple of years a trend towards the inclusion of more countries in the referencethecountries inmore inclusion ofthe towards trend ayears ofcouple lastthe Over It It has been argued that EPR is in some countries only a “price collection” exercise which has According to the results of this study, we see that national authorities in Europe consider basketwas noticed. Countries, which have recently adjusted their EPR policy, e.g.Greece, have moved from only a few countries to over twenty countries in the reference basket. This trend as supportive information (e.g. Belgium, Italy). In fact most European countries have well defined well have countries European most fact In Italy). Belgium, (e.g. information supportive as pricing rules and regulations. This study showed that many countries shaped their policies Docteur as (2007) highlighted in her study of having fixedand well-definedrules, such as capping the allowable price at the of average prices in the countries or comparator choosing the median [2]. countries comparator in prices outlier to sensitive being not of advantage the having withincountries26EU welltheasimplementationas theproportionthe€,of pharmaceuticalof expenditure as% of total health care spending declined by approximately 25% Stargardt showed in his study that the composition of the country basket reductionsand have anpossible influence on the priceprice level in other countries [13]. no real impact on national pricing [9]. This might only be true for those countries which use EPR of EPR in the Netherlands and came to the conclusion that EPR Merkurresulted and in Mossialoslower pricessimulated the effect of EPR on medicine pricesthat this in would Cyprus lower prices and and showedcontain costs after identifying Cyprus as a high price country for pharmaceuticals lowestarithmeticsixwhichincludedcountriesthetheintroduction basedtheon of mean EPR of However, when almost all countries reference each other the differences between countriesdiminish. EPR will then eventually lead to one price level and other policies e.g. pharmaceutical expenditureevaluation might be more cost-effective. Policy makers seemto see opportunities tocontain costs by regulating prices of medicines through benchmarking them with the prices of other countries. Differentresearch studies have provided evidence that using EPR as pricing policy leads to lower prices, e.g. Windmeijer who measured the effects of the implementation methodology to better reach their policy goal of countriesreferenceapplyingdifferentthebasketloweror in price a calculation method.thereforeWe medicine prices by including more do not agree with the forecast by EPR will soon reach the end of its useful life cycle useful tool in establishing an objective benchmark for pricing policies and responding opportunistic,to the profit-centred pricing policies of international and national drug companies. showed that EPR is a dynamic policy tool which is adjusted by policy makers over time. EPRas arelevant pricing policy. They regularly adjust their EPR methodologies as was observed over the last years and stated for next year; e.g. sincenew 2010 medicines.Malta uses EPR Over to set past prices for years countries have gained experiences in shaping their EPR DISCUSSION This study showed that EPR is a widely used pharmaceutical pricing tool in Europe (in 24 of 28 European countries). Including fewer than 10 countries in the reference basket and taking the average of the reference prices were the most common EPR methodologies. The results also Why is it crucial to understand the differences and commonalities of EPR systems? EPR may Another point of discussion is whether EPR is a useful pricing policy for all types of Another result of the study showed that there was a tendency to include high-income withapplying EPR reported that EPR istime consuming and challenging exercise when itcomes comparisonspriceunderstanding paper, his countries.toother (2010)inlistedEspinpricesin As – hence EPR - are complex due to the following facts: considerable resources (human and 36 showed that EPR was mainly appliedexperiences reported for by the reimbursablemembers of the medicines. PPRI network However, this is further accordingonly confidential the price negotiationsstarting to between publicpoint authoritiesfor and industry. seem to be a fairly easy pricing procedure. Nevertheless, those who have practical experience not explicitly address this research question as data were not readilyEPR available,is mainlyit usedseems forthat patent protected products that are timewidelyreimbursable; asother marketmarketed dynamics and policy tools andareapplied for generics mostand OTC of the (e.g. market competition) and newly launched products However for (pharmaco-economicsmall countries applying EPR for off-patent evaluation). medicines is an effective tool as often generic competition fails due to few competitors being in the market. The present overview for prescription-only medicine (POM) or reimbursable medicines [21]. In contrast in 2003 the European Commission adopted free pricing for “medicines neither purchased nor reimbursed by the state” [27,28]. In practice, many EU scopeMember of their States pricing regulationhave to optedthe reimbursementfor segment, determiningand this theis also theexternal case pricefor referencing (see Table 1). Still some countries on (e.g. applyingFrance, externalSpain) price even referencing focus for innovative medicines. Even though this study did price determinants such as pharmaco-economic evaluation as used in Sweden. medicines (over-the-counter medicines, patent protected products, generics, and reimbursable non-reimbursable medicines). Within the framework of particular somethe Transparency Directive),overall pricing and reimbursementEU remains a nationallegislation decision (in launch country as it does not have price control at ex-factory price level. As stated by Docteur (2007), this may be, to some extent, opportunistic in that these large high are likely income to countrieshave prices available for reference soon after first launch [2,23-26]. However,comparable the price in Germany is often much higher than in other European countries. Hence, public authorities need to find the rightcomparable balancemedicines in countries betweenof similar national incomes easily or the use accessibleof other methods informationof on countries such as Germany in the basket.question the to leadsThirteen This basket. the in countriesKingdom United had and/or France includedcountries elevenGermany and/or Spain and as to why some countries with a lower gross domestic product (GDP) such as some Central and Eastern European countries have high-income countries such as Germany in their comparator basket. Arguments to include Germany in the country baskets is that it is very often a first seems surprising as it is known that EPR is a timetimes ofconsuming the financialand crisis,complex countriesmethodology. mayIn not be willingto spend publicchecking money the prices on of allregularly reimbursable products in other countries on a regular basis. But with a limited basket of countries there is a risk that there will be no comparable products available.

Differences in external price referencing in Europe - A descriptive overview 2.1 Differences in external price referencing in Europe - A descriptive overview 2.1 37 However, Germany is an example of a country [27]. Products are first launched in high price countries, [25]. Pharmaceutical companies – not only in Europe but also in the US – apply strategic pricing The The method of EPR may have effects on the access to reimbursable medicines as industry that applies tendering-like systems for reimbursable medicines. This means, that industry and insurance institutions reach lower prices through discounts/rebates. are However, confidentialthese andprices are not published. This leadsto the effect that the initial high list price price list to prevent “reverse referencing” price to list the to referencing” prices “reverse prevent in other bigger in markets the EU. These Slovakia. in officials public by to agreed not were industry of attempts methods when launching products suchas Germany, with relatively high prices Slovakia changed its EPR methodology by including all 27-EU Member States in the reference basket. basket. (2009) [22]. reference He the described the Slovakia made in experiences when changing the States EPR methodology. Member 27-EU all including by methodology EPR its changed or Slovakia methodology EPR implemented newly the ignore to tried companies when faced were Difficulties However, accessibility. in delays to lead could This products. their of exemptions for lobbied actively Filko came to that another conclusion were companies willing initially to lower the prices to the of official kind on any appear not would price the that on condition only however level, requested population, gross domestic product, national industrial policy, prescribed volume pricing andpolicies othermay influence the level of the final price [11]. In case theproduct is not on the market in the reference countries an alternative could be to use internal price referencing by comparing the prices of the same medicine with alternatives 5 on 4or level.ATC ATC might not provide all needed for information authorities to set prices, as it was shown by Filko pricecalculation pricetimeandofgathering strategiesorproduct marketthe caseonnotain is in a reference country should be defined in legislation. Theseimplemented factorsas for mayinstance affectlarge packages how have EPR a is lower average price per unit thanpackages. smaller Furthermore, authorities need to decide which calculation method e.g. to only use larger in packagecase sizes are available on the market. Other factors such as size of the network and the network of competent authorities on pricing and reimbursement under thePresidenciesEUthelead of withDirectoratethe General(DG) Enterprise, providepossibilitythe exchangeto onthe experiences with different pricing policies as well to informallyas exchange information on prices of reimbursable medicines to better understand the “real” price productofin the other country the especially important for discounts/rebates orother price-volume agreements. In addition, elements such as package size, price type, dosage as well as time of [9]. Depending on the EPR methodology – e.g. taking the lowest price per basket – prices countriesof may vary to a great extent. Choosing the right EPR methodologycalculation in method terms and ofcountries price in the basket is crucial. This study could not identifypractice a bestEPR model as the national policy framework always needs to be However,certain takenelements importanceofare into whenapplying EPRsuchaccount.regular as price revisions and informal exchange of information on prices. Networking initiatives, such as the PPRI material) are needed to analyse the price data andsystems are required in-depthto identify the same knowledgeproduct (different commercialon names, dosage pharmaceuticalforms andpackaging inother countries) but also betoable understandto the different prices quoted (different margins, taxes and confidential agreements in other countries) to be compared 38 In addition, they supported the work of this study by giving information on recent changes or by raising critical questions. possible limitations of these pricing methods. ACKNOWLEDGMENT Deep acknowledgements are given to the members of the PPRI network.achieved byThe the workPPRI networkthat members was by writing the PPRI Pharma Profiles are of great value. of prices and by identifying alternative countries in case a product is not on the market. These recommendationscould lead toless bureaucracy and the time consuming process of checking prices might be reduced. We also see the need for formal information sharing (e.g. congresses dedicated to pricing strategies and systems) with about the otherdifferent EPR methodologies public as pricing well as the authorities national experiences. to These congresses learn might also give room to better understand national pricing methods including discussions on with many different national characteristics; some countries evenrecently implemented EPR. A tendency of changing the EPR methodology over time was noticed; in particular in terms of the composition of the reference basket as the number of reference countrieshas inincreased the overbasket time in many countries. We conclude thatcountries overhave increasinglythe establishedpast yearsexpertise Europeanon the EPR methodology. However, we stillsee room for improvement by implementing more detailed legislations in terms of the revision companies“gaming”tothesystemincrease to prices Europe ingloballyor throughtheir launch sequences in order to increase prices. CONCLUSIONS Europe, in policypricing used widely and dynamic a is EPR conclusionthat the to comesstudy This means that prices delivered by pharmaceutical industry need to be checked seeand ifanalysed they to are correct. In addition, set prices should be reviewed on toa price regulardevelopments basis in other to countries.adjust However, even though supply side controls have an effect expenditureon these might completelybe counteracted overspendingby and the use of expensive originators when generics are available [29]. Thus, the widespread use of this policy savepublicefficientservefundsmaybytoolto prevent price setting not will pharmaceuticalbut is taken as a benchmark when other public countries authorities have need Germany to in be their aware baskets. when of choosing Therefore, or those adjusting the dynamics pricing policies and for their take countries. Any them pricing policyeffective into is ifonly consideration its regulation is enforced by public authorities as well asregularly reviewed. This

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Differences in external price referencing in Europe - A descriptive overview 2.1

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Impact of external price referencing on medicine prices – a price comparison among 2.2 14 European countries

South Med Rev 2012;5(2):34-41

Christine Leopold, Aukje Mantel-Teeuwisse, Leonhard Seyfang, Sabine Vogler, Kees de Joncheere, Richard Laing, Bert Leufkens The study showed that for patented products, prices are in general lower in case : This study aims to examine the impact of external price referencing (EPR) on

Pricedata of on-patent 14 products, in European 14 countries in 2007 and 2008 were

This study showed that on average EPR as a pricing policy leads to lower prices. However, However, prices. lower to leads policy pricing a as EPR average on that showed study This

44 EPR could be identified. Possible explanations could be found through a correlation betweenpharmaceutical industry andthescaled price ranks. conclusion,In wefound thatimplementing external reference pricing could lead to lower prices. the the large variation in price levels among countries using EPR confirmedthat the price not level only driven by is EPR. The unadjusted linear regression model confirmsthat applying EPR in a after persisted interaction This (p=0.002). rank weighted scaled lower a with associated is country model. final the in per capita GDP and per capita expenditure pharmaceutical total of inclusion Conclusions thecountry applied EPR. Nevertheless substantial pricedifferences among countries that apply each country had the same sum of weights but within a country the weights were proportional toits sales volume in the year (data obtained from IMS Health). the Taking scaled ranks, several statistical analyses were performed by using the program “R”, including a multiple regression analysis (including variables such as GDP per capita and national industry size). Results: expenditure (TPE), and size of the pharmaceutical industry. Methods: obtained from the Pharmaceutical Price Information Service of the Austrian Based Health Institute. on the unit ex-factory prices calculated.regression inthe Foranalysis scaled thecountryperranks product weighted; and were €, scaled ranks per country and per product were ABSTRACT Objective: on-patent medicine prices, adjusting for other factorssales volume,that exchange rates,may gross domesticaffect product (GDP) price per capita, levels total pharmaceutical such as

Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 45 Economic evidence on the impact of external reference pricing is scarce, but literature has Only a very small number of studies addressed general aspects of EPR as a policy. Heuer [9] One of the supply side measures is regulating medicine prices. The most commonly showed that EPR would lead to lower prices. Filko [15] changestated to use EPR inin Slovakia, 2009which includedthat the introductiondue of EPR to based on thethe arithmeticpolicy mean of the six lowest countries within all other European Union countries as well as the generally shown that the introduction of EPR reduced prices. effectsWindmeijer of the[13] implementationmeasured of EPRthe in the Netherlands and found that EPRresulted in prices.lower Merkur [14]simulated the effect of EPR on medicine prices in Cyprus, after having found that Cyprus had relatively high prices compared to other European Union (EU) countries, they prices. Stargardt [11] developed an analytic model to simulate the effectin ofGermany. aThey pricefound reduction that if there was a one € price reduction in Germany to this woulda leadreduction of € 0.15 to € 0.36 in 15 in Europeantheir basket.countries Another that perspectiveuse wasEPR developedand haveby RichterGermany that[12], pharmaceuticalwho companiesargued tend to keepin prices hishigher in studyGermany for the reason that the prices in those countries would later become references for other countries. income countries and different EPR methodologies can be observed. looked at the relationship of external price referencing and delays in the launch of medicines. In addition, Mariñoso [10] developed a scenario in which the to potentialeither engagedrivers in for externala pricecountry referencing or to directly negotiatefewOnlystudiesa have explicitly analysed pricestheimpact external of pricereferencing medicineonwere analysed. or negotiating the price of the product in a given country” [3,4,6]. One may argue that due to the fact that EPR is frequently used this makes it a powerful tool to influence not only national medicine prices but also prices worldwide due to the interlinking ofnecessary understandto prices whether European public[7,8]. authorities Hence,chargepricinginof medicinesof it is are actually reaching the desired aim of EPR, thus stabilising and eventually lowering medicine prices. Of particular interest is to understand whether differences among lower or higher countries have implemented various policies to contain pharmaceutical expenditure [5]. [5]. expenditure pharmaceutical contain to policies various implemented have countries used pricing policy in Europe (applied by 24 out of referencing28 (EPR), which isdefined European as “the practice of usingcountries) the price(s) of medicinea in one or is external price several countries in order to derive a benchmark or reference price for the purposes of setting medicine, medicine, thus appearing to have low price and elasticity patent holders often have governments the European market market; unregulated an not is this controls, price without Even [1,2]. power extensive is already so there patents, and grant citizens to their coverage health provide generally in health of fundingcoverage, specific sustainable in Guaranteeing intervention the market [3,4]. Due measures. policy side demand and supply certain requires expenditure, pharmaceutical public European funding, care ofways health different and differences cultural developments, historic to INTRODUCTION by market The is low pharmaceutical characterized and price elasticity strong market power not enforced. are patents and widespread is insurance health which in markets all in but Europe, in only In countries, where medicines are subsidised, patients do not generally see the true price of a Price data were provided by the Austrian Health Institute, which has been running a A basket of fourteen products was chosen. The main criterion for choosing the products Building upon the findings of these previous studies, thisresearch aimsto examine the Pharmaceutical Price Information Service (PPI) for many years [20]. Based on Austrian law, the PPI service was set up in the late 1990’s as a supportive tool for the Austrian Price Commission 46 Data Sources PharmaceuticalEuropeanReimbursementtheandPricing obtainedfrom were EPR on dataPolicy Information PPRI network [19] as well as from Leopold [7] which is a descriptive study on EPR in European countries. Medicines Agency. In addition, the medicines patient weresector and predominantlywere included prescribedin the reimbursement in system. the Finally, price out- available.data As hadshown to in Table be 1 products represent a broad spectrum of therapeutic areas such as obesity, diabetes, HIV/aids and others. The products are arecently came oncombination the market (and thereforeof have relativelyproducts low sales volumes)that and others that havebeenthemarketon fornearly years ten (and therefore have relatively highsales volumes). referencing were also included. The countries included were Austria, Belgium, Denmark, Germany, Germany, Denmark, Belgium, Austria, were included countries The included. also were referencing Republic. Slovak Sweden, Spain, Portugal, Norway, Netherlands, the Italy, France, Finland, Greece, was the patent status of each medicine:countries under investigation; it therefore had the date of to market authorisation be was checked on-patent either in at the 2007 website of and the European 2008 Medicines in Agency (centralised the procedure) or at the Austrian METHODS Selection of countries and products A basket of fourteen European price countries with external different economic apply situations not and do from currently different which States Member EU Three selected. was (EU) the of parts capita, total pharmaceutical expenditure (TPE) and size of Whiletheconducting the present thesestudy, pharmaceuticaladditional factors were also taken into account. industryThis [17]. study provides policy makers and scientists in the field of pharmaceutical policy with detailed information as to whether the desired effect of EPRachieved – for originatorto products have in 2007 and 2008. lower medicine prices – was and government expenditure and by producer’s5.6% revenues by 5%. impact of EPR on medicine prices using a countries.sample The of medicines 14 prices originatorwere obtainedproducts from ina period 14 of European2007-2008. pricelevelsvarydifferencesmayItacrossresultcountriesof factorsnational a in as such aspricing is known that and reimbursement policies, sales volume, exchange rates, gross domestic product (GDP) per implementation of the €, the proportion of pharmaceutical expenditure as percentage of total health care spending declined by approximately 25%. On the contrary Kaiser [16] came to the conclusion that in Denmark medicine prices decreased more than 26% after a internalEPRfromto pricereferencing.policy Further thepatient changeco-payment wentpercentdown 3by

ATC = Anatomical Therapeutic Chemical, INN = International Non-Proprietary Name, f/c=film coated f/c=film Name, Non-Proprietary International = INN Chemical, Therapeutic Anatomical = ATC

L01BC06 500 mg mg 500 Xeloda Capecitabine Oncology February 2001 February Roche Tabs

J05AX09 150 mg 150 Celsentri Maraviroc antiviral Other September 2007 September Pfizer Tabs

Non-nucleoside reverse transcriptase inhibitors transcriptase reverse Non-nucleoside J05AG03 600 mg 600 Stocrin Efavirenz May 1999 May MSD tab f/c

J05AF07 245 mg mg 245 Viread fumarate disoproxil Tenofovir HIV February 2002 February Gilead Tabs

J05AF06 300 mg mg 300 Ziagen sulfate Abacavir HIV July 1999 July GSK Tabs

J05AE10 300 mg 300 Prezista Darunavir inhibitors Protease February 2007 February Janssen-Cilag Tabs

J05AE07 700 mg 700 Telzir calcium Fosamprenavir inhibitors Protease July 2004 July GSK tabs f/c

Other antithrombotic agents antithrombotic Other B01AX05 Prefilled syringe syringe Prefilled ml mg/0.5 2.5 Arixtra Fondaparinux March 2002 March GSK

B01AB05 Prefilled syringe syringe Prefilled mg 100 Lovenox Enoxaparin syndrome coronary Acute November 2000 November Sanofi-Aventis

Diabetes A10BG03 Actos hydrochloride Pioglitazone Eli Lilly Eli Tabs mg 30 October 2000 October

Diabetes A10BG02 Avandia maleate Rosiglitazone GSK Tabs mg 4 July 2000 July

Obesity A08AB01 Xenical Orlistat Roche Tabs mg 120 July 1998 July

Obesity A08AA10 Reductil Sibutramine Abbott Caps mg 10 April 2001 April

Proton pump inhibitors pump Proton A02BC04 Pariet Rabeprazole Janssen-Cilag Janssen-Cilag Tabs mg 10 November 1998 November

Therapeutic Area Therapeutic code ATC Product INN Company form Strength [18]

Pharmaceutical Pharmaceutical EMA Authorisation Authorisation EMA

List of selected products included in this study study this in included products selected of List 1. Table In addition to economic factors, it was tested whether there is a possible relationship Data on economic variables such as gross domesticeconomiccapita,pharmaceuticalgrossproducttotalpervariableson as Data such To To perform the statistical analysis volume data of the 14 products in both years as well as fixed exchangerate for as2007/2008, some exchangerates (e.g. Norwegian Krone) fluctuated more than the price differences. The prices were convertedto scaledranks price levels so were ineffectual that as well different as it guaranteed arobust data set. 48 EuropeanFederation of Pharmaceutical Industry Association (EFPIA) and referred to 2006 [23]. This was converted into a rate per 100,000 population. Statistical analysis Theunit ex-factory prices in €of all products, all countries and of both years were adjusted toa Power Parities (PPPa) followed the methodology suggested by OECD. between the importance of national pharmaceutical industry and medicine prices, as national governments seek to find the right balancepolicies. The between variable social/healthemployment in policiespharmaceutical andindustry economicpopulation proxyfortheimportance was theofpharmaceutical collectedindustry country.ain Data weretaken thefrom as a etc. If IMS does not collect data from all suppliers in a country they project the sample of a particular particular a of sample the project they country a in suppliers all from data collect not does IMS If etc. annually. validated are projections These level. national the to channel distribution expenditure (TPE) per capita in € Purchasing Power Parities as well as data on 100,000 inhabitantswere extractedper from the Organization of Economic Co-operation and Development (OECD) Health database and referred to 2006 [22]. The calculation of per capita Purchasing pharmacies or drugstores. The volume data referred to annual sales data of to annual 2007 and 2008 of the data referred The volume or drugstores. pharmacies forms. dosage same same and products, strengths as companies commonest the price the data. IMS from its displays volume data in derived is and IMS by used measure a is This (SU). units standard one equals SU one Usually medicine. the of formulation the on depending differently measured is suspension It oral an of ml 5 or medicine inhaled of dose one syringe, prefilled one tablet, one capsule, the prices were analysed in prices per units. If products were known to be used exclusivelyhospitals inin some countries, their prices were disregarded. data on such economic variables as gross national domestic product or total health expenditure were collected. Volume data were provided by IMS Health data Institute consumption outlets dispensing from such pharmaceutical hospitals and/or wholesalers, as [21]. IMS Health collects Health Institute offers as well. The price datareferred to October / November 2007 and 2008 and represent ex-factory prices per unit. The price data were collected for the same product, the same strength, the same pharmaceutical form and, if available, the same pack size. In case the country did not use the €, the conversion rate was taken from the Austrian National Bank of the previous month in that year. Discounts or rebates were not considered. As prices refer to the ex-factory price level, no value added was tax included. (VAT) For the price comparisons andsince 2004 toalso check prices reported by manufacturers in the process of EPR in Austria. Prices are obtained from official priceInsurance Institutions. databases The validation ofof the PPI Ministriesprices is high, ofas for the Healthinterpretationprices of knowledge orthe on Socialthe Health underlying pharmaceutical system is required which the Austrian

Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 49 The correlation between EPR and pharmaceutical employment per 100,000 inhabitants was plotted separately as there is interaction between the two variables (cf. figure 4). It is unknown in which direction the interaction of the two variable goes. An analysis was undertaken to assess how homogeneous the price level in a country was by looking at each product. It also showed whether countries with EPR had lower prices than countries that do not apply EPR. relationshipThe between scaledthe ranksseveralandexplanatory variables modelledwas bya linear regression model. The following variables were considered as predictors in the model: EPR, TPE per capita and GDP per capita. As mentioned before, those countries who apply EPR still show different price levels. Figures 2 Figures levels. price different show EPR still who apply countries those before, As mentioned Figures 2 and 3 give a more detailed picture on the variances of the scaled ranks among Figure 1 shows the distribution of the scaled ranks in a country as well as across countries. For the regression analysis the scaled ranks per country and product were weighted. Each level of the different products was all around the average. None of the products showed a very high high very a showed products the of None average. the around all was products different the of level EPRin a applying that confirms model regression linear nor a price The unadjusted very low price. but also Denmark and Sweden had in each year around two or three products with high price levels but also had some products where the price level was relatively low. and Austria Finland, Netherlands, the (Norway, capita per GDP high a with countries that show 3 and Greece Spain, as such capita per GDP a lower with countries than scores price price the higher have where Belgium) country a of example an is EPR, applies that country a Netherlands, The Portugal. and products within a country and over time. These segment plots confirmwithout thatEPR those(Denmark, countries Germany, Sweden) had in general especially truehigher for Germany in bothprice years (2007: 8 out of levels.14 products for which priceThis data were result is availablewereamong themostexpensive products theofproducts under observation, 2008: 11 outofproducts 14 were among the most expensive ones of the products included in the study) The median of the scaled ranks (incl. both years) of the countries varies from as low as 0.23 in Italy to 0.83 in Denmark. It is visible that two of the countries that do not apply EPR (Germany and Denmark) have the highest scaled ranks. But it is also visible that the scaled ranks vary to a great extent among the countries that apply EPR. Out of the fourteen analysed countries, three did not apply EPR (Germany, Denmark, Sweden) at the time of investment. As shown in 2, Table large variations in GDP per capita (ranging from Portugal € 14,684 to Norway € 41,346) and TPE per capita (ranging from Denmark € to PPPaGreece 246 € PPPa 503) existed among the included countries. Employment in pharmaceuticalindustry also showed large variations within Europe employees/100,000 inhabitants (10-fold and Denmark 313 difference; employees/100,000 inhabitants). Slovak Republic 37 • RESULTS • • country had the same sum of weights. Within a country the weights saleswere volumeproportional in theto year. itsBased on the scaled ranks several analyses were performed by using the Program “R” version [24]: 2.11.1

0.71 0.33 0.33 0.52 0.23 0.42 0.54 0.26 0.46 0.50 0.50 0.64 0.64 0.84 scaled ranks Median of the 37 97 92 98 99 121 119 114 313 173 127 281 129 169 industry per 100,000 100,000 per industry Pharmaceutical empl. empl. Pharmaceutical

2 351 391 413 327 327 365 416 475 453 503 330 246 443 469 TPE per capita in € PPPa 2006 2006 19,123 21,145 33,031 30,187 25,419 22,291 31,067 23,797 31,709 28,184 29,025 28,601 41,346 14,684 GDP per capita in €

Y Y Y Y Y Y Y Y Y Y Y N N N EPR (Y/N) Overview of EPR, economic variables and the median of scaled ranks One of the results of the study was that price differences among countries could be observed. be could countries among differences price that was study the of results the of One Lookingrelationshiptheat pharmaceuticalof employment inhabitantsper100,000 theand 1 Medicines Agency TPE for the Netherlands and Norway as of 2007 AT AT = Austria, BE = Belgium, C. = country, DE = Germany, DK price= referencing,Denmark, EL empl.= Greece,= ESemployment, = Spain, EPR FI = = ExternalFinland, FR = France, GDPn.a. =not available, = GrossNL =Netherlands, DomesticNO =Norway, PE =Pharmaceutical Product, Expenditure, IT PPPa ==Purchasing Italy, Power Parities adjusted, PT = Portugal, SE = Sweden, SK = Slovak Republic, TPE = Total Pharmaceutical Expenditure Italy: EPR is only an additional pricing policy complementing negotiations between the manufacturer and the C. SK FR IT NL NO PT SE BE DE DK EL ES FI AT Table 2.Table This was especially the case in countries which apply EPR. One reason could be the fact that EPR is is EPR that fact the be could reason EPR. One apply which countries in case the especially was This updates price of frequency basket, country the of terms in countries the in applied differently very 50 DISCUSSION This study showed that in general the use of EPR as a prices. pricing However, policythe largeis priceassociated variationwith among lower countries confirms that pricesdriven are by EPR policies not but onlyalso by other unobserved factors (such as other pricing policies). scaled ranks per country and product in Figure 4, it is visible that there is a significanta correlationisvisiblethere thatis it country4,scaledFigureper ranksproductinand (p-value: 0.0063). This means the higher pharmaceutical the industry. scaled However ranks it is the unknown higherin which the directionvariables employmentthe causality goes: in of the do two companies countries (thus with high prices or do countries pharmaceutical with high prices attract investments by companies? employment) decide to produce in country is associated with a lower scaled rank (p=0.002). This association persisted after inclusion of of inclusion after persisted association This (p=0.002). rank scaled lower a with associated 3). is Table country (see model final the in capita per GDP and capita per expenditure pharmaceutical total

Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 51 AT = Austria, BE = Belgium, C. = country, DE = Germany, DK DK Germany, = DE country, = C. Belgium, = BE Austria, = AT : light grey boxes are countries that apply EPR, dark grey boxes are are boxes grey dark EPR, apply that countries are boxes grey light : Reading support Reading The fact that some products are hospital medicines can be seen as a limitation of this study. It was was It study. this of limitation a as seen be can medicines hospital are products some that fact The An additional explanation for the price variances can be found in the selection of the (abacavir sulfat)) were only used in a hospital setting for which the price was not available. commonly is EPR firstly as hospitals in applied exclusively products of prices the exclude to decided productsincluded inthis study: Most products werereimbursable medicines inthe out-patient sector. We observed that in a few countries e.g. Portugal, the prices of several products were notavailable. The reasons were that either the products were not onthe market orsome ofthe products (e.g. Telzir (fosamprenavir calcium), Viread (tenofovir disoproxil fumarat) or Ziagen pharmaceutical price regulation policies pharmaceutical price regulation For applied instance Italy in uses eachEPR only country. and manufacturer between the negotiations price complementing policy pricing additional an as relevance the veryopenly, EPR of role supplementary this states Italy While Agency. Medicine the time the is fact Another countries. other for clear so not is negotiation (confidential) versus EPR of lag between the variables; pricing referencing in countries does not happen so instantaneously, variables. periods’ independent time previous the by be explained may factor price current the Figure 1. Impact of EPR on scaled ranks (incl. both years). years). both (incl. ranks scaled on EPR of Impact 1. Figure Portugal, = PT Norway, = NO Netherlands, = NL Italy, = IT France, = FR Finland, = FI Spain, = ES Greece, = EL Denmark, = Republic. Slovak = SK Sweden, = SE country. per ranks scaled the of median the equals box each in line thick The EPR. apply not do that countries many of one only is EPR that is factor confounding Another [3-5]. method calculation price the and : : Each pie chart displays one country in the year 2007 (Figure Reading Reading support Another point for discussion is whether countries take into account possible discounts and rebates when they are applying EPR. Very often publicly available prices for reimbursable medicines do not reflect discounts from price negotiations between third party payers and 52 Xeloda. Viread is the product with the highest price and the standardised price rank of Reductil is very close to 0. very Reductil is to of close rank price standardised the and price highest the with product the is Viread Xeloda. not applied for of hospital products number and limited secondly a actual only hospital to prices are pertained this often as the outcome However, of [25]. public made not are which negotiations results. overall our affected have will this that feel not do we countries, and products Figure Figure 2. Price variances among the selected products within individual countries; countries are displayed in order of GDP per capita in 2007. 2) and the year 2008 (figure3); eachpiece of the pie representingthe scaled score for the selected 14 products. If the piece of the pie for one product is fully grey (= rank 1) then this product has a high price in this country in this In case year. the legend of the product is light grey this indicates that the product was either not on the market or surveythe from used only as it was excluded was product or the available not was price on the information the that in hospitals. Austria Taking in 2008 (cf. Figure 3) as an example, it is visible that there was no price information for

Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 53 With regard to the methodology chosen in this study it was decided to take the unit ex-factory ex-factory unit the take to decided was it study this in chosen methodology the to regard With Even Even though the selected products are not primarily subject to parallel trade, it needs to price price as the majority of the countries that apply EPR also use the ex-factory their price set which Sweden and level Netherlands the Finland, Denmark, for are (exceptions the comparison price be mentioned that parallel trade plays an important role also with respect to EPR. Parallel trade effectivelyarbitrage price differences across countries and therefore has similar a effect EPR to in terms of compressing price differencesand inducing strategiclaunch behaviourby firms. The [26,27]. EPR adopt to prices high with countries of incentive the reduces trade parallel of presence Figure 3. Price variances among the selected products within individual countries; countries are displayed in order of GDP per capita in 2008. companies as they are confidential. This limits the positive effectsaccount the lower ofdiscounted prices EPR when referencing by to other countries. not taking into P-value 0.10781 0.88718 0.00206 0.00000 3.113 1.614 5.925 0.142 - t-value Std. Error 0.0905139 0.0458698 0.0000012 0.0000029 Estimate 0.5362546 -0.1427916 0.0000019 0.0000004 Linear multivariable regression With respect to price comparisons, either with prices in other countries or with similar Dependent variable: scaled ranks per country and product; N = 262 Total pharmaceutical expenditure per capita per expenditure pharmaceutical Total GDP per capita (Intercept) EPR Table 3.Table Danzon [29] argued that “valid measures of average price comparisonslevels based can on a only comprehensivebe or obtainedrepresentative from sample of products, appropriatelyweighted, following standard index number methods”. Following these considerations the 54 literature on price comparisons [2, on price price is comparisons the 28]. supportedThe use unit decision ex-factory to literature or price level that by pharmacy retail on price the is comparison pharmacy purchasing argument onmedicines. VAT and margins) distribution and ( schemes remuneration different to due difficult existing treatments, numerous studies have discussed different methodological approaches. FigureScatter4. plat ofpharmaceutical employment per inhabitants 100,000 vs. the scaled ranks. by supported is approach methodological this Furthermore level). purchasing pharmacy at prices

Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 55 This argument is supported This by argument a report by the Commission European (Sector Inquiry), which Our Our results support the assumption that EPR places greater pressure on countries that are Medicine prices are the results of many different policy effects. Hence the price of a medicine a medicine of price the Hence effects. policy different many of results the are prices Medicine volume data for 2007 and 2008 for the 14 products. We would like to express sincere gratitude to the Austrian Health Institute for providing price data and to the PPRI network members for providing data on implementation of EPR in their respective countries. apply external price referencing. This could be explained by different methodologies with respect to respect with methodologies different by explained be could This referencing. price external apply price. the calculating for method the or basket reference a in countries of selection the ACKNOWLEDGMENTS Deep acknowledgements are given to Peter Stephens from IMS Health for providing sales CONCLUSIONS association an through found be lower that prices in were for products generally This the study patented demonstrated countries could explanations Possible pricing. reference external applied which However, ranks. price weighted scaled and size industry pharmaceutical the with ranks scaled the of which countries be between could found difference price huge that it to needs be acknowledged same trend. For example, Germany - a country with the tradition of free pricing price at level ex-factory - was not only the country with the highest prices highest in availability of products. Hence, it canboth be concluded that ERP years may have negative impacts but also with the policies. such applying countries in country consequences unexpected and individual prices on the other countries that use EPR for regulating prices on their markets [30]. markets their on prices regulating for EPR use that countries other the stated that to their initiate companies product launch preferred in countries with no direct price control Sweden (Germany, and United Kingdom) or in countries that are used as references by others and have received approval from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (Italy and Sweden) [31]. The results of our study showed the across countries, which makes finding any difference in the cross-section more of a challenge. a of more cross-section the in difference any finding makes which countries, across market early want they if especially high, prices keep to country reference a as others by selected entry of new or products supportin to A order consequence a national pharmaceutical industry. of EPR is illustrated by a tendency for pharmaceutical industries to set high entry prices for new products in countries without basic regulations. These pricing levels then become indicative for equivalent enters the market. Therefore, it is difficult to separate the effects of one pricing policy policy pricing one of effects the separate to difficult is it market.Therefore, the enters equivalent observed the in on-patent were that medicines only why reason the was This prices. medicine on countries in 2007 and 2008 were included in the study. In addition, it should be acknowledged that other factors (e.g. other national pricing policies) were not considered which may account for variation in price levels as well. For example (changing their launch EPR strategies) would be expected to compress the distribution of prices by barring endogenous responses by firms methodology chosen in this study takes into account an indicative sample of 262 observations (including the 14 products and volume data from two years). may change as soon as it is included in the reimbursement schemes or as soon as a generic . . . ftp://ftp.zew.de/ Available from: http://www.goeg. . Pharmacoeconomics http://papers.ssrn.com/ The Slovak experience in the the in experience Slovak The [updated 2012/08/01; cited . PPRI (Pharmaceutical Pricing and and Pricing (Pharmaceutical PPRI . http://whocc.goeg.at/Publications/ Available from: at/en/Reports-Service.html IMSHealth MIDAS. 2007-2008. 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Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 Impact of external price referencing on medicine prices – a price comparison among 14 European countries 2.2 57 . Accessed 20 May 2011. May 20 Accessed . part1.pdf Rosian I, Vogler S, Stürzlinger H. Internationale Arzneimittelpreisvergleiche: Pharmig 2004; Available Meta-Analyse. from: goeg.at/Publications/BooksReports. http://whocc. Accessed July2012.20 Danzon PM, Chao differences for LW, pharmaceuticals: how large, and Cross-national Health pricewhy?J Econ. 2000Mar;19(2):159-95. Price ofImpact L.The Wang RY, Wang PM,Danzon Regulation on the Launch Delay of New Drugs - Evidencefrom Twenty-Five Major Markets in the 1990s.Health Econ.2005Mar;14(3):269-92. European Commission Competition Directorate- General. final Pharmaceutical report. Brussels, http://ec.europa.eu/competition/sectors/ sector 2009. Available pharmaceuticals/inquiry/staff_working_paper_ from: inquiry

28. 29. 30. 31. . http://phis.goeg.at/ http://www.efpia.eu/ Eurohealth2009;15(2):1-4. AccessedJuly2011.12on . ISBN 3-900051-07-0 Available Available from: from: Available http://www.R-project.org Costa-i-Font J, Kanavos P. Medicines in parallel trade trade parallel in Medicines P. Kanavos J, Costa-i-Font LSE specification. a Union: gravity in the European of School London June. 2007 papers working Health UK. London, Science, Political and Economics affordable on trade parallel of effects The D. Glynn accessmedicines.to from: Vogler S, Habl C, Leopold C, Morak S, Mazag J, Zimmermann N. PHIS Hospital Pharma 2010. Report Pharmaceutical System. Available Health from: downloads/hospitalPharma/PHIS_Hospital%20 Information Pharma_Report.pdf 2012/01/05]. content/default.asp?PageID=559&DocID=9158. R Development Core and Team. environment R: for statistical A Foundation computing. language R for Statistical Vienna, Austria. Computing. 2010.

26. 27. 25. 24.

CHAPTER

Is Europe still heading to a common price level for on-patent medicines? 2.3 An exploratory study among 15 Western European countries

Health Policy. 2013;112(3): 209-216

Christine Leopold, Aukje Mantel-Teeuwisse, Sabine Vogler, Kees de Joncheere, Richard Laing, Bert Leufkens Previous studies have suggested that medicines prices in Europe converge over Our study period included the time of the recession and several pricing policy measures measures policy pricing several and recession the of time the included period study Our

To explore whether ex-factory prices of on-patented medicines in Western Prices of ten on-patent medicines in five years (2007, 2008, 2010, 2011, 2012) of 15 : The prices between countries and selected products varied to a great extent from as : 60 remained stable around the country average. Further research is needed to expand the study to the is to study a needed expand research Further average. the country around stable remained countries. European Eastern and data prescribing include and size, sample bigger thecountry average. Prices lessofexpensive medicines remained relatively stable decreasedor over time, while prices of expensive medicines relatively increased. a observed we Conclusions: convergence price expected the of Instead medicines. of countries prices the European affected other All have may countries. 15 the of two only in changes price by driven divergence price Results low as an average price of € 1.3/DDD for sitagliptin in 2010-2012 to an average of € 221.5/DDDfor alemtuzumab in 2011. Between 2008 and 2012, a price divergence was seen which was fully driventwobycountries, Germany 27%expensivemore(upto thantheaverage) andGreece (up 32%to 14 cheaper than the average). All other countries had stable prices and centered around Objective: European countries have converged over a recent period of time. Methods Europeancountries wereanalyzed. Theunitanalysisof wastheex-factory perpricedefined€in daily dose (exchange rate indexed to 2007). A score (deviationproduct and per countryfrom as wellthe as the ranges wereaverage calculated for allprice) medicines. per ABSTRACT Background: time as a result of policy measures such as external price referencing.

Is Europe still heading to a common price level for on-patent medicines? An exploratory study among 15 Western European countries 2.3 Is Europe still heading to a common price level for on-patent medicines? An exploratory study among 15 Western European countries 2.3 61 The The European Competiveness Report 2006 illustrated that EU price convergence for With With respect to medicine prices research showed that depending on the extent of market Looking at the broader picture of consumer goods such as food, clothing and footwear, significant significant footwear, and clothing food, as such goods consumer of picture broader the at Looking medicines was more rapid in the second half of the 1990s as a results of the process of EU monetary EU of process the of results a as 1990s the of half second the in rapid more was medicines price price in 11 surveyed EU are Member due Differences States. to a expensive range of from thefactors: amountranging of medicines of kind different comprising mix the dispensed, pharmaceuticals original medicines to lower priced generics, the share of the price that is reimbursed by third party payers as as well as countries, EU pricing of strategies companies. Despite price significant across pharmaceutical medicines on-patent for convergence price be to appears there differences, [24]. EPR and trade parallel States, Member single of level the at regulation of effect combined the an important role allowing for trade of lower priced medicines from other countries [20,21]. [20,21]. countries other from medicines priced lower of trade for allowing role important an regulation, medicine prices previously in Germany, and Europe Kingdom vary United the to as such a – prices great extent: semi-regulated or prices free for with branded countries medicines in – are (such France applied as are than higher price Italy, regulations in statutory where countries highest the and lowest the ato between up25% of differences price to leads This [22,23]. Spain) or Between 1995 and 2010 a price convergence could be identified for the group of EU-27 countries [18]. [18]. than this average. lower countries 56% were prices in while Macedonia of EU-27 the 27 (EU-27), of EU States Member group the for identified be could convergence price a 2010 and 1995 Between market and for the market since it is do of the that rules for known not the medicines apply market asymmetries However, by characterized is general, in care health for market the does as medicines, plays trade parallel Still, market. regulated highly a is market pharmaceutical the Hence, [19]. failures product product in a given country [6]. It is the most used frequently pricing policy in (in Europe 2012, 24 factors these of All [7-10]). Kingdom United and SwedenDenmark, excluding countries European medicines[11-17]. of prices in differences of magnitude a leadto may differences in consumer prices exist across Europe according to Eurostat theaverage 2011.than 43%higher were in A Denmark prices Europe: recentacross study differences these highlighted (e.g. (e.g. Denmark) have free pricing at the manufacturer price level. Differencesalso exist in terms methodology which and applied is referencing) price internal or (external policy pricing which of (e.g. for external price which referencing and how many countries are included in the basket or referencing price External [2-5]. chosen is basket) a in price average an versus minimum the taking (EPR) is the practice of using the price(s) of a medicine in one or several countries in order of the price the or negotiating of setting purposes the for price to or reference a benchmark derive Slovak Republic (27.4%) in public control spending 2011 on [1]. medicinesTo countries have been Slovak Republic (27.4%) implementing different cost-containment mechanisms – focusing on medicine prices and/or on their prescribed volume. As pharmaceutical policies are national countries adopt competences differentapproaches to regulating European medicines prices. The majority of countries a few medicines. Only countries reimbursable to policies restricted pricing implementing for opt INTRODUCTION In the last decades pharmaceutical expenditure of total accounted health for care spending a in Europe. considerable These percentages percentage varied countries ranging to from a 6.8% in great Norway extent to among 33,4% in Hungary followed by Greece (28.5%) and : Variety of marketing authorization holders : Inclusion in the reimbursement market and therefore under price control : Different price segments (i.e. less expensive: ≤ €and 99/DDD expensive: ≥ € : On-patent during the observation period. As information on patent expiry : Five different therapeutic classes eachrepresented by two medicines ATC groupsATC Reimbursement Marketing authorization holder Price segment 100/DDD, DDD = defined daily dose accordingto [30]) A basket of ten products (cf. 1)Table was selected according to the following criteria: This study follows up on the results of previous research on price convergence of medicine Since the economic recession in 2008 many European countries have been forced to implement implement to forced been have countries European many 2008 in recession economic the Since Patent status

Price data were provided by the research institute Gesundheit Österreich GmbH / Austrian Health Health / GmbH Austrian Österreich Gesundheit institute by research the provided were data Price years many for service (PPI) Information Price Pharmaceutical the running been has which Institute, 62 1. 2. 3. 4. in the individual countries is scarce, theMedicine Agency date was of used [29]. authorization It was accordingassumed that to the patent the next wouldten Europeanyears.not expireIn addition,within the the price data was delivered for the active anothersubstance, indication which which gaveproducts were on the market. This information on whether generics were already on the market was included in Table 1. pricesHowever, of the on-patentin products thewere considered. price analysis only the in 15 Western European countries was chosen for this study. The country basket included followingthe countries: Austria, Belgium, Denmark, Finland, Italy,France, the Netherlands, Norway, Germany,Portugal, Spain, SwedenGreece, and Switzerland. Ireland, 1) the time of the recession (2007 – 2012). METHODS Study design and data sources A longitudinal study design over six years for a selected sample of ten on-patent medicines changes may have had an influence on medicine prices and on European price convergence. convergence. price European on and prices medicine on influence an had have may changes hypothesisexamineconvergencethepricethat to is study objectivethisTheEurope. of pricesin of on patented medicines in Westernrecession. Particularly, European this exploratory countriesstudy aims remainsat analyzing whether in medicine small timessample pricesof 10 on-patent medicines of in Western European ofa countries have converged during economic cost-containment policies to maintain their high-level healthcare services. Countries which were hit hit were which Countries services. healthcare high-level their maintain to policies cost-containment a bundle implemented andSpain Portugal) Greece, bycountries, (the the Baltic crisis significantly rates reimbursement in changes cuts, price as (such measures policy reimbursement and pricing of been have to appeared also countries European other all while medicines), on tax added value and policy these consequence a As [28]. systems pharmaceutical their optimizing on working constantly convergence. Starting from 2000 two clusters of countries were identified: the core EU countries countries EU core the identified: were countries of clusters two 2000 from Starting convergence. Benelux countries, Sweden,with a Denmark,Finland, and Ireland) Kingdom United Italy, (France, 15% price average gap; and the of cluster newer EU Member States as well as Spain, Portugal and [25-27]. level EU-15 the lower than 40% almost prices average had who Greece,

*less expensive: ≤ € 99/DDD and expensive: ≥ € 100/DDD ≥ expensive: and € 99/DDD ≤ expensive: *less

Centre for Drug Statistics Methodology Statistics Drug for Centre

ATC = Anatomical Therapeutic Chemical Classification; DDD = defined daily dose; EMA = European Medicines Agency; WHO CC = World Health Organization Collaborating Collaborating Organization Health World = CC WHO Agency; Medicines European = EMA dose; daily defined = DDD Classification; Chemical Therapeutic Anatomical = ATC

Immunosuppressants L04AA10 Wyeth/Pfizer Rapamune sirolimus Less expensive Less No 13/03/2001

Immunosuppressants L04AD02 Astellas Pharma Astellas Advagraf tacrolimus Less expensive Less Yes 23/04/2007

Interferon / Hepatitis C Hepatitis / Interferon L03AB11 Roche Pegasys alfa-2a peginterferon Less expensive Less No 20/06/2002

Interferon / Hepatitis C Hepatitis / Interferon L03AB10 Bayer Schering Bayer PegIntron alfa-2b peginterferon Less expensive Less No 25/05/2000

(withdrawal August 2012) August (withdrawal

Antineoplastic agents Antineoplastic L01XC04 Bayer Schering Bayer MabCampath alemtuzumab Expensive No 06/07/2001

Antineoplastic agents Antineoplastic L01XC06 MSD Erbitux cetuximab Expensive No 29/06/2004

Direct acting antiviral /HIV antiviral acting Direct J05AF09 Gilead Emtriva emtricitabine Less expensive Less No 24/10/2003

Direct acting antiviral /HIV antiviral acting Direct J05AE06 Kaletra ritonavir / lopinavir 20/03/2001 Abbott Less expensive Less No

Type 2 diabetes mellitus diabetes 2 Type A10BX04 Byetta exenatide 20/11/2006 Lilly Eli Expensive No

Type 2 diabetes mellitus diabetes 2 Type A10BH01 Januvia sitagliptin 21/03/2007 MSD Less expensive Less No

Therapeutic class Therapeutic code ATC authorization holder authorization name Brand ingredient Active of authorization of Price segment Price available

date EMA Marketing Generics Generics

Overview of the selected medicines selected the of Overview 1. Table year x) / average price of all products year x Thisscore per product was indexed tothe year 2007 toshow the price development over time. 64 Score per country year x = (average price country year x)A / average priceyear of all countriesx year x – average price of all countries illustrateTo the price development per product over time, a score per product was calculated, whichexpressedis thepercentageas deviation theaverageof priceallproductsof eachinyear: Score per product year x = (average price of product 1 year x – average price of all products To analyzeTo the price variance between countries for each product the range (the country with the highest and the lowest price level) as well as € the per average DDD of indexedthe unitto ex-factory2007 (=price referredin to as price price)convergence, wasa score calculatedper country in was calculated,each which year. is To expressed test as the for percentage deviation of the average price of all countries in each year: Fortwo active substances (cetuximab and alemtuzumab) no recommended DDD was available. Therefore the authors followed the recommendations Report of(EPAR) as published on the website the of the European Medicine EuropeanAgency [29]. Information Public Assessment on the recommended DDDs is provided in 2.Table Data analysis Definition of price type The unit of analysis was the ex-factory price per unit in €. accountTo for currency fluctuations exchangeratesfor Denmark, Norway,Sweden andSwitzerland wereindexed theexchange rate enhance comparabilityTo January 1of theunitasprices 2007. calculatedwere definedinto daily CollaboratingWHO definedthe asdosesby (DDD) StatisticsDrug Centre for Methodology [30]. commonly available in the 15 countries under investigation, which is manyalso caseslisted thesein selected Table 2. strengths In were the same as the recommended DDDCollaborating byCentre forDrug Statistics theMethodology cannotWHO[30]. We anydrawconclusions on whetherthese selected products alsorepresent theproducts with thehighest consumption, as we did not have any consumption data available. did not include information on official (statutory) discounts nor on commercial (voluntary) rebates. (voluntary) commercial on nor discounts (statutory) official on information include not did Definition of product gives2 Table anoverview ofthe available strengths, pharmaceutical forms andpack sizes ofthe selected products in the European countries. For the purpose of this study, we have selected thepresentation (i.e. the strength, the pharmaceutical form and the pack size) which was most [31]. Reasons for choosing price data from the Austrian Health Institute were: 1) accessibility of the 1) accessibility were: Institute Health Austrian the from data price choosing for Reasons [31]. data by the as 2) authors, the reliability data have been as collected part of [32] legal obligations for the [33] and 3) a became the of PPI point service Committee reference Pricing for the Austrian and European Commission for many EU Member States. The price data for provided this survey

In 2012 discontinuation of the 135 mcg strength mcg 135 the of discontinuation 2012 In

In August 2012 the EMA marketing authorization of alemtuzumab was withdrawn was alemtuzumab of authorization marketing EMA the 2012 August In

* The Nordic countries and Switzerland have traditionally bigger pack sizes e.g. 98 units units 98 e.g. sizes pack bigger traditionally have Switzerland and countries Nordic The *

DDD = defined daily dose; WHO CC = World Health Organization Collaborating Centre for Drug Statistics Methodology Statistics Drug for Centre Collaborating Organization Health World = CC WHO dose; daily defined = DDD

Tacrolimus (Advagraf) Tacrolimus 5 mg prolonged release capsules, 50 units 50 capsules, release prolonged mg 5 units 100 50, 30, capsules release prolonged mg 5 3, 1, 0.5, 5 mg, oral oral mg, 5

Sitagliptin (Januvia) Sitagliptin 14, 28, 50, 56, 98 units 98 56, 50, 28, 14, tablets coated Film mg 100 or 50 or 25 0.1 g, oral g, 0.1 units 28 mg, 100

(Rapamune) containing oral solution oral containing

Sirolimus Sirolimus 1, 30, 100 units 100 30, 1, bottle ml 60 tablets, coated Film mg 2 1, 0.5, 3 mg; oral mg; 3 units 30 tabs, f/c mg, 2

alfa-2b (PegIntron) alfa-2b 160, 200, 240, 300 mcg 300 240, 200, 160, injection, 1 unit 1 injection,

Peginterferon Peginterferon 80 mcg, vial containing powder for for powder containing vial mcg, 80 units 4 1, injection for powder containing Vial 150, 120, 100, 80, 50, 7.5 mcg, parenteral mcg, 7.5

alfa-2a (Pegasys) alfa-2a containing solution for injection, 4 units 4 injection, for solution containing injection for solution containing

Peginterferon Peginterferon 135 mcg, 0.5 ml prefilled syringe syringe prefilled ml 0.5 mcg, 135 units 12 4, 1, syringe prefilled ml 0.5 mcg 350 270, 134, 26 mcg, parenteral mcg, 26

(Kaletra) units mg 80+20 or 200+50

ritonavir / Lopinavir 80+20 mg, 60 mg oral solution, 5 units 5 solution, oral mg 60 mg, 80+20 360 180, 120, 60, 5, capsules or solution oral mg 60 or 133,33+33,3 or 100+25 0.8 g, oral g, 0.8

or 1.2 ml prefilled pen with solution for injection injection for solution with pen prefilled ml 1.2 or with solution for injection, 1 unit 1 injection, for solution with

0.25 mg 0.25 (Byetta) Exenatide 2.4 ml prefilled pen with solution for injection injection for solution with pen prefilled ml 2.4 0.25 mg, 2.4 ml prefilled (=10 mcg) pen pen mcg) (=10 prefilled ml 2.4 mg, 0.25 units 3 or 1 15 mcg, oral mcg, 15

(Emtriva) containing oral solution oral containing

200 or 10 mg 10 or 200 Emtricitabine bottle ml 170 or Capsules 200 mg, capsules, 30 units 30 capsules, mg, 200 units 30 or 1 0.2 g, oral oral g, 0.2

containing solution for infusion for solution containing parenteral

2 or 5 mg 5 or 2 (Erbitux) Cetuximab vial ml 100 or 50 or 20 5 mg/ml 20 ml vial for 1 infusion, 1 unit 1 infusion, 1 for vial ml 20 mg/ml 5 unit 1 No recommendation, recommendation, No

(Mabcampath) for solution for infusion for solution for for solution for infusion, 3 units 3 infusion, for solution for parenteral parenteral

10 or 30 mg 30 or 10 Alemtuzumab concentrate containing vial ml 1 30 mg, 1 ml vial containing concentrate concentrate containing vial ml 1 mg, 30 units 3 No recommendation, recommendation, No

Available strengths Available name) (brand Available pharmaceutical forms pharmaceutical Available as basis for this study* this for basis as sizes pack DDD DDD

substance Active Most commonly used presentation used commonly Most Available WHO recommended recommended WHO

Details on the selected medicines included in the study the in included medicines selected the on Details 2. Table 2012: exclusion of alemtuzumab EMA withdrawal in August 2012. Average = average of all countries included included countries all of average = Average 2012. August in withdrawal EMA alemtuzumab of exclusion 2012: points). points). = FI Spain, = ES Greece, = EL Denmark, = DK Germany, = DE Switzerland, = CH Belgium, = BE Austria, = AT study, the in Sweden = PTPortugal,SE = Norway, = NO Netherlands, = NL Italy, = IT Ireland, = IE France, = FR Finland, 66 Figure Figure 1. Country score 2007 - 2012.2007: exclusion of FI, IE, PT not sufficientnumber of data points (<4 data expensive country with up to 27% higher prices in 2012. The other countries in the basket are fairly fairly are basket the in countries other The 2012. in prices higher 27% to up with country expensive average. country the above or lower 10% around center to continue and stable Figure Figure 1 displays the score per country for whereas the average; selected country products. In the than 2007 expensive a more 15% price is is divergence Finland in basket product the noticeable: is Greece nearly 20% than In cheaper the decreases, 2008 country average. the price divergence are in a countries more of range price 10% 2008 below 2012 From until or the above the average. the be to continues Greece Germany. and Greece countries: two by driven only is divergence price most the remains Germany side other the On 2012. in prices lower 32% to up with country cheapest as as exenatide, cetuximab and sitagliptin, but larger had sirolimus substance active The and lopinavir/ritonavir. and increasing, tacrolimus, as such products for years, especially in more recent the largest relative price difference betweencountries, especiallyin the years 2010-2012 (2012: 22.2/DDD € Germany and average) (+88%)). the to compared (-61% 4.7/DDD € Greece Price convergence – score per country as as low as an average price of € 1.3/DDD for sitagliptin in 2010-2012 to an average of € 221.5/DDD Finland and (n=10) Denmark prices), maximum 50 of out (n=10 Germany 2011. in alemtuzumab for (n=8) were the countries with the highest prices; Greece was the country with the lowest prices percentage as (expressed range price The (n=4). France and Spain (n=5), Italy by followed (n=20), of the average price) was relatively small and constant over the years for some products such RESULTS Price variance prices medicine ex-factory of maximum) and (minimum range the and average the shows 3 Table from extent great a to varied products selected and countries between prices The products. all for

Tacrolimus Exenatide, Sitagliptin Lopinavir Emtricitabine, Cetuximab Sirolimus 2012

2a ‐ Peginterferon alfa Peginterferon alfa-2b Emtricitabine Lopinavir / ritonavir 2011 2007: no data for tacrolimus and exenatide, 2010 Years Exenatide Sitagliptin Peginterferon alfa-2a 2008 Tacrolimus Cetuximab Alemtuzumab Sirolimus ‐ ‐ 2007 5% 0%

-5%

10%

-10% -15% Average price per product ind product per price Average exed to 2007 to exed therefore products scores were indexed to 2008 2012: in noAugust data 2012) for and of peginterferon alemtuzumab alfa-2a (EMA(discontinuation market of segment “expensive”withdrawalthe are labeled135 with dotted lines.mcg strength). Products from the price Figure 2. Average price per product 2007 – 2012 indexed to 2007. the lowest price country (Greece) and the highest countriesprice remaining stablecountry within a price range(Germany) of 10% lower or higherwith as the countrythe average. other Further, the average prices of products which are less expensive seemed to remain stable over time, whereas the average prices of expensive products increased over time. DISCUSSION This study confirms the findings ofprevious studies [34-39] that prices of thediffer same medicine among European countries. Our study cannot convergence.confirm Our previous results rather clearshowed trends that there ofwas a price growing price divergence between less expensive products did not change over time as compared to the average price of all products. products. all of price average the to compared as time over change not did products expensive less average the with difference the i.e. 2012; in decreased ritonavir / lopinavir of score indexed the Only less a expensive relatively / price of the because average price became smaller lopinavir ritonavir, group the in products three the of two contrary the On 3). Table price also (see 2012 average in the increased that product, meaning 1, above scored cetuximab and (alemtuzumab medicines price. expensive of product average the to compared as time over increased products expensive of group the of Price development – score price average the to per as compared time over productproduct per development price the 2 illustrates Figure remained products expensive less most for score indexed The of year. a specific group within the of products of all year per price average the that meaning period, study the across 1 to close and stable Sirolimus Alemtuzumab Peginterferon alfa-2a Peginterferon alfa-2b Emtricitabine Cetuximab Sitagliptin Lopinavir / ritonavir Tacrolimus Exenatide 2012 2011 2010 Years 2008 2007 1

1,1 0,9 0,8

1,05 0,95 0,85 exed to 2007 to exed ind score Product ------1.3 6.4 13.1 2012 12.0 14.8 14.8 10.2 121.8 128.4 1.1 (82%)1.1 1.5 (116%) 4.7 (39%) 4.5 (70%) 5.2- (51%) 10.1 (68%) 10.1 8.5 (134%) 10.5 (80%) 16.7 (127%) 112.5 (88%) 16.2 (159%) 21.2 (107%) 135.3 (111%) 107.7 (88%) 107.7 22.2 (184%) 140.0 (109%) 140.0 1.3 6.4 2011 13.4 31.4 10.7 12.0 14.8 116.8 221.5 128.7 7.6 (71%) 7.6 1.2 (87%) 11.1 (75%)11.1 9.2 (77%)9.2 1.5 (112%) 5.0 (42%) 5.0 65.1 (56%) 65.1 11.0 11.0 (82%) 24.7 (78%) 4.9 (144%) 4.9 37.5 (119%) 37.5 16.2 (151%) 17.2 (129%)17.2 21.2 (143%) 159.8 (72%)159.8 114.3 (89%) 22.2 (185%) 135.3 (116%) 150.4 (111%)150.4 273.8 (124%) 273.8 1.3 6.4 13.7 31.7 10.9 14.6 12.0 2010 121.5 131.8 217.4 1.2 (86%) 5.3 (45%) 11.1 (76%) 11.1 7.6 (69%) 7.6 4.9 (76%) 4.9 7.7 (119%) 7.7 1.4 (107%)1.4 11.0 11.0 (80%) 37.5 (118%) 37.5 22.3 (70%) 17.2 (126%) 17.2 21.2 (145%) 114.3 (87%) 135.5 (111%) 146.1 (111%)146.1 16.2 (148%) 109.4 (90%) 109.4 169.4 (78%) 169.4 22.2 (185%) 266.9 (123%) 266.9 1.5 6.9 15.1 11.9 13.8 12.0 138.1 34.4 2008 226.1 124.7 1.3 (86%) 4.9 (71%)4.9 9.9 (83%) 9.9 1.7 (116%) 5.8 (49%) 11.4 (76%) 11.4 8.7 (127%) 11.0 11.0 (79%) 13.7 (115%) 17.1 (144%) 17.1 27.6 (80%) 27.6 17.4 (126%) 17.4 108.9 (87%) 108.9 261.5 (116%) 261.5 124.4 (90%) 124.4 142.8 (115%) 142.8 20.5 (136%) 166.1 (120%) 166.1 42.7 (124%) 184.7 (82%) ------1.4 6.4 11.8 13.7 14.8 34.6 2007 126.9 220.6 1.3 (91%) 7.5 (117%) 7.5 4.9 (77%)4.9 5.8 (49%) 11.5 (78%) 11.3 (83%) 1.5 (107%) 17.1 (144%) 17.1 28.5 (82%) 17.4 (127%) 17.4 123.0 (97%) 123.0 47.4 (137%) 47.4 191.4 (87%)191.4 261.5 (119%) 261.5 20.5 (139%) 134.9 (106%) 134.9 Indicator Minimum (as% of average) of (as% Minimum Average average) of (as% Maximum average) of (as% Minimum Average average) of (as% Maximum Maximum (as% of average) of (as% Maximum average) of (as% Minimum Average average) of (as% Maximum average) of (as% Minimum Average average) of (as% Maximum average) of (as% Minimum Average average) of (as% Maximum Minimum (as% of average) of (as% Minimum Average average) of (as% Maximum average) of (as% Minimum Average average) of (as% Maximum average) of (as% Minimum Average average) of (as% Maximum average) of (as% Minimum Average Minimum (as% of average) of (as% Minimum Average average) of (as% Maximum

Overview of averages and ranges of ex-factory medicines prices in €/DDD (exchange rate indexed to pinavir / pinavir € = Euro, DDD = defined daily dose Active substance Active (product) Tacrolimus (Advagraf) Peginterferon alfa-2a (Pegasys) Peginterferon alfa-2b (PegIntron) Sirolimus (Rapamune) Lo (Kaletra) ritonavir Sitagliptin (Januvia) Emtricitabine (Emtriva) Exenatide (Byetta) Alemtuzumab (Mabcampath) Cetuximab (Erbitux) Table Table 3. 2007) for all products in the basket (2007-2012) 68

Is Europe still heading to a common price level for on-patent medicines? An exploratory study among 15 Western European countries 2.3 Is Europe still heading to a common price level for on-patent medicines? An exploratory study among 15 Western European countries 2.3 69 : : since 2008 European countries have been struggling : European countries tend to regulate prices of reimbursable : As the currencies of non-Euro countries fluctuate over time, we There is a magnitude of factors leading to price differences, some of which include Currency fluctuations Price regulations for medicines Differencesin pharmaceutical policies exchange rate continuously decreased to around 20% below the rate in rate in2007. DenmarkThe remained more orexchange less stable. These facts need to be taken into account when interpreting the results. to control public spending on medicines. 3) decided to index the exchange rates of Denmark, Norway, Sweden and Switzerland to the year annualrealTheexchange countriesallof rate 2007. Norway of Swedenand increased 2007from –2008, but decreased from 2008 – 2012 to around 10% below the 2007 rate. In Switzerland the pricereferencing. This effect might be unfortunate for countries with less ability such as to pay, PortugalGreeceor even orformoreEastern European countries thehighasreference prices of earlylaunchthecountrieshigher their nationalthan are possibilities Germany But[35-37]. pay to withthe implementation of the AMNOG health care reform which links pharmaceutical pricing to added therapeutic benefit scores in 2011 and Sweden with its planspriceto referencing implement in 2013/2014external suggest that even more affluent European countriesare urged traditionally do not regulate medicines prices at pricesmanufactureratwholesale level andvia value-based pricing).level Another fact is,that these countries (Swedenhave only controls a long tradition of pharmaceutical industry representations in their countries. For this reason, they are very often first launch countries for new medicines as manufacturersfreely may which sethas pricesagain an influence on prices within other European countries dueto external but this divergence was largely driven by Greece having substantial lower prices starting in 2010. In In 2010. in starting prices lower substantial having Greece by driven largely was divergence this but contrast, some countries have managed to introduce well in policy advance prepared measures, 2009, in system price reference a by followed 2003 in substitution generic introduced Finland e.g. [40]. periodtime of longer a over decreases price in resulted which 2) medicines. Only a few countries (Denmark, Germany, Sweden and United Kingdom) payers payers to patients through increased out-of-pocket payments are common measures European authorities implemented in the last fiveyears [28]. In 2010/2011 Greece butalso Portugal had to their decrease prices by an of average 20-25%. Due to policies such as price external referencing clearly results Our [21]. countries other of level price the influencing are cuts price these Europe in countries, 15 of sample the at looking when divergence price a to led cuts price these that showed as market forces which include exchange rate fluctuations or competition post patent expiry[34-39]. Especially three factors are relevant for our study: 1) with an economic recession leading to cuts in healthcare budgets. Hence, public authorities are short-term of introduction the Especially medicines. on spending public contain to pressure under public from costs of shifts also but medicines, reimbursable for cuts price as such measures policy variations in a country’s income level, different value assessment of pharmaceuticals, different pharmaceutical policy regulations, other policies outside sector the such as pharmaceuticala country’s political or decision on healthcarebalancing social and industrial interests as well 70 Special thanks are given to the Austrian Health Institute for products.providing price data for the ten changes in only two of the 15 countries. All other European countries remained stable around the country average. We suggest further research inproduct sample size, thisand include prescribingarea data as well as Easterntaking European countries.into account a larger ACKNOWLEDGEMENTS recession which leads countries to implement cost-containment policy measures. CONCLUSIONS This exploratory study confirms differences in medicine prices across countries and over time. Instead of the expected price convergence we observed a price divergence driven by price limited financialresources volume data could not be acquired. A few authors suggest weighing medicine prices according to volume for better comparability [13]. However, as we looked price at convergence trends, we believe that additional information on volume would affected ournotresults. we Finally, had a small samplehave size. Dueto this small sample size it is a study findingsthe conclusions.tentative However, draw onlycan we and explorativecharacter, an with of the study add value to existing literature as it takes into account the current economic rebate dynamics are not transparent.notdynamics decisionex-factoryunitReasonsthetaking are rebate theforpriceof were: 1) countries apply external price referencing on the ex-factory price level, 2) no margins or (value-added) taxes (which vary to a great extent among European countries) are applied [4] on the manufacturer price level and 3) other policy mechanisms are appliedinstance when the takingreimbursement for price such as reference pricing and price negotiations includingdiscounts and Arebates second[4,6,21,37]. limitation is the unavailability of volume data: due to We We acknowledge that we faced several limitations during our study. The firstdisregardslists nationalprice in listed asex-factory priceunit the limitation discounts/rebates: of disregard is the official (statutory) as well as commercialtransparency (voluntary)as price convergence might discounts/rebates.have taken Thisplace but was is„hidden” as discounts anand issue of

20. 21. 14. 15. 16. 17. 18. 19. 10. 11. 12. 13. . http:// Drugs and and Drugs . Accessed 20 http://whocc.goeg.at/ . Accessed 10 May 2011. May 10 Accessed . http://apps.who.int/medicinedocs/pdf/ on medicines prices Series and on Pharmaceutical availability Pricing ReviewInterventions. May2011. Policies and pricing versus external price referencing. EMINet.referencing. price externalversus pricing 2010. Available from: Literaturliste/Dokumente/FurtherReading/Short-%20and%20longterm%20effect%20of%20value-based%20pricing.pdf May2011. Espin J, Rovira J, de Labry AO. Working Paper 1: External Price Referencing. WHO/HAI project Joncheere J, Leufkens HG, LeufkensJoncheere HG, Laing J, ExternalR. Price Referencing in Europe – a descriptive overview of one policy with many national characteristics. Health Policy. 2012;104(1):50-60. doi: 10.1016/j. healthpol.2011.09.008.Epub2011Oct19. Kanavos P, Nicod E, Espin J, van S. den Short- Aardweg and long-term effects of value based file/0008/98432/E83015.pdf. Accessed June 2012. June Accessed file/0008/98432/E83015.pdf. WHO Collaborating Centre for Pharmaceutical ReimbursementandPricing Policies.301Glossary of pharmaceutical terms. Latest update of print version:2011; regularly updated online. Available from: http://whocc.goeg.at/Glossary/Search.Accessed June2012. Leopold C, Vogler S, Mantel-Teuwisse AK, de whocc.goeg.at/Publications/BooksReportsAccessedMay202011. Mossialos E, Mrazek M, pharmaceuticals Walley T. Regulating in efficiency,equity, and quality. Maidenhead (UK): Europe: Open University striving Press. 2004; http://www.euro.who.int/__data/assets/pdf_ Available for from: from: from: s4912e/s4912e.pdf LeopoldRosian-SchikutaC,C,Hablde S, I, Vogler Joncheere K, Lyager Thomsen Pharmaceutical T. Pricing and (PPRI): final report. Reimbursement and Luxembourg. Consumer DG Health Information Protection Commission. of 2007; the European Available from: Vogler S, Habl C, Bogut M, Voncina, L: ComparingL:Voncina, M, Bogut C, Habl S, Vogler pharmaceutical pricingMember Union European the to Croatia in policies and reimbursement States.201115;52(2):183-97.AprCroatIn:Med J. al. et FM, Haaijer-Ruskamp MNG, Dukes containment. cost and affordability Prices, Money. WHO Regional Officefor Europe 2003; Available OECD. Pharmaceutical expenditure. As percentage percentage As expenditure. Pharmaceutical OECD. on Key Health: of health. Tables expenditure total from OECD. 2013; 2013. doi: August 17 Accessed 10.1787/pharmexp-table- 2013-1-en.

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Is Europe still heading to a common price level for on-patent medicines? An exploratory study among 15 Western European countries 2.3

CHAPTER

Re-evaluation and adjustment of pharmaceutical policies in times of economic recession 3

CHAPTER

Impact of the recession on the pharmaceutical policy environment and medicines sales 3.1 in eight European countries

Submitted

Christine Leopold, Aukje Mantel-Teeuwisse, Sabine Vogler, Silvia Valkova, Kees de Joncheere, Bert Leufkens, Anita Wagner, Dennis Ross-Degnan, Richard Laing Countries’ responses to the recession differed.We observed a higher density of To analyze how European pharmaceutical pricing and reimbursement policies Based on a wereview, literature describe pharmaceutical policy changes (2008-2011).

Economically stable countries (Austria, Estonia, Finland) implemented between two 78 policy changes implemented by less economically stable countries. Unexpectedlycountries showed moderatealmost increases in pharmaceuticalall sales volume despite declines in sales value, especially in the less economically stable countries. changesoccurred 2010in(n=33/88) and2011andincluded(n=40/88) changes out-of-pocketin payments (n=16/88), changes in price mark-up schemes (n=13/88) and price cuts (n=11/88). All countries showed moderate increases in sales volumesshowing slight (except declines after Portugal 2009), while and sales value Greece, decreased in both both country groups, greaterwith declines in economically less stable countries. Conclusions: constant dollars (value). We present sales growth rates, comparing economically stable versus less versus stable economically comparing rates, growth sales present We (value). dollars constant countries. member OECD of plans consolidation fiscal 2012 on based classified countries stable Results: and seven policy changes each; whereas economically less stable countries (Greece,Slovak Republic,Ireland, Spain, Portugal) implemented between 10 and 22 policy changes. Most policy economically stable and less stable countries in terms of expectedimplemented declines in pharmaceuticalpolicy expenditure.measures and Methods: Using IMS Health data (2006-2011), we analyzed quarterly sales of products in the 10 selling highest- therapeutic classes in eight European countries, in IMS standard units (volume) and ABSTRACT Objective: have changed and to describe changesclasses during the economic recession. in We hypothesized that differences pharmaceutical would exist between sales within major therapeutic

Impact of the recession on the pharmaceutical policy environment and medicines sales in eight European countries 3.1 Impact of the recession on the pharmaceutical policy environment and medicines sales in eight European countries 3.1 79 Because countries by thewere differently and Because affected countries to recession responses used different Vogler and colleagues [20] examined pharmaceutical policies implemented in Europe Historical Historical experience has shown that a recession, defined as two successive quarters of In Europe, Iceland was one of the first countries affected by the financial crises with the collapse collapse the with crises financial the by affected countries first the of one was Iceland Europe, In prior to and after the recession in these two country groups. We expected that some cost-containment cost-containment some that expected We groups. country two these in recession the after and to prior pharmaceutical that hypothesized and patients to medicines for burden financial shift would policies countries. stable economically less in especially period, this during decline would sales overcome budgetary constraints, we overcome budgetary constraints, planned to analyze in a way systematic how the European policy changed environment during pharmaceutical the recession by pharmaceutical describing and stable economically between them comparing and changes policy reimbursement and pricing classes therapeutic major in products of sales in changes described we Further, countries. stable less during 2010-2011 and found that countries, countries Greece, significantly Spain affected and by including the Portugal) price cuts, crisischanges abruptlyin reimbursement (therates and value-added implemented Baltictaxes on medicines. multipleIn other European policy countries (e.g. Italy), measures, with cost-containment measures already in place when the crisis began, ongoing policy changes were accelerated [21]. in in Greece and among many results they found that patients lost access to care and preventive services and that patients were facing higher risks of HIV and sexually transmitted diseases [18]. sales, medicines on recession the of impact the examined (WHO) Organization Health World The the that concluded authors The countries. 84 in 2009 and 2007 between prices and expenditures economic recession had mixed effects,with the largest declines in medicines sales occurringin [19]. Baltic States the in particularly Europe, in and countries high-income men men and women when unemployment rose rapidly during times of recession in Europe [12]; the [13] 2009 and 2007 between million 5.6 by increased Americans non-elderly uninsured of number [14]. recession this during care medical routine reducing reported Americans of quarter a over and Over the same period, deductibles and co-payments for officevisits and prescription medicines increased, leading to greater cost burden for consumers [15-17]. Similar Greece. effectsKentikelenis and colleagues werelooked at the seen health effects caused in by the economic crisis urged to implement public cost-saving measures, which affected public financing of healthcare [10]. [10]. healthcare of financing public affected which measures, cost-saving public implement to urged negative growth canin GDP, have severe negative impacts on population health due to a strong deterioration and utilization care health in declines and downturns economic between association in health outcomes [11]. For example, suicides and homicides increased among working-age of all three major banks in September 2008, followed by the Baltic countries (Latvia, Lithuania and Lithuania (Latvia, countries by the Baltic followed 2008, in September banks major of all three not was Estonia) recession [7-9]. the The Soon recession 2011. in and 2010 Europe in continued and Ireland and impacted especially Italy) Southern and European Portugal Spain, (Greece, countries but a of crisis theEurozone wholecountries, European of individual debtproblem only a financial were All countries Parliament. Bank and the European Central of and a the European priority high European public authorities have struggled to maintain high levels of access to care, while restraining restraining INTRODUCTION while care, to access of levels high maintain to struggled have authorities public European due in to increases expenditure higher [1-4]. demand for older care populations and increasingly [5-6]. budgets public on pressure additional exerted has recession global recent The Data included prescription-only medicines (on-patent as well as off-patent) limited to Further, we analyzed quarterly pharmaceutical sales data from January 2006 to December We sales received data in units and standard (volume) in dollars A constant (value). standard Slovak Republic and Spain) with social security majority of their systems populations, which orwere intended to represent national a cross-section of geographic health services for the 80 those with total sales of products by volume accounting for at least 50% of sales in each of the eight countries from 2008 to 2011 (Table 2). Data were aggregated by therapeutic class in each country; we did not have access to product-level data. Selection and grouping of countries We chose eight European countries (Austria, Estonia, Finland, Greece, Ireland, Portugal, the exchange rate for the latest study quarter (4th quarter 2011). Inflation was not taken into account. account. into taken not was Inflation 2011). quarter (4th quarter study latest the for rate exchange the retail market. We received data for the 10 highest-sellingeight study countries. therapeuticTherapeutic classes basedare ontheclasses European Pharmaceutical acrossResearch the Association (EphMRA) classification of Anatomical Therapeutic Chemical (ATC) classification[25]. The highest-selling therapeutic classes across the eight countries were identified among factory, wholesaler-to-pharmacy, factory, public. wholesaler-to-pharmacy, Average conversion factors are determined with the of co-operation the industry and pharmaceutical for each the country, data reflectlocal market IMS conditions. Health prices do not wholesalers account for between discounts manufacturers, exchange constant a at Dollars US to converted sales currency local are dollars Constant payers. or Dollar US the by period time each in value currency local the multiplying by calculated are They rate. unit, as defined by IMS Health, is the smallest dose of a product, equivalent to one tablet or capsule capsule or tablet one to equivalent product, a of dose smallest the is Health, IMS by defined as unit, injectable an for vial or ampoule one and syrup a for 5ml) (i.e. teaspoon one form, dosage oral an for for accurate most is that deemed level at the price captured are dollars in Sales constant product. Ireland, and Greece, Finland, in Estonia, level; price ex-factory the countries, most (in country, the wholesale prices were calculated back to ex-factory level). IMS Health applies average standard factors to conversion prices estimate at various price levels along the chain, e.g. ex- distribution 2) reimbursement, and 3) generics. 1Table lists and defines policy measures by foci. 2011. Sales data from IMS MIDAS Quantum (Multinationalwere provided Integrated by IMSData HealthAnalysis and System)are generated from reports pharmaceuticalby companiesmultinational to IMS Health [24]. and national from experts in national pharmaceutical pricing and reimbursement authorities who regular providepharmaceutical policy updates [22]. We also obtained data on pharmaceutical policies from PharmaQuery provided by IMS Health [23]. from We published added literature and informationgrouped changes on into six-monthpolicy implementationchanges periods from January 2008 until December 2011. We categorized policy foci in three main groups: 1) pricing, METHODOLOGY Data sources We used data from two sources to derive information on pharmaceutical policies. Information Pharmaceuticalcollectedthe by ReimbursementPricing and Information (PPRI)Networkcomes

Impact of the recession on the pharmaceutical policy environment and medicines sales in eight European countries 3.1 Impact of the recession on the pharmaceutical policy environment and medicines sales in eight European countries 3.1 81 For theanalysisFor dividedwe sales volume andsalesthenational valueofsizeby population to A number of changes in pharmaceutical policies occurred andafter Table 4 outlinethe the crisispolicy changes began.that were implementedTable 3a-cduring the observation period (2008-2011). We identified a total of 88 policy changes; the economically stable countries changes in sales value or volume attributable to any specific policy or set of setof policies. or specific any policy to attributable volume or sales in value changes RESULTS Pharmaceutical policy context during the recession Annual growth rate = ((per capita sales in year / per capita sales in previous year) -1) * 100 Average growth rate = (∑ annual growth rates / the number of years) * 100 the of complexity the and country each in recession the for points starting varying the of Because the estimate to unable were we period, this during implemented policies pharmaceutical of array per country but combined for all 10 therapeutic classes. As the picture was similar for individual and and individual for similar was picture the As classes. therapeutic 10 all for combined but country per combined. classes therapeutic all for results the present only we classes, therapeutic total control for population growth, using annual populations estimated from the Organization for EconomicCo-operation andDevelopment [27].(OECD)pharmaceutical Taking sales per capita both by volume and value, we calculated: We We firstthe categorized policy pharmaceutical measures by implemented each country in each six-month study period, and described the number of policy measures implemented per (in by volume sales year, pharmaceutical we Next, depicted category. per policy and group per country of quarter last the to 2006 of quarter first the from dollars) constant (in value by and units) standard then and separately class therapeutic per and country per data the at looked we step first a In 2011. needs (e.g. Norway, Sweden and Switzerland) [26]. For the purpose of this study, economicallywe definedless stable countries as countries belonging to category 1 or 2 (Greece, Ireland,Slovak Republic, Spain, Portugal) and economically category stable 3 or 4 (Austria, Finland countries and Estonia). as those belonging to Data analysis generalgovernment gross debt or targeting a long-term 60% debt-to-GDP ratio. They defined fourcategories of countries: 1) countries with International Monetary Fund /European Union / Europeancommission programsGreece, (e.g. Ireland and Portugal), countries2) underdistinct market pressure (e.g. Belgium, Hungary, Italy, Slovak Republic, and Spain), substantial3) countries deficits with and/or debts, but less marketFrance, pressure Germany, (e.g. and United Austria, Kingdom), Denmark,and 4) Finland, countries with no or marginal consolidation regions, economic wealth and stability, and different severity of therecession. selected To countries, group the we followed the categorization of countries defined byfor the OrganizationEconomic Co-operation and Development (OECD) with regard to 2012. fiscalOECD consolidationdefined in fiscal consolidation according to concrete policies aimed at stabilizing

reimbursed medicines or a group (e.g. specific indication), or out-of-schedule. or indication), specific (e.g. group a or medicines reimbursed

performed in combination with reimbursement reviews. Price reviews can be done systematically (e.g. once a year) for all all for year) a once (e.g. systematically done be can reviews Price reviews. reimbursement with combination in performed

Extraordinary price review price Extraordinary Review process of the decision on the previously set price of a medicine. Price reviews may, or may not, be be not, may or may, reviews Price medicine. a of price set previously the on decision the of process Review reviews: Price

: Introduction or abolishment of VAT on medicines, or increase or decrease in VAT rates on medicines. on rates VAT in decrease or increase or medicines, on VAT of abolishment or Introduction : VAT in Changes

medicines services, including medicines. including services,

Value added tax (VAT) on on (VAT) tax added Value A sales-tax on products collected in stages. It is a wide-ranging tax usually designed to cover most or all goods and and goods all or most cover to designed usually tax wide-ranging a is It stages. in collected products on sales-tax A VAT:

medicines, prescription-only medicines) to which the distribution remuneration applies to. applies remuneration distribution the which to medicines) prescription-only medicines,

type of distribution remuneration for a defined actor. Changes may also regard to the scope of medicines (e.g. reimbursable reimbursable (e.g. medicines of scope the to regard also may Changes actor. defined a for remuneration distribution of type

A decrease or increase in wholesale or pharmacy mark-ups or margins, or a change of of change a or margins, or mark-ups pharmacy or wholesale in increase or decrease A remuneration: distribution in Changes

as percentage of the selling price. selling the of percentage as

service remuneration service amount is added on to the cost of a good to create a profit (at the wholesale and/or retail levels), whereas a margin is expressed expressed is margin a whereas levels), retail and/or wholesale the (at profit a create to good a of cost the to on added is amount

dispensing fee/fee-for- dispensing schemes or, in the case of pharmacies, a fee-for-service remuneration. In case of a mark-up a defined (linear or percentage) percentage) or (linear defined a mark-up a of case In remuneration. fee-for-service a pharmacies, of case the in or, schemes

(mark-ups / margins/ / (mark-ups the case of pharmaceutical distribution, wholesalers and pharmacies are remunerated by linear mark-ups, regressive margin margin regressive mark-ups, linear by remunerated are pharmacies and wholesalers distribution, pharmaceutical of case the

Distribution remuneration remuneration Distribution The payment of a health care provider (individual or organization) for the services provided. In In provided. services the for organization) or (individual provider care health a of payment The remuneration: Distribution

changes of the basket of reference countries, in the ways of calculating the price to benchmark with etc.) with benchmark to price the calculating of ways the in countries, reference of basket the of changes

include the introduction or abolishment of this pricing policy as well as changes in the methodology (e.g. (e.g. methodology the in changes as well as policy pricing this of abolishment or introduction the include EPR in Changes

(EPR) benchmark or reference price for the purposes of setting or negotiating the price of the product in a given country. given a in product the of price the negotiating or setting of purposes the for price reference or benchmark

External price referencing referencing price External The practice of using the price(s) of a medicine in one or several countries in order to derive a a derive to order in countries several or one in medicine a of price(s) the using of practice The referencing: price External

Price cuts Price Pricing A cost-containment measure where the set price of a medicine is reduced by the authorities. the by reduced is medicine a of price set the where measure cost-containment A

Policy measure Policy focus Policy Definition

Overall policy foci, specific policy measures and definitions and measures policy specific foci, policy Overall 1. Table 82

whocc.goeg.at/Glossary

WHO Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policies. Glossary of pharmaceutical terms. Update 2013 (in print). Accessible at at Accessible print). (in 2013 Update terms. pharmaceutical of Glossary Policies. Reimbursement and Pricing Pharmaceutical for Centre Collaborating WHO Source: http://

patients/consumers and other stakeholders. other and patients/consumers

the use of generics and/or (licensed) off-patent medicines. Generic policies may be targeted at prescribers, pharmacists, pharmacists, prescribers, at targeted be may policies Generic medicines. off-patent (licensed) and/or generics of use the

Public campaigns campaigns Public Policies, regulation, measures and initiatives, typically undertaken by the government authorities, to promote promote to authorities, government the by undertaken typically initiatives, and measures regulation, Policies, policies: Generic

(imposing/eliminating financial incentives), change from indicative to obligatory generic substitution generic obligatory to indicative from change incentives), financial (imposing/eliminating

Introduction or abolishment, change in the way how generic substitution is organized organized is substitution generic how way the in change abolishment, or Introduction substitution: generic in Changes

substitution).

active ingredient(s). Generic substitution may be allowed (indicative generic substitution) or required (mandatory generic generic (mandatory required or substitution) generic (indicative allowed be may substitution Generic ingredient(s). active

or unbranded generic), with a less expensive medicine (e.g. branded or unbranded generic), often containing the same same the containing often generic), unbranded or branded (e.g. medicine expensive less a with generic), unbranded or

Generic substitution Generic Practice of substituting a medicine, whether marketed under a trade name or generic name (branded (branded name generic or name trade a under marketed whether medicine, a substituting of Practice substitution: Generic

eliminating financial incentives), change from indicative to obligatory INN prescribing INN obligatory to indicative from change incentives), financial eliminating

(generic) prescribing prescribing (generic) Introduction or abolishment, change in the way how INN prescribing is organized (imposing/ organized is prescribing INN how way the in change abolishment, or Introduction prescribing: INN in Changes

instead of the brand name. brand the of instead (INN) name proprietary

International non- International Generics Requirements for prescribers (e.g. physicians) to prescribe medicines by INN, i.e. the active ingredient name name ingredient active the i.e. INN, by medicines prescribe to physicians) (e.g. prescribers for Requirements prescribing: INN

Delisting Exclusion of a medicine from a reimbursement list (e.g. positive list), often resulting in exclusion from reimbursement. from exclusion in resulting often list), positive (e.g. list reimbursement a from medicine a of Exclusion

fixed or percentage co-payments and informal payments to health care providers. care health to payments informal and co-payments percentage or fixed

Out-of-pocket payments Out-of-pocket Payments made by a health care consumer that are not reimbursed by a third party payer. They include cost-sharing, cost-sharing, include They payer. party third a by reimbursed not are that consumer care health a by made Payments OOP:

identical or similar medicines, to determine the reference price reference the determine to medicines, similar or identical

Introduction or abolishment of a RPS, change in the methodology on how to build clusters (grouping by by (grouping clusters build to how on methodology the in change RPS, a of abolishment or Introduction RPS: in Changes

pricing) payments (e.g. prescription fees, percentage co-payment rates). rates). co-payment percentage fees, prescription (e.g. payments

or therapeutic reference reference therapeutic or difference between the reimbursed fixed amount (reference price) and the actual pharmacy retail price, in addition to any co- any to addition in price, retail pharmacy actual the and price) (reference amount fixed reimbursed the between difference

also referred to as internal internal as to referred also ingredient or in a given therapeutic class. If the price of the medicine exceeds the reference price, the insured must pay the the pay must insured the price, reference the exceeds medicine the of price the If class. therapeutic given a in or ingredient

Reference price system (RP, (RP, system price Reference Reimbursement The third party payer determines a reference price to be reimbursed for medicines with a given active active given a with medicines for reimbursed be to price reference a determines payer party third The system: price Reference http://www.ephmra.

1 Therapeutic class ACE Inhibitors, single ingredient as well as in combination with other antihypertensives other with combination in as well as ingredient single Inhibitors, ACE Anti-rheumatics Non-narcotic analgesics Anti-depressants Allergy, systemic and nasal preparations, topical products Respiratory agents Anti-diabetes products Anti-ulcer products Platelet aggregation inhibitors Lipid regulators 1 Ten Ten highest-selling therapeutic classes, accounting for 50% of product sales volumes across the ATC classification ATC accordingto European Pharmaceutical Research Association EphMRA, ATC = AnatomicalATC Therapeutic Chemical classification 1 org/classification/anatomical-classification.aspx ATC 3 levelATC N6A R1A6, R1B, R6A I,J,X A,B,C,D,E,F,G,H, R3 A2B B1C C10A,C,C11A C9A,B M1A, M2A N2A A10C,H,J,K,L,M,N,S,X Table Table 2. countries under investigation decreased decreased in all economically unstable countries. After the severe year-on-year decline in 2009, Estonia experienced increased a positive sales growth of rate 17% in whereas economically 2010, 84 countries countries average sales volume growth rates during the study period were marginal, from 1% ranging (Greece and Portugal) to 3% (in Estonia, Ireland and Slovak Republic). No differences were observed between economically stable versus unstable countries. When looking at annual above rates growth had countries all 2007 to 2006 from diverse: more is picture the rates growth 4%, with Estonia highest at 12%. In 2008 and 2009 growth rates remained fairly stable in Austria and Finland, but sharply decreased in Estonia (0% and –9%, respectively) and more gradually policies; only a few changes represented newly implemented policies such as the introduction of internal reference pricing in Finland [20]. Changes in medicines sales During the observation time all countries showed positive growth in per capita medicines sales volume for the 10 highest-selling therapeutic classes (Figure 1 and Table 5). However, in all occurred in 2010 (n=33) and 2011 (n=40), changes with in mark-up changes regulations in (n=13) out-of-pocketand price paymentscuts (n=11) (n=16), being policy the measures. most No frequentlychanges wereused implemented with regard to generic substitution.policies Pricing were implemented multiple times per country duringSpain enactingthe priceobservation cuts fourperiod, times with during 2008-2011. Most changes medicines,targeted reimbursableas the aim was to contain public spending on medicines, and built on existing (Austria, Estonia and Finland) implemented fewer policy changeshaving the (n=<10fewest (n=2),each) while withthe lessFinland economically stable countries (Greece, SlovakIreland, RepublicSpain, and Portugal) implemented between 10 and 22 changes per country. Portugal (n=22) and Spain (n=17) were the countries with the most changes. Most policy adjustments

85 economically stable and unstable countries. unstable and stable economically Figure 1. Total pharmaceutical sales by volume (in standard units) and value (in constant dollar) per capita of products in the 10 highest-selling therapeutic classes in in classes therapeutic highest-selling 10 the in products of capita per dollar) constant (in value and units) standard (in volume by sales pharmaceutical Total 1. Figure Value in constant dollar Value in constant

Volume in standard units Volume instandard

Economically stable countries stable Economically Economically unstable countries unstable Economically 35% of changes gradual price changes in regressive changes in resulting in new pharmacy

2nd half 2011 ES: decreases EL: originators upon patent expiry, and 15% for generics EL: calculation method PT: reference countries EL: in remuneration PT: remuneration (in effect in February 2012) EL: price list with price reduction of on average 10.23% -

changes in wholesale remuneration changes in wholesale remuneration changes of calculation method price cuts changes of calculation method abolishment of supply chain discounts decrease from 11% to 6.5% changes in wholesale remuneration changes in pharmacy remuneration increase from 8-10% for healthcare changes in wholesale remuneration for changes in wholesale remuneration for for remuneration wholesale in changes 1st half 2011 IE: EL: SK: EE: EL: EL: ES: ES: IE: Scheme”) Tech (“High medicines high-cost IE: general scheme of low-income patients products - EL: ES: new price lists

based on reimbursed medicines brands and parallel imports 7,5% price 7,5% cut for price increase for amoxicillin- for increase price 2nd half 2010 ES: 10-20% by medicines containing from withdrawal their avoid to market the PT: biologicals and HIV products - - EL: including price cuts IE: SK: - Policy measure Price cuts External price referencing (EPR) Distribution remuneration Extraordinary Extraordinary review price Value-added Value-added tax

emergency price cuts of up to a changes in calculation method price review took price cuts into 1st price cut for generics up to 30% to up generics for cut price 1st changes in calculation method changes in wholesale changes in pharmacy increase from 5% to 6% additional active substances changes in wholesale 2nd price forcut health7.5% increase non-oral preparations : by 40% for off-patent medicines 1st half 2010 ES: PT: ES: remuneration PT: remuneration PT: remuneration IE EL: maximum of 27% on all reimbursed medicines (except orphan drugs); for off-patent medicines priced at 90% below original ES: ES: care products, including original medicines), imposed in the form of a discounts shared by all actors in the supply chain, and 20% for incontinence products IE: to 21% PT: ES: account PT:

changes in in changes changes in in changes changes 2nd half 2009 EL: method calculation SK: countries reference IE: in wholesale remuneration - -

increase from from increase 5-12% price decrease decrease 1st half 2009 - - PT: cuts on generics AT: 10% to 20% from EE: 9% to 5% 30%

2nd half 2008 - - PT: price cuts for generics - IE: reimbursed medicines 1st half 2008 - - - - - Overview of pharmaceutical pricing policy changes implemented from 2008 until 2011 Policy measure AT =AT Austria, EE = Estonia, EL = Greece, ES = Spain, EPR = external price referencing, FI = Finland, IE = Ireland, PT = Portugal, SK = Slovak Republic, = value VAT added tax Distribution Distribution remuneration External price referencing (EPR) Price cuts price review price Value-added Value-added tax Extraordinary Table 3a.Table 86

Impact of the recession on the pharmaceutical policy environment and medicines sales in eight European countries 3.1 Impact of the recession on the pharmaceutical policy environment and medicines sales in eight European countries 3.1 87 changes 35% of gradual price changes in regressive changes in resulting in new pharmacy

2nd half 2011 EL: calculation method PT: reference countries EL: in remuneration PT: remuneration (in effect in February 2012) - EL: price list with price reduction of on average 10.23% ES: decreases EL: originators upon patent expiry, and 15% for generics

changes in wholesale remuneration changes in wholesale remuneration changes of calculation method price cuts decrease from 11% to 6.5% changes of calculation method abolishment of supply chain discounts changes in wholesale remuneration changes in pharmacy remuneration increase from 8-10% for healthcare changes in wholesale remuneration for changes in wholesale remuneration for for remuneration wholesale in changes 1st half 2011 ES: ES: IE: Scheme”) Tech (“High medicines high-cost IE: general scheme of low-income patients EL: ES: products - EL: SK: EE: EL: EL: IE: new price lists

based on reimbursed medicines brands and parallel imports 7,5% price 7,5% cut for price increase for amoxicillin- for increase price 2nd half 2010 - EL: including price cuts IE: SK: - - ES: 10-20% by medicines containing from withdrawal their avoid to market the PT: biologicals and HIV products Policy measure price review price Value-added Value-added tax Extraordinary Distribution Distribution remuneration External price referencing (EPR) Price cuts

emergency price cuts of up to a price review took price cuts into changes in calculation method 1st price cut for generics up to 30% to up generics for cut price 1st changes in pharmacy increase from 5% to 6% additional active substances changes in calculation method changes in wholesale 2nd price forcut health7.5% changes in wholesale increase non-oral preparations : by 40% for off-patent medicines 1st half 2010 remuneration PT: remuneration IE: to 21% PT: ES: account PT: ES: ES: ES: care products, including original medicines), imposed in the form of a discounts shared by all actors in the supply chain, and 20% for incontinence products ES: PT: ES: remuneration PT: IE EL: maximum of 27% on all reimbursed medicines (except orphan drugs); for off-patent medicines priced at 90% below original

changes in in changes changes in in changes changes 2nd half 2009 - EL: method calculation SK: countries reference IE: in wholesale remuneration -

increase from from increase 5-12% price decrease decrease 1st half 2009 - - AT: 10% to 20% from EE: 9% to 5% PT: cuts on generics 30%

2nd half 2008 - - - IE: reimbursed medicines PT: price cuts for generics 1st half 2008 - - - - - Overview of pharmaceutical pricing policy changes implemented from 2008 until 2011 AT =AT Austria, EE = Estonia, EL = Greece, ES = Spain, EPR = external price referencing, FI = Finland, IE = Ireland, PT = Portugal, SK = Slovak Republic, = value VAT added tax Policy measure External price referencing (EPR) Distribution remuneration Value-added tax Extraordinary review price Price cuts Table 3a.Table

shorter reimbursement frequency of publishing pricing at or below in the course of price price of course the in : limitation of certain

2nd half 2011 EL: reference price PT: reviews SK reimbursement categories SK: the reimbursement list EL: delisted medicines 49 review specificationsto compulsory e-prescribing and opening Faster market entry for introduction of optional 2nd half 2011 ES: generic prescribing PT: generic prescribing - PT: hours of pharmacies PT: generics subject to patent disputes (25 active substances)

increase in prescription fee elimination of co-payment limit optional generic prescribing cost-sharing agreements price calculation method and new delisting of(16 OTC branded introduction of negative list (including unit dose dispensing for four price calculation based on lowest daily co-payment linked to income delisting of selected medicines : new clusters 1st half 2011 1st half 2011 SK: - ES: substances ES: treatment costs PT: generic group SK AT: EE: ES: SK: EL: contraceptives, lifestyle medicines) ES: PT: non-prescription medicines, including paracetamol, omeprazole oral, contraceptives and antihistamines)

nation-wide generic campaign change from optional to e-prescribing calculation method establishment of instituteHTA Greece price cuts are taken into rebates for generics abolished Campaign to promote rational changes in reimbursement rates Madrid: underprivileged patients introduction of €0.50 per 2nd half 2010 2nd half 2010 EE: compulsory generic prescribing - IE: EE: ES: PT: medicines use; unit dose dispensing; display of prices on packs SK: EE: SK: account IE: medicine on prescription ES: will be given free access to products for seven rare diseases PT: (including antipsychotic medicines) - -

generic campaign 1st half 2010 - - EE: increase in price volume abolishment of OOP 1st half 2010 PT: agreement specified AT: prescription fee PT: for organ, tissue and stem cell transplant procedures 2nd half 2009 - - - 2nd half 2009 - - -

1st half 2009 - - -

2nd half 2008 - - - increase prescription fee increase in reimbursement introduction of internal increase in reimbursement rate rate reimbursement in increase Seroquel 1st half 2009 AT: PT: generics for 100%) to 95% (from pensioners income low for PT: rate for infertility drugs from 37% to 69% FI: FI: reference pricing

2nd half 2008 - - -

generics 1st half 2008 information campaign - - AT: increase 1st half 2 008 AT: prescription fee - - Overview of pharmaceutical reimbursement policy changes implemented from 2008 until 2011 Overview of pharmaceutical generics policy changes implemented from 2008 until 2011 AT AT = Austria, EE = Estonia, EL = Greece, ES Ireland, =PT = Portugal,Spain, SK = Slovak RepublicFI = Finland, HTA = Health Technology Assessment, IE = Policy measure AT = Austria,= Estonia,AT =EE Greece,=EL Spain,ES= Finland, =FI Ireland,=IE OOPout-of-pocket= payments, OTC = over the counter medicines, PT = Portugal, SK = Slovak Republic Policy measure Genericsubstitution Public campaigns and other generic policies Generic prescribing Delisting Out-of-pocket payment Reference price system Table 3c.Table Table 3b.Table 88

shorter reimbursement frequency of publishing pricing at or below in the course of price price of course the in : limitation of certain

2nd half 2011 EL: delisted medicines 49 review EL: reference price PT: reviews SK reimbursement categories SK: the reimbursement list specificationsto compulsory e-prescribing and opening Faster market entry for introduction of optional 2nd half 2011 ES: generic prescribing PT: generic prescribing - PT: hours of pharmacies PT: generics subject to patent disputes (25 active substances)

increase in prescription fee elimination of co-payment limit optional generic prescribing cost-sharing agreements delisting of(16 OTC branded price calculation method and new introduction of negative list (including unit dose dispensing for four co-payment linked to income delisting of selected medicines price calculation based on lowest daily : new clusters 1st half 2011 1st half 2011 substances SK: - ES: AT: EE: ES: SK: EL: contraceptives, lifestyle medicines) ES: PT: non-prescription medicines, including paracetamol, omeprazole oral, contraceptives and antihistamines) ES: treatment costs PT: generic group SK

nation-wide generic campaign e-prescribing change from optional to calculation method establishment of instituteHTA Greece price cuts are taken into rebates for generics abolished Campaign to promote rational changes in reimbursement rates Madrid: underprivileged patients introduction of €0.50 per 2nd half 2010 2nd half 2010 display of prices on packs SK: - IE: EE: ES: PT: medicines use; unit dose dispensing; EE: compulsory generic prescribing for seven rare diseases PT: (including antipsychotic medicines) - account IE: medicine on prescription ES: will be given free access to products EE: SK: -

generic campaign 1st half 2010 - EE: - increase in abolishment of OOP price volume 1st half 2010 cell transplant procedures AT: prescription fee PT: for organ, tissue and stem PT: agreement specified 2nd half 2009 - - - 2nd half 2009 - - -

1st half 2009 - - -

2nd half 2008 - - - increase prescription fee increase in reimbursement introduction of internal increase in reimbursement rate rate reimbursement in increase Seroquel 1st half 2009 FI: FI: reference pricing AT: PT: generics for 100%) to 95% (from pensioners income low for PT: rate for infertility drugs from 37% to 69%

2nd half 2008 - - -

generics 1st half 2008 - - AT: information campaign increase 1st half 2 008 - - AT: prescription fee Overview of pharmaceutical reimbursement policy changes implemented from 2008 until 2011 Overview of pharmaceutical generics policy changes implemented from 2008 until 2011 Ireland, PT = Portugal, SK = Slovak Republic AT = Austria,= Estonia,AT =EE Greece,=EL Spain,ES= Finland, =FI Ireland,=IE OOPout-of-pocket= payments, OTC = over the counter medicines, PT = Portugal, SK = Slovak Republic Policy measure AT = Austria, EE = Estonia, EL = Greece, ES = Spain, FI = Finland, HTA = Health Technology Assessment, IE = Policy measure Delisting Generic prescribing Genericsubstitution Public campaigns and other generic policies Reference price system Out-of-pocket payment Table 3c.Table Table 3b.Table 5 7 8 8 6 4 0 11 13 16 10 88 policy Total Total per 1 1 1 1 3 3 3 5 2 2 0 PT 22 2011=40 1 1 1 3 2 2 IE 0 0 0 0 0 10 1 1 1 1 1 1 3 2 2 4 0 ES 17 73 2010 =33 1 1 3 3 2 2 2 0 0 0 0 EL 14 Less stable countries 1 1 1 3 2 2 0 0 0 0 0 SK 10 2009=11 1 1 2 FI 0 0 0 0 0 0 0 0 0 1 1 1 1 1 7 2 0 0 0 0 0 15 EE 2008=4 1 1 6 4 0 0 0 0 0 0 0 0 Stable countries AT Extraordinary price review price Extraordinary Internal reference pricing Out-of-pocket payment Delisting Generic prescribing Generic substitution Public campaigns and other generic policies Price cuts pricing reference External Mark-up regulation Value-added tax Summary of policy changes from 2008 until 2011 With respect to sales value in constant dollars, the picture is more divergent. Average AT = AT Austria, EE = Estonia, EL = Greece, ES = Spain, FI = Finland, IE = Ireland, PT = Portugal, SK = Slovak Republic Policy focus and measures Total number of policy changes by country by changes policy of number Total Total number of policy changes by group Total number of policy changes by year Generics Reimbursement Pricing Table 4.Table werethe most frequently implemented policies. Both economically stable and less stable study countries experienced slight increases in medicine consumption (in standard units per capita) of the 10 highest-selling therapeutic classes during this period; however, economically less 90 DISCUSSION Countries adjust their pharmaceutical policy framework continuously, but a concentration of policy changes took place during the economic recession in 2010 and 2011, economicallyespecially stablein less European countries. Changes in out-of-pocket payments and mark-ups annual growth rates in sales value over the whole study period varied between -2% in Portugal to 5% in Estonia. However, from 2009 onwards all countriesvalue. The largest declines experiencedwere observed in Greece decreases(negative year on year growth in rate of -14% sales in 2010) and Portugal (-11% in 2011). Negative growth rates predominated in the economically unstable countries in 2010 and 2011. unstable countries continued to decline (for example, -4% in Greece and -1% in Portugal in 2010). 2010). in Portugal in -1% and Greece in -4% example, (for decline to continued countries unstable In 2011, two less economically stable countries experienced high growth in in sales Spain and volume 8% in (6% Ireland), while most other countries had a growth rate between 1% and 3%; 2011. in -4% of rate growth negative a had still it as exception the Portugalwas

Impact of the recession on the pharmaceutical policy environment and medicines sales in eight European countries 3.1 Impact of the recession on the pharmaceutical policy environment and medicines sales in eight European countries 3.1 91 2.1% 1.3% 1.5% 3.3% 3.5% 2.3% 2.3% 2.9% 2.4% 3.0% 4.3% 4.7% 0.9% 0.6% 0.8% -1.9% 2006-2011 2006-2011 Ø annual growth rate Ø annual growth rate 1.5% 1.1 % 1.1 3.1 % 3.1 1.5 % 0.7% 7.8 % 7.8 5.5 % 1.0 % 1.0 % 1.0 -3.7% -3.4% -3.2% -11.1% -2.4% -0.9% -3.7 % ’10 vs. ‘11 ’10 vs. ‘11 % 4.1% 7.0% 1.5 % 0.5% 0.4% -1.9% 3.4 % 3.4 17.1 % 17.1 0.7 % 0.8 % 0.8 -2.6% -4.6% -0.5% -4.1 % -4.1 -0.4 -13.5% ’09 ’09 vs. ‘10 ’09 ’09 vs. ‘10 1.1% 1.5% 1.7% 3.6% 2.3% 2.7% 2.7% 2.2% 6.8% 4.3% 0.3% 0.6% 0.7% -2.2% -2.2% -9.0% ’08 ’08 vs. ‘09 ’08 ’08 vs. ‘09 Annual growth rate Annual growth rates 7.1% 3.1% 1.4% 1.8% 7.2% 7.0% 5.2% 3.8% 6.3% 6.3% 0.3% 2.0% 0.2% 4.0% 14.6% -0.5% ’07 ’07 vs. ‘08 ’07 ’07 vs. ‘08 3.1% 6.1% 6.1% 6.1% 7.3% 7.6% 4.1% 5.6% 3.7% 5.4% 6.4% 4.6% 13.3% 12.2% 12.0% 20.5% ’06 ’06 vs. ‘07 ’06 ’06 vs. ‘07

IE PT SK AT EE FI EL ES IE PT SK AT EE FI EL ES Country-specific growthrates oftotal pharmaceutical sales volume in standard units and sales value in

countries countries countries countries

Our study showed that economically stable countries (Austria, Estonia and Finland) Unstable Unstable Stable Stable Less stable stable Less Stable Stable Ø = average, AT = Austria, EE SK= = Slovak Republic Estonia, EL = Greece, ES = Spain, FI = Finland, IE = Ireland, PT = Portugal, Country Value in constant dollar per capita Country Volume in standard units per capita Table Table 5. constant dollars per capita of the ten highest selling therapeutic classes from 2006 – 2011 strict medicine price cuts implemented in Greece, Spain and Portugal could have had negative effects on the availability of medicines if they caused pharmaceutical companiesto their withdraw products from national reimbursement lists [38]. However, contrary to our expectation, implementedfewerpolicyeconomicallymeasuresless compared to stablecountries (especially Spainand Portugal) during the study period. The most frequently implemented policy changes were in patient out-of-pocket payments. Previous studies have paymentsshown such as prescription feesthat tend to lead to decreasesincreases in medicine utilization,in especially co- in times of economic recession and increased unemployment [29-37]. Policy measures like the stablecountries showed decreases inannual growth ratesof medicines sales measured invalue percapita 2010inand 2011, which could however bepartially attributed inflationto was it as not taken into account in our study. Our Our study had several limitations. All study countries had different pharmaceutical policy The case of Estonia needs to be discussed separately. After a After decade The of case growth rapid prior of to needs Estonia to be separately. discussed price price systems may take several years, since many stakeholders are involved [46]. Most observed of the policy changes related to the implemented be recession could which referencing), were price external for adjustments basket the in countries of the changing existing policies (e.g. 92 pharmaceutical policies exist (e.g. in Italy or Spain), which we disregarded in our study of national national of study our in disregarded we which Spain), or Italy in (e.g. exist policies pharmaceutical reaction short-term a as policies implemented countries whether clear always not was It policies. changes. system planned long-term were policies if or constraints budgetary recession-related to For instance, in Finland, the implementation of internal reference pricing in 2009 was planned long before the recession [45]. The implementation of major policy changes such as reference alternative alternative policies for sharing the financialrisk of selected new, high-cost medicines including value-based pricing models (e.g. the UK) or risk-sharing agreements (e.g. Italy) [40-44]. determined. to be need will new these approaches effects of The frameworks prior to the economic recession and and at different adjusted times following their the policies recession. Even in within countries, different regional ways differences in reductions reductions in coverage of sick leave and increases in clinical staff workloadwithout increases in Our data salaryshow that [7,19]. by 2010, pharmaceutical consumption had returned to a similar level as prior to the recession, paralleling relatively Estonia’s quick recovery from the recession overall [26]. Interestingly, early in the recession, none of the countries implemented targeting policies consumption by specific patient groups or in specific rather adjusted therapeutic and areas;enforced existing countries policies. More recently, several countries have explored a a reduction of 100 million with Euro compared 2008, with € 50 million cut health from insurance expenditures [7]. implemented A Estonia previous study response, detected In severe declines data. in our pharmaceutical by consumption mirrored of finding a [19], Estonia in 2008/2009 in -18% strict cost-saving measures, including changes in out-of-pocket payments, rates increases on medicines in and changes VAT in mark-ups for medicines. In addition, regulators introduced of lowering public spending while maintaining access to study levels.medicines However, at some relativelyof the stable policies, e.g. increases in out-of-pocket payments formay have shiftedpatients, financial burdento patients. the recession, during which public sector expenditures grew 6.5 times [26], Estonia experienced 6.6%, by cut was spending sector Public 2009. in (GDP) product domestic gross of decline major a of important medicines for chronic dropped diseases, drastically in such Greece and as in Portugal ACE in 2010 [38-39]. inhibitors Despite pre-recessioncomparedgrowthsalestorates, positivedownturn innevertheless a been or have appears to growth, there anti-depressants, which ranged from 5% to 12%. In contrast, pharmaceutical sales by value experienced declines during the recession, especially in less policies economically implemented stablein less countries.economically The stable countries pharmaceutical may have had the desired effect we did not find major declines in pharmaceuticaltherapeutic consumption categories duringstudied theas recession most countries in except the for Greece to and Portugalhave continuedmoderate positive annual growth in pharmaceuticalmedia reports saleson drug shortagesvolumes. in Greece Butand Portugal,in our data lineshowed that with sales volumes

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Impact of the recession on the pharmaceutical policy environment and medicines sales in eight European countries 3.1

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Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland 3.2 and Portugal: interrupted time series analyses

Submitted

Christine Leopold, Fang Zhang, Aukje Mantel-Teeuwisse, Sabine Vogler, Silvia Valkova, Dennis Ross-Degnan, Anita Wagner We obtained monthly IMS sales data in standard units of antipsychoticofstandardunits obtainedmedicinesinmonthlysalesdata IMSWe Different policy approachesto contain pharmaceutical expenditures in the study To To analyze the impacts of two different pharmaceutical policies – the : : Both countries’ policy approaches were associated with slight, likely unintended, : 100 impacts. The latter finding stresses the importance of monitoring and evaluating the effects of pharmaceutical policy interventions. in Portugal resulted in a substantially increased generic market share for amisulpride (estimate oneyear post-policy compared tobefore: generic 22.95%[21.01%, risperidone24.90%]; already dominated the market prior to the policy interventions. Conclusions countries had different intended – increased use of generics – and likely unintended – slightly decreased overall sales possibly consistent with decreased access to needed medicines – Results decreases in overall use of antipsychotic medicines and to increases in generic market share of major antipsychotic products. In Finland quetiapine and risperidone experienced substantially increased generic market shares quetiapine: 6.80% (estimates risperidone:[3.92%, 9.68%]; 11.13% [6.79%, 15.48%]. The policy one interventions year post-policy compared to before, payer in Portugal – on the utilization of antipsychotic medicines. Methodology: in Portugal and Finland for the period January 2007 to December 2011. We used an interrupted time series design to estimate changes in overall use and generic market shares by comparing pre-policy and post-policy levels and trends. ABSTRACT Objectives implementation of a reference price system in Finland and a mix of policies including changes in reimbursement rates, a generic promotion campaign and discounts granted to the public

Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2 Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2 101 On April Finland 1, 2009, implemented a reference price system whereby all medicines with Our Our intent was to assess the impacts of differentcost-containment policiesin Finland and Antipsychoticmedications essentialare treatment forsevere chronicofmental illness, such European Commission, the European Central Bank and the International Monetary [23]. International Fund) Bank the and Central European the Commission, European therapeutic alternatives on the National Social Security’s reimbursement list were clustered implement implement already planned policy changes. The recession affected bothcountries differently. recession. the during (GDP) product domestic gross in declines major experience not did Finland Portugal, sufferedhowever, a decline 2.9% in GDP growth between2008 and 2009 and another plan savings budget public year three strict a to leading [22] 2011 and 2010 between 1.7% of decline between the Portuguese Ministry of Finance and (consisting of of the representatives the Troika antipsychotic agents among patients with severe mental illness [21]. Portugal on medicines utilization within each country and to compare the magnitude of effects. We focus on antipsychotic medicines because they are included in the public reimbursement systems in both countries and because of the public health relevance of antipsychotic disorders and their treatment. The recent recession has put additional pressure on both countries to selective serotonin reuptake inhibitors while introduction was associated of with therapeuticreduced cost referenceper defined pricing daily dose of these medicationset [19].al. Soumerai found that implementation of a policy that required ofprior approvalspecific for atypicalreimbursement antipsychoticsto control expendituresdiscontinuityincreasedantipsychoticofresultedrates programinof treatmentdrug These [20]. in one US state public insurance resultsare consistent with an earlier study of the effects of other policies on discontinuation of in light of increased out-of-pocket payments [16] or to shift to other possibly less appropriate or more costly treatments [17]. For example, Wladysiuk etrisperidone al.for schizophreniashowed in Polandthat decreased the with increasedutilization patient co-payments,of while olanzapine use increased once co-payments were reduced when generic olanzapine became available [18]. Andersson et al. determined that introduction of a tiered co-payment schedule was associated with decreased cost and volume for all groups of acetic acid derivates and World Health Organization describes schizophrenia as a severe form of mental illness affecting about 7 per thousand of the adultbetween population;15-35 years aboutold [15]. 24 Due million to their people high large component worldwide cost,of public spending on mostlyantipsychotic medicines and are therefore amedications frequent target of cost- represent a containment. Reimbursement restrictions may, however, force patients to forego treatment strategies to contain costs [1-5]. Changes in co-payments and increases in value-addedfrequentlymedicinesmosttheamongimplementedon were cost-containment (VAT) taxesmeasures in 2010 [6]. Pharmaceutical cost-containment policies do not necessarily achieve the intended financial savings and may have unintended effects on medicines utilization[7-12]. as schizophrenia, which are among the leading major chronic diseases in Europe [13,14]. The INTRODUCTION Europeansocialsecurity difficultguaranteeingsystemsthe face of task their citizens sustainable access to medicines. Innovative, specialized, often costly medicines as have well put as enormousthe recession pressure on public budgets. European countries have chosen different We We hypothesized that the implementation of price the system and reference delisting of the In In contrast, Portugal introduced several contemporaneous cost-containment policies: on purchases of registered medicines by retail pharmacies from wholesalers in each country. IMS audits audits IMS country. each in wholesalers from pharmacies retail by medicines registered of purchases or cover 812 100% pharmacies of or the in 99% market pharmacies and retail of Finland 2,910 the of view consistent a globally into audits national combines MIDAS IMS [35]. Portugal in market retail 102 METHODOLOGY Data source We analyzed monthly sales pharmaceutical in Finland and Portugal between January 2007 and December 2011 provided by IMS Health [34]. Data are through generated audits of aggregated brand product Seroquel in Finland would lead to an increase in but sales of generics, (by volume) an would increase in leadFinland to Seroquel product brand rates also hypothesized that the We no in utilization. in change reduction reimbursement overall medications antipsychotic of volume by sales in decrease unintended an to lead would Portugal in an expected we Finally, changes. policy the after co-payments higher pay to had patients many as campaign. generic the of result a Portugal as in share market generic the in increase about about the use of and generics to alert to consumers the lower price of as generics to compared effect took price of retail the 2010 on 15, a maximum deduction October 6% [32]. Finally, originals for medicines that public had the not to already lowered prices actors earlier; this deduction chain did not supply affectand the final industry by granted discount statutory a is and price consumer applied. still was deduction this 2013 of beginning the In [33]. payer antipsychotic medicines for free as physicians could state certain pathologies (as listed in legislation) legislation) in listed (as pathologies certain state could physicians as free for medicines antipsychotic to co- the were without dispensed patient medicines for on which antipsychotic the prescription payment [31]. Following the change in rates, reimbursement no co-payment indication-specific launched INFARMED 8 2010, October to 15 September from addition, In allowed. were exemptions public the inform to we save”) all save, (“you generics promote to campaign radio and a television its reimbursement scheme on January 1, 2009, because the manufacturer did not decrease its price to that of the 40% less expensive generics when it became available [27,28]. (INFARMED) Products Health and Medicines for Authority National Portuguese the 2010, 15, October Prior [29,30]. of to 90% charges medicines for antipsychotic rates the reimbursement harmonized received patients all in reality but at 37%, reimbursed were medicines antipsychotic change, the to that a hoped for effect ofreference pricing is thatexpensive manufacturers, (mostly anticipatinggeneric) products, shifts decreaseto less prices to not lose customers to Pohjolainen[24]. Accordinget al., the average price level for all medications decreased significantlyfirst in the four quarters after the implementation of thereference led to price€ 109 systemmillion savings in [25,26]. Finland, In addition which to establishing reference pricing, the SocialNational Security Scheme delisted the antipsychotic brand product Seroquel (quetiapine) from according to therapeutic similarity based on each medicine’s Medicinesindication in andclusters werepharmacology. considered substitutable. For each substitution group a reference price was set at the price of the least expensive medicine in to the pay cluster thewith patientsdifference having for higher cost medications out-of-pocket. Danzon et al. highlighted

Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2 Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2 103 We extracted information on policy changes in each country from the WHO Collaborating resultswere similar we display only the results fromthe models with phase-ina period. Further, we estimated absolute changes from the counterfactual one year after the policy intervention, giving detail on the difference between the actual and predicted values.We performed the given month after the policy represented the full policy effect.To allowan for anticipatorythe possibility response of to implementation of the policy, we of considered four a monthsphase-in priorperiod to the policy interventiondata pointsin fromboth the countries time-series and model excluded [41-44]. theseWe also fourcomparing performed results from interrupteda timessensitivity series models analysiswithout a phase-inby period, but as the segmented regression models to statistically estimate aggregate changes in levels and trends of monthly sales by volume from the pre-policy period to the post-policy period. Each model included a term to estimate the baseline trend, a binary indicator for all post-policy months to estimatetheimmediate level change inthe outcome measure following thepolicy change, and a term indicating the number of months after policy implementation to estimate thein changetrend (slope) during the post-policy period. The combined change in level and trend at a period and country, and generic products which are not subject to patent protection. Study design and data analysis We used an interrupted time series design, the strongest quasi-experimental designestimatechanges salesin attributable[40], thepoliciesto to comparingby sales afterthe interventions to estimated sales based only on pre-policy levels and trends (the counterfactual). We used A standard unit, as defined by IMS Health, is the smallest dose of a product, equivalentto one tablet or capsule for an oral dosage form, one teaspoon (i.e. 5 ml) for a syrup and one ampoule injectablevialanforor product. Percentmarket percenttheshareistotal volumeof retailthe in market for each active substance in two categories – be originatorprotected or no-longer-protectedbrand byproducts, patents dependingwhich on their canexclusivity status in each percentage market share by volume in a therapeutic class. For the total volumedivided analyses, the we total volume, which is the number of thestandard national populationunits to control(SU) for populationper growth, month,using annual bypopulations estimatedsize of from the Organization for Economicanalyses Co-operation included prescription-only and antipsychotic Development which medicines (OECD) represented 98% limited [39].of medicines to sales Our by thevolume in Portugal retail and 87% market, in Finland in 2011. Centre for Pharmaceutical Pricing and Reimbursement Policies [37] and the IMS PharmaQuery databases[38].addition,In information policyon changes wasverified nationalby experts from Finland and Portugal through written communication. Outcomes We used two outcome measures: total volume of antipsychotic medicines per capita and pharmaceutical markets. Documentation on the IMS data collection and validation process is available available is process validation and collection data IMS the on Documentation markets. pharmaceutical upon [36]. request from (EphMRA) the medicines were authors. Association Antipsychotic those in Research Therapeutic Anatomical Pharmaceutical European the of N5A category (ATC) Chemical

11.13 4.59 6.80 -0.97 22.95 -3550 -4686 (95% CI) (95% (2.67, 6.51) (2.67, (3.92, 9.68) (3.92, (-3.75, 1.81) (-7354, 254) (6.79, 15.48) (6.79, (-8758, -613) (21.01, 24.90) one year post-policy post-policy year one Absolute estimated change change estimated Absolute

- 0.19 0.19 -273 0.82 -0.25 -2.06 -2.06 -2.04 (95% CI) (95% (-572, 26) (0.56, 1.09) (0.06, 0.31)(0.06, (-2.18, (-2.18, -1.95) (-0.36, -0.13) (-2.20, -1.88) Monthly trend trend Monthly change post-policy post-policy change

- 2.16 2.16 2.22 37.65 33.61 12.23 -4686 (95% CI) (95% post-policy post-policy (0.76, 3.57)(0.76, (0.30, 4.14) (9.61, 14.85) (9.61, (31.61, 35.61) Level change change Level (-8913, -458) (34.60, 40.69) (34.60,

- - 2.19 704 2.07 0.07 0.07 -0.08 (95% CI) (95% (519, 889)(519, (1.97, 2.17) (1.97, (2.03, 2.34) (-0.02, 0.17) (-0.15, 0.01) (-0.15, trend pre-policy pre-policy trend Monthly baseline baseline Monthly

Estimates of baseline trend, level and trend changes, and absolute changes one year after the policy interventions interventions policy the after year one changes absolute and changes, trend and level trend, baseline of Estimates Variable (unit) Total sales growth per per growth sales Total population 100,000 (SU) Risperidone (%) share market generic Amisulpride (%) share market generic 100,000 population (SU) (SU) population 100,000 Quetiapine (%) share market generic Risperidone (%) share market generic Clozapine (%) share market generic Total sales growth per per growth sales Total

Figure Figure 1 and Table 1 show the total monthly sales of antipsychotics in standard units per Portugal Finland CI = confidence interval, SU = standard unit Data source: IMS MIDAS®, January 2007 and December 2011, IMS Health Incorporated. All Rights Reserved. for total antipsychotic sales and for generic market share of major active substances in Finland and Portugal and 1. Finland in Table substances active major of share market generic for and sales antipsychotic total for 104 predicted predicted sales) one year after the implementation of the reference an was price there interventions, policy the system. after however policies; In the to prior Portugal constant remained sales estimated decrease in level of antipsychotic sales of 4,686 SU (95% -458) CI: per -8,913, 100,000 policy. the yearafter the in constant remained sales), which predicted of 4.5% people(or capita capita in both countries. In Finland, prior to the implementation of the reference price system, antipsychotic sales were increasing by 704 SU (95% 889) CI: perpeople 519, 100,000 per month; after the policy intervention sales growth decreased by 273 SU (95% CI: -572, 26) people per per month 100,000 compared to pre-policy sales growth. There was no discontinuity in level of sales at the time of intervention. This resulted in an estimated reduction of 254) 3,550 -7,354, per SU 100,000 people in (95% actual CI: sales compared to predicted sales (or around 2.3% of The antipsychotic market in Finland quetiapine (31%), clozapine was (12%) and risperidone dominated(12%), based on aggregated sales by by volume three from leading 2007 to 2011. In activePortugal risperidone (17%), substances: quetiapine (17%) and amisulpride (12%) were the top three active substances sold in the class during that period. analyses in SAS 9.3 and used a stepwise selection predictorsapproach, (p >= 0.2) from whichthe model in order ofremoved least significance.non-significant RESULTS

Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2 Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2 105 Observed Figure 2 displays the time series of generic market shares as percentage of total standard In Finland, retail generic market share of all three antipsychotic substances was around by(95%33.61% CI:31.62%, 35.61%);accompanied decreasebya inmarket share growth of2.06% (95% CI: -2.18%, -1.95%) per month, which resulted in an estimated increase of 6.80% (95% CI: generic 3.92%, 9.68%) market share one year after the policy implementation period. A similar 20% prior to the implementation of the reference price system with rapidly increasing generic market shares of risperidone (2.19% (95% CI: 2.03%, 2.34%) per month) and quetiapine remainedclozapineshare(2.07%marketgeneric inincrease themonth),while per 2.17%) 1.97%, CI:(95% low (0.07% per month (95% CI: -0.02, 0.17)). After the implementation of the reference pricesystemdelisting theand Seroquel,of generic themarket quetiapineshareof increased abruptly units for the three leading antipsychotic substances in each country. We examined quetiapine, clozapinerisperidoneand Finlandin amisulprideand risperidoneand Portugal;in nowerethere generic quetiapine products on the market in Portugal at the time of the intervention. Figure 1a & b. Interrupted time series of the total retail antipsychotic markets in Finland and Portugal. and Finland in markets antipsychotic retail total the of series time Interrupted b. & 1a Figure values and interrupted Portugal. and time Finland in series interventions policy the estimates of period of phase-in the after the and before total month) per retail persons antipsychotic 100,000 market volume (standard unit per All Rights Reserved. IMS January Incorporated. December Health and 2011, 2007 IMS MIDAS®, source: Data Observedvalues 15.48%) 15.48%) in generic market share due to the policies. shares Post-policyfor clozapine were changesrelatively minor comparedin to the genericother two activemarket substances. After the introduction of the reference price system, there was a slight increase of 2.22% (95% CI: 106 abrupt shift to generics was seen for risperidone. After the introduction of the reference price system, there was an immediate increase (95% ofCI: 37.65% 34.60%, 40.69%) in generic market share accompanied by a decrease in slope of 2.04% (95% CI: -2.20%, -1.88%) per month, which resulted in a generic market share that continued to increase slightly period.during the One post-policy year after implementation, we estimated an increase of 11.13% (95% CI: 6.79%, FigureInterruptedb. &a 2 time series ofretail generic market shares inFinland andPortugal. and interrupted time series estimates of the retail generic market shares (percentage, standard units of generics per month) of the three top active substances in the antipsychotic market before and after the phase-inof theperiod policy interventions in Finland and Portugal. Data source: IMS MIDAS®, January 2007 and December 2011,IMS Health Incorporated. All Rights Reserved.

Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2 Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2 107 The two countries’ policy trajectories differed. Thereference price system in Finland was In Portugal, the generic market prior to the multifaceted policy changes looked quite and the actual price, generating an incentive for patients to request a medicine that is pricedat or below the reference price. We demonstrated that Finland achieved the reference price guaranteeing a successful implementation of a generic policy is a transparent implementation pharmacists,doctorsstakeholders,and involvement allprocessaccompaniedasearly such ofby detaileda wellasmethodologyas positiveand perceptions patientsof towardsgenerics [47,48]. Systemchanges such asreference price systems areintended facilitateto changes inbehaviors patientsof healthandproviders encouraging byprice-sensitive;more be them to referencea in price system patients have to pay out-of-pocket the difference between thereference price (amisulpride); generic risperidone already dominated the market prior the policy interventions. interventions. policy the prior market the dominated already risperidone generic (amisulpride); prepared well in advance of implementation. generic In substitution, April 2003 requiring Finland pharmacists introduced to substitute mandatory with higher-pricedless-costly generic branded versions. medicinesThe mandatory generic substitution at elementskeytheAmongoftheaveragesubstitutable prices of [45,46]. medicines10%than timemore by decreased unexpected in Finland. In Finland two of the three leading active substances in the antipsychotic but share, market generic in increases substantial experienced risperidone) and (quetiapine class not the third substance (clozapine). In contrast, in Portugal the combination of policies which included statutory discounts granted to public payers, changes in reimbursement rates, and a generic campaign resulted in a major increase in generic market share only for one molecule DISCUSSION Our analyses showed that both countries’ policy approaches were associated with an increased use overall in decrease slight unintended likely a to also but expected, as generics of share market of antipsychotic medicines. The decrease in overall use was expected in Portugal, but somewhat market share one year after the policy intervention. The market beenfor almost risperidoneentirely generic priorhad to thealready reimbursement policy. After the policy, there was an estimated increase in generic market share of 2.16% (95% CI: 0.76%, 3.57%) and an increase in trend of 0.19% (95% CI: 0.06%, 0.31%) per month, resulting in an estimated increase of 4.59% (95% CI: 2.67%, 6.51%) in total generic market share one year after the policy mix. Details of the time series estimates and confidence intervals are summarizedTable in1. different from that in Finland. Generic market shares for amisulprideremained and between20% throughout the 10% pre-policy period with no increasing trend, while the generic market share of risperidone was already around 90% prior to the policy. After implementation of the policies, there was an immediate increase in generic market 14.85%)share for amisulpride andof an increase in market12.23% share trend of 0.82% (95%: 1.09%) per 0.56%, (95% CI: 9.61%, month, resulting in an estimated increase of 22.95% (95% CI: 21.01%, 24.90%) in total generic 0.30%, 4.14%) in generic market share accompanied by a (95% per CI: -0.13%) 0.36%, month,slight resulting in an estimateddecrease decrease (95% CI: of 0.97% -3.75%, in slope of 0.25% -1.81%) generic market share one year post-policy. IMS data represent country pharmaceutical markets consistently over time. They allow Adherence Adherence to therapies is especially challenging in this patient group, and changes in cost- In both countries, one of the most frequently sold active substances did not increase in generic generic in increase not did substances active sold frequently most the of one countries, both In In Portugal,In wefoundthat thecost-containmentmixof measures thatwereongoing before reductions in reimbursement rates on utilization and long-term health outcomes. outcomes. health long-term and utilization on rates reimbursement in reductions application of the strongest quasi-experimental research design for evaluating system-wide 108 [54]. Soumerai et al. demonstrated that limits on coverage for the costs of outpatient prescription prescription outpatient of costs the for coverage on limits that demonstrated al. et Soumerai [54]. medicines can increase use of acute mental health changes policy servicesthat suggested He payers. to among costs increased in low-income result and illnesses mental patients chronic with that pose substantial risks to vulnerable populations should undergo careful evaluation before their widespread adoption [55]. is More research needed on the potential unintended effectsof [53]. [53]. Under Due to group. the severity therapeutic of this the of illness share and strict market guidelines the prescribing generic generic campaign in in increases to lead not did probably Portugal effect. additional observable an have not did policies the circumstances, these sharing or reimbursement benefits put additional pressure on vulnerable populations of low- income and chronically ill patients that may lead to lower utilization and worse health outcomes patients from clozapine to generic alternatives due to reports of worsening clinical status associated associated status clinical worsening of reports to due alternatives generic to clozapine from patients to price its lowered clozapine of manufacturer originator the Further, [52]. substitution generic with might there so system, price reference the of introduction the after soon quite price reference the not have been any financialincentive for patients and to ask risperidone of for use the a lower recommended priced Portugal generic.in Prescribing schizophrenia of treatment the interventions for policy guidelines the to prior Portugal in share market the of 90% had already risperidone generic market market share (in Finland clozapine and in Portugal which risperidone), we attribute to different circumstances. Many countries have implemented strict prescription guidelines for clozapine by limiting prescriptions only to schizophrenia patients treatment-resistant as potentially life- side effectsthreatening, are with associated [51].clozapine may Clinicians be toreluctant switch paymentsShortlyco-paymentpublic[19].changeconcernsintheafterPortugal2010, inin rates emerged that higher co-payments would have a negative medicines impact includingon utilization antipsychotic of medicinesessential [49]. Our than findings the presentstudy by aOng differentet al., picture who did not findmedicines permanentafter a co-payment decreases increase in Sweden in in 1995, usealthough the of use of psychotropicantidepressants among women was later found to decrease after a co-payment increase in 1997 [50]. antipsychotic use – assuming a three tablet per day oral treatment, policy changes may resultedhave in 6 to 97 fewer treatment days among 100,000 peoplecannot perdisentangle month which in of Portugal.the We policies may have exerted most the influenceend of on2010, utilization.Portugal At was urgently seeking ways to cut public thespending Portugueseon medicineseconomy ashad not recovered from the recession in 2009. Somemeasures shiftedof coststhe to patientspolicy by lowering reimbursement levels and requiring higher co- policy goal of greater genericgreaterutilization.observedreductionutilizationalsoofpolicy goal in a We post-policy, which was gradual, not statistically significant andrelatively smaller comparedto Portugal. and after October 2010 led to a sudden, slight, statistically significant overall decrease ofretail

Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2 Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2 109 ), IMS Health Incorporated. ), All IMS Health Incorporated. January January 2007 and 2011 December The statements, The findings, statements, views, conclusions, and opinions contained and expressed in this article are based in part on data obtained under license from the following IMS Health Incorporated Incorporated Health IMS following the from license under obtained data on part in based are article expressed and ( MIDAS™ service(s): contained information opinions and views, entities. conclusions, subsidiary or findings, affiliated statements, its The of any Reserved. or Rights Incorporated Health IMS of those necessarily not are herein We wouldexpressWe liketo ourgratitude Ms.toHanna Koskinen thefromFinnish Social Insurance Institution (KELA) for providing feedback on the Finnish antipsychoticespecially data. thankfulFurther, we for are the input from Agency (INFARMED) Ms.as well as Ms. SóniaCeu Mateus from the CaldeiraPortuguese National School from of Public the Health Portuguese for sharing Medicineswith us details on the different policy interventions in Portugal.would like Finally, to thank we Peter Stephens from IMS Health for critically reviewing the data. policy measures as increases in cost-sharing may have beneficial short-term impacts on public spending, but might also entail unintended long-term reductions in utilization and shifting of costs to other types of health care. ACKNOWLEDGEMENTS CONCLUSIONS Different policy approaches to contain pharmaceutical expenditures in the study countries had different intended – increased use of generics – and likelyoverall unintended – sales slightly decreased possibly consistent with Especially decreasedthe latter access finding tostresses the needed importance medicines of examining – the impacts. long-term effects of for which antipsychotics were indications prescribed, in addition since to schizophrenia, these policy-induced medicationssome decreases indications in may are antipsychoticbe considered use used appropriate. for We for suggest expandingpatient-and indication-specific other future assessmentsresearch of to the impacts of the policy changes on accessto antipsychotics and other therapeutic classes. policy interventions. Nevertheless, the data pose some limitations. determine They the do actual not number allow of us prescriptions to issued or the payersactual amountsor that patients third-party pay for each medicine. of We patients also receivingdid not antipsychotics. have Lastly, access we to were actual not numbers able to determine the conditions . Accessed 10 January 2013. January 10 Accessed . http://www.imf.org/external/np/ extractedOctober1 2012. Letter of Intent, Memorandum of Economic and Financial Policies, and Technical Memorandum of Understanding between Portugal International and Monetary the Fund. Available: May 17, loi/2011/prt/051711.pdf 2011. Wagner AK, Effect Ross-Degnan of New York D, State regulatory benzodiazepine action Gurwitz on prescribing JH. and rates.AnnInternMed. 2007;146(2):96-103. hip fracture Wladysiuk M, Influence Araszkiewicz of A, patient co-payment antipsychotic Godman on choice B. atypical in once generic atypical are available. AAppl Health Poland: implications Econ Health Policy. 2011 March; doi: 9(2):101-110. 10.2165/11318840-000000000-00000. Andersson K, Petzol MG, Sonesson C, Lönnroth K, Carlsten A. pharmaceutical reimbursement schedule Do affect policy drug changes expenditures? in Interruptedanalysis of the cost, time volume and series trend cost per in volume Sweden 2006;79:231-243. 1986-2002. Health Policy.Soumerai SB, Zhang F, Ross-Degnan D, Ball DE, LeCates RF, Law MR, Hughes TE, Adams Chapman AS. Use D, of atypical antipsychotic for drugsschizophrenia in Maine Medicaid Following a policychange. Health Aff (Millwood). 2008 May- Jun;27(3):w185-95. doi: 10.1377/hlthaff.27.3.w185. Epub20081. Apr Ray WA, Daugherty JR, Meadora KG. Mental Effect Health of ‘Carve-Out’ Continuity Program of on Antipsychotic the Therapy. N Med. Engl2003May 8;348(19):1885-94. J OECD Health Data 2012. GDP per capita. Data WHO Regional Office for Europe. PoliciesPractices and for mental health in Europe: meeting challenges.the 2008;115-124. European Commission Consumers. Major DG Available: and Health chronic_diseases/diseases/index_en.htm. http://ec.europa.eu/health/major_ chronic and diseases. August2012. Accessed 9. World Health Organization. Schizophrenia. Available: Mental http://www.who.int/ Health: mental_health/management/schizophrenia/en/.Accessed August92012. Zeber J, Grazier KL, Valenstein medication M.copayment increase in veterans with Effect of a schizophrenia.ManagJCare.2007;13:335-46.Am

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Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal 3.2

CHAPTER

Personalized medicine as a challenge for policy makers 4

CHAPTER

Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 – a survey among 27 European countries (including Iceland and Norway) on the example of trastuzumab

Health Policy. 2013 Oct 25. [Epub ahead of print]

Christine Leopold, Sabine Vogler, Claudia Habl, Aukje Mantel-Teeuwisse, Jaime Espin The example of trastuzumab and its accompanying diagnostic test highlights

To survey possible funding models and pricing practices as well as prices for the Qualitative descriptive data on national pricing pharmaceutical and funding policies In 2011, testing and treatment mainly took place in hospitals or in specific day-care 118 but also with regard to the interface between medical device.the The findings suggestmedicine a need for further developingapplied and refining policy optionsin combination with a to address the identified interface issues. managed entry agreements. National pricing procedures are different for trastuzumab versus its diagnostic test, as most countries apply price control policies for trastuzumab but have free pricing for the diagnostic test. The ex-factory price is, on average, € 609 per 150 mg powdervial in 2013;with in nine countries the price of trastuzumab went down from 2005 till 2013. Conclusion: some problems of the interface between different funding streams(out-patient and hospital) ambulatory clinics. In the European countries either both trastuzumab and the accompanying diagnostic test were funded from hospital budgets (n=13) or only medicines were funded from thethird party payers such social insurances and the test from hospital budgets (n=14). Neither combined funding of both medicine and diagnostic test by third party payers was identified in the surveyed countries nor did the respondents from the competent authorities identify any Methods: years the a from (for among survey obtained were test data diagnostic price and its accompanying to trastuzumab applied Further, 2011. August of as countries European 27 from authorities competent analysed. and surveyed were countries European respective the in trastuzumab of 2013) to 2005 Results: ABSTRACT Objectives: treatmenttrastuzumabpackageaccompanyingofits and diagnosticEuropean countries,in test as an example of personalised medicines.

Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 119 In literature personalised medicine is often discussed from the point of pharmacogenomics or or pharmacogenomics of point the from discussed often is medicine personalised literature In Secondly, are there challenges to related the health Secondly, care system. Personalised medicines are However, there is growing disappointment from industry and health professionals but also from from also but professionals health and industry from disappointment growing is there However, that that still important lessons need to be learned with respect to assessing the whole ‘treatment package‘ including the test and the medicine [21]. A recent report published by the Personalised that factors of terms in systems reimbursement European the analysed (PMC) Coalition Medicine assess assess the value of co-dependent technologies as a ‘treatment package‘ has only recently been by a addressed few publications as well Merlin as et.at conferences. European how al. presented Australia recently developed a national framework for reviewing and assessing co-dependent of co-dependent processes in assessment differences compared and [20]. Lu Ward technologies health technologies between the United Kingdom (UK) and Australia with the conclusion facilitate facilitate a swift and reliable approval [13-14]. Not only Australia recognised that co-dependent technologies are problematic to assess in its recent review of Health Technology Assessment [15], but also at the European Union level public authorities are struggling to find‘treatment these for decisions packages‘. reimbursement and pricing take to appropriate procedures The question on howauthorities public national used in [16-19]. clinical trials information genetic often often used at the interface between the hospital and requiring therefore the sector, out-patient different funding streams [12]. An additional concern is protocols to ensure the physicians follow through difficulty with appropriate patient care based enforcing of on the standard test result. Furthermore a major point of concern is how the differentregulatory entities involved in the assessment of either the medicine or the test may align their review process in order to the the evidence package available at time of market authorisation. Drug development for cancer late- by followed early-then research pre-clinical from pathway an follows established treatments direct of risk lower a to due rigorous less been have tests diagnostic for regulation The trials. phase harm. This results in an level unbalanced of evidence on the time of [10]. admission In addition, medicine markers personalised requires predictive as opposed to markers, prognostic requiring [11]. programmes trial conventional by provided that to research of types different and additional three examples of approved personalised medicines and their diagnostic tests [8]. tests diagnostic their medicinesand personalised approved of examples three do medicines that not personalised authorities live up public and pricing to reimbursement their including expected expectations savings [9]. This suggests that there are quite a few challenges in appraising treatment packages in personalised medicine. The first challenges are related to medicines by using diagnostic testing (including genetic testing) to maximise clinical benefits and and benefits clinical maximise to testing) genetic (including testing diagnostic using by medicines be may technologies co-dependent new these of cost the that forecasted is It cost-effectiveness. higher at first,but their predictive potentialcould avert unnecessary costs as it provides precise diagnostic results leading to effective[4].and In therapies targeted some casesthese treatment packages are for a large group of patients such as for the treatment of breast cancer, in other 1 gives Table cases it as for is it smaller patient relevant groups is diseases [5-7]. the case with rare INTRODUCTION Personalised medicines, also known as co-dependent or stratifiedtechnologies, are defined as the plan treatment based on molecular and screening other tests that suggest which regime will high-cost) (often of use the improve to approach an is It [1-3]. patients specific in effective most be Approved companion diagnostic HER2 immunohistochemistry tests, HER2 gene-amplificationstests EGFR immunohistochemistry test c-kit immunohistochemistry test Mechanism Targets HER2Targets to treat metastatic breast cancer cancer colorectal metastatic treat to EGFR Targets receptor kinase cell-surface tyrosine the Targets tumours stromal gastrointestinal in c-kit Examples of approved medicine and companion diagnostic trastuzumab is one of the first welltesting knownto being prescribed [29] and therefore personalisedEuropean public pricing and reimbursement medicines which require prior authorities have many years of experience in assessing this ‘treatment package‘. factor Receptor 2 (HER-2) protein which is over-expressed cancer. inA therapysome womenwith trastuzumabwith breastis only prescribed overexpress‘if the cancer HER-2 has [24-27], been shown thus to ensuring on ineffective that pharmaceutical (public) care. expenditures The two are mainimmunohistochemistry not methods (IHC) and fluorescence in-situ used wasted hybridization (FISH) for [28]. HER-2 testing are breast cancer is among the leading diseases in women worldwide with (newly an incidence diagnosed rate cases per 100,000 females) incidences that in Belgium, in 2008 [24]; ranges from 50 in Estonia trastuzumab to is 109.4 among the first line therapies targeting at the human epidermal growth Against this background of discussions at national and international level about ways of dealing dealing of ways about level international and national at discussions of background this Against

Source: Hamburg MA, Collins FS. The path to personalized10.1056/NEJMp1006304. medicine. N Engl J Med. 2010. 363:301-304. DOI: Approved medicine Erbitux (cetucimab) Gleevec (imatinib) Herceptin (trastuzumab) Table 1.Table 3. 120 accompanying diagnostic test as an illustrative example. The reasons for selecting trastuzumab for trastuzumab for selecting The reasons example. as test an illustrative diagnostic accompanying multifaceted: are medicine personalised for example an as cancer breast of treatment the 1. 2. with the ‘treatment package‘ or ‘joint product‘, this study explores the current practices of European European of practices current the trastuzumab explores of study this example the product‘, on ‘joint or package‘ package‘ ‘treatment the ‘treatment with the of funding and pricing to regard with countries funding national of patterns possible survey to aims study The test. diagnostic accompanying its and models with (outto regard settings orpatient different care) and in-patient payers.Additionally, its and of trastuzumab years recent during development price at the look and prices survey we will for for evaluation and funding of personalised medicine [22]. Meckley and Neumann came to the conclusion that in order to achieve favourable coverage and reimbursement premium and prices to for support personalised medicines, manufacturers will need evidence to to the marketplace bring and better establish better the value of clinical their products [11]. In addition, a panel session at the 2012 conference of the International Society for Pharmacoeconomics and [23]. co-dependenttechnologies of value the assess to how discussed (ISPOR) research Outcome support or impede market access personalised to medicine. Conclusions of the report that were the UK countries high such and ranked were with as France respect Germany, to other European therapeutic, and diagnostic combined for systems reimbursement current their to due countries previous support and investments in personalised countries medicine technologies. Conversely, such as the Netherlands, Finland and Norway were ranked lower due to lack of clear pathways

Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 121 pricing procedure of trastuzumab and its companion diagnostic procurementaccompanyingtrastuzumabfundingandtheprocedureabouttheofand and diagnostic. setting of treatment (in- versus outpatient sector) eligibilitycriteria for public coverage of the treatment (accessibility for all female patients and whether co-payment has to be paid) the process of funding the medicine versus diagnostic regional decision-making)(which institutions, national or For trastuzumab they could provide historic price data for the period from 2005 till 2013 The second part presents the results of a price survey on trastuzumab. Price data were The survey was based on a structured questionnaire asking for information as of August 2011 on: 2011 August of as information for asking questionnaire structured a on based was survey The Finland, Germany, Greece, Italy, the Netherlands, Norway,United Kingdom (= England Spain, and Wales). We received price data Sweden, of one vial 150 mg trastuzumab Switzerland and for all three price levels - ex-factory, pharmacy purchasing and pharmacy retail price level - of the data by the authors, 2) reliability as the data are / have obligationsbeen [34]collected for the as Austrianpart Pricing of Committeelegal [35] and 3) the PPI service became a point of reference for the European Commission and for many EU Member States. (no price data were available for 2009) for 14 countries, i.e Austria, Belgium, Denmark, France, and Iceland as represented in the above mentioned networks. Out of the 29 European countries 27 countries 93%. European 29 the of Out of networks. rate mentioned above the in response high represented as a Iceland and in resulting hence replied; Greece) and Luxembourg except (all countries provided by the research institute Gesundheit Österreich GmbH / Austrianwhich Healthhas Institute,been running the Pharmaceutical Price [33].Information Reasons forService choosing (PPI)price data for from themany Austrian years Health Institute were: 1) accessibility • • Norway In (EEA) Area total Economic 29 European European the countries plus were States approached to Member (EU) participate in Union European the 27 all survey. These included countries • • • Authorities of Pricing and Reimbursement (CAPR) [32]). In September 2011 a reminder was sent to to sent was reminder a 2011 September In [32]). (CAPR) Reimbursement and Pricing of Authorities all countries and if needed individual answers were clarifiedthrough telephone conversations with country representatives. The outcomes of the survey were circulated to the CAPR network in November 2011 and then presented and discussed with national representatives at the CAPR results. the of clarifications final some to leading December in 2011, Warsaw meeting in undertaken undertaken by the Gesundheit Österreich GmbH / Austrian Health Institute and commissioned by the European Commission Directorate-General Enterprise under the the of timeframe The European [30]. project (EMINet) Reimbursement and Pricing on MedicinesNetwork Information survey was 1st of July to 30st of September 2011; the survey was sent via mail to selected staff Pharmaceutical of the of (members reimbursement and pricing pharmaceutical for authorities public Competent of network the to as well as [31] network (PPRI) Information Reimbursement and Pricing METHODOLOGY This study presents the results of two major parts: the firstpart is an assessment of the current practices of pricing and funding of trastuzumab and its accompanying diagnostic test as as a price well survey of the diagnostic test. Data was received from an European survey, which was

the diagnostic test as well as the medicine was funded through the hospital budget. Figure 1 illustrates four possible national funding models of the treatment package whose Descriptive statistics were performed on the data collected by the survey as well as on the model 1 Here the hospital had the opportunity to either buy one of the commerciallytheavailable diagnosticof one buyopportunityeither thehospitalto had the Here testsorperform itsown test. Inthis model funding waslinked thetonational funding system of hospitals and the decision on funding was taken within the scope of the hospital; this was the 122 with with trastuzumab whereas patients with 2+ results required re-evaluation by a test). additional paysthe Roche and Institute Oncology an more to sent is biopsy (a technique sensitive use in practice we surveyed. The data refers to 2011: In trastuzumab trastuzumab was funded by social insurance (so-called reimbursement of the restricted diagnostic procedure was granted to all patients reimbursement); when required, whereas in Latvia the medicinal treatment was only reimbursed for a limited number of patients due to budgetary limitations. In Poland patients had to be included in the respective which therapeutic programmes, offered public funding for specific diseases including their patients treatment; with and the in HER-2 test Portugal results of 3+ were considered positive and eligible for treatment and its diagnostic test As of 2011, in all European countries trastuzumab was only prescribed if cancer HER2-positive was breast diagnosed on the basis of prior testing. In addition, a number to the national in according Belgium for ofpublicfunding trastuzumab: criteria specificeligibility of countries stated rules reimbursement prior of approval the sickness fund was before the required treatment with that the treatment was provided in the out-patient sector, specifically in day-care ambulatory clinics under the supervision of oncology/chemotherapy specialists as for instance in Sweden. However, in the majority of countries the diagnostic test These different wassettings of care leadprovidedto differences in fundingin systems. hospital settings. National funding models of the treatment package trastuzumab Point of care In 2011, all replying countries granted patients access with to demonstrated trastuzumab HER2-postive and breast its cancer. diagnostic With with to respect the femaleto treatment the of point HER2-positiveof care breast cancer place medicinesin the in in-patient thirteen sector, countries i.e. it in tookhospitals. The remaining fourteen countries indicated the monthly exchange rate of May 2013 as published by the European Centralto eradicate exchangeBank. rate fluctuations, In we convertedorder the exchangerate to the level of 2013. price data. RESULTS for all fourteen countries (if available). Prices referred to June2006 andof 2010each prices year refer (exceptto December)in and 2005, were mainly applied to for publicinformation hospitals,onofficial or commercial discountsno rebatesand were available. Prices in non-Euro- countries (Denmark, Norway, Sweden, Switzerland and England and Wales) were converted to

Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 123 the third party payer (which can either be a social security institution or a national health health national a or institution security social a be either can (which payer party third the foresees a combination of funding sources from hospitals as well as from third party model 2 2 model was funded by the third party payer; this was the case in most Bulgaria,European countries (Belgium, Czech Republic, Estonia, France, the Netherlands, Germany, Poland, Slovenia Greece, and Slovak Hungary, Republic). However Iceland, in this model Lithuania, there was no service) was responsible for funding the treatment package. None of the surveyed countries applied In applied countries surveyed the of None package. treatment the funding for responsible was service) settings. hospital in funded therefore and provided always was test diagnostic the as model this Model 3 performedwashospitals,hospitals,medicinefundedit byinthewas test as and the payers. Here responsible for deciding on the reimbursement of trastuzumab whereas the reimbursement of the diagnostic was established at a regional level. As trastuzumab impacted hospital considerablybudgets some countries foresaw an extra funding code in their national hospital funding system, e.g. in the Austrian DRG-based scheme, meaning that extra money was allocatedhospitalisation forcosts in case of patients who were treated with trastuzumab. case in thirteen European countries (Austria, Cyprus, Denmark, Finland, Ireland,Malta, Italy, Norway,Latvia, Portugal, Spain, Sweden and United Kingdom). National wasfunding either providedof by the statehospitals (the National Health Service or the Ministry of Health), which was the case in Cyprus, Ireland, Latvia, Malta, Norway, Portugal hospitalsand were thefunded throughUnited regions/counties/municipalities, Kingdom, which wasor the case in Austria, Denmark, Finland, Spain and Sweden. In Italy, however, the National Medicine Agency was FigureFunding1. models oftrastuzumab andits companion diagnostic, 2011. Statutory pricing All other EU-countries, Iceland countries EU-Member All Norway and Iceland plus All other EU-countries, Iceland and Norway Negotiations Denmark, Finland, Finland, Denmark, Norway, Netherlands, Sweden - Italy, France, Spain Free pricing Free Denmark, Germany, Finland, Finland, Germany, Denmark, Poland, Netherlands, Latvia, Kingdom United and Sweden - -

funding funding is split between pharmaceutical industry and party third payers; this concept Overview of pharmaceutical pricing policies in European countries, 2011 model 4 EU = European Union Price level (linear or regressive mark-ups) regressive or (linear Ex-factory purchasing Pharmacy mark-ups) regressive or (linear retail Pharmacy Table 2.Table 124 and UK), where the price of a medicine is set on the basis of the price in one or several countries. As countries. several or one in price the of basis the on set is medicine a of price the where UK), and pharmacy or wholesale apply not do countries many hospitals in administered mainly is trastuzumab Medicine prices can be controlled at ex-factory, pharmacy purchasing or pharmacy retail level. Most Most level. retail pharmacy or purchasing pharmacy ex-factory, at controlled be can prices control Medicine price applied Kingdom) United and Sweden Germany, Denmark, (except countries European prices Spain) and mechanisms either for France all (Italy, medicines or countries few a limited in to medicines. reimbursable These enactments; or price laws on control based set were mechanisms is referencing price external 2011, In payers. party third and manufacturer between negotiated were Sweden Germany, Denmark, except countries (all procedure control price used commonly most the reported that this model was applied for trastuzumab in their country their in 2011. in trastuzumab for applied was model this that reported could test Pricingdiagnostic its and practices trastuzumab between difference major a policies pricing to respect With be in was observed: to subject rules 2011 pricing but trastuzumab national for test the diagnostic 2). Table (cf. pricing in free resulting policies pricing similar elaborated not had countries European is known as risk-sharing agreements, in recent times summarized as managed entry agreements. entry agreements. managed as summarized times recent in agreements, risk-sharing as known is and manufacturers between shared is medicines new of uncertainty to due risk financial the Here payers. In some cases industry provides the diagnostic test for free to hospitals, in other cases manufacturers grant either discounts to third party payers or only receives payment in case the respondents the of none received information official the to According successful. was treatment In addition, some countries applied specific funding schemes for a definedgroup of high-cost medicines to which trastuzumab belongs to. For instance, Netherlandsat the the hospital timereceived 80% of reimbursement the from thesurvey, health ininsurer for the medicines on the list of high-cost medicines, such as trastuzumab. The remaining 20% as well as the extra costs for the diagnostic was paid by the hospital out of its own budget. In commonassessment of the treatment package; each item was assessed and funded separately. encounterTo this gap Hungary for example established national prescribing guidelines as well as advising committees for evaluating trastuzumab and its diagnostic test as a package taking into account an economic evaluation with a special emphasis on cost-effectiveness analyses.

Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 125 ). Ø = average, as published by the European Central Bank of May 2013 Theaverage ex-factory price was calculated based onbasketa countries:of 14 Austria, Belgium, Denmark, http://www.oenb.at/de/stat_melders/datenangebot/zinssaetze/wechselkurse/wechselkurse.jsp ( CH = Switzerland, EL = Greece, PT = Portugal, UK = only England and Wales, UK: price paid by the National Health Service France: 20082006, 2007, no price available Belgium: 2008 no price available. Source: [33] Figure 2. Price development of the average ex-factory prices per unit in € of 1 vial, 150 mg trastuzumab, 2005 2013.- France,Finland, Germany,Greece, theItaly,Netherlands, Norway, Spain, Sweden, Switzerland andEngland=UK ( & Wales). Prices refer to June of each year (except mainlyin applied to2005, for public hospitals. 2006 Prices in non-Euro-countries and 2010 (Denmark, pricesNorway, Sweden, Switzerland refer and to December) and theare UK) were converted to the monthly exchange rate the diagnostic test and Estonia a price of € 418 for a FISH test and € 29 for an IHC test. paid€ 420 and the highest priced country (Switzerland) paid € 878; while in 2013 the difference betweenthehighest (Switzerland andthelowest€ 782) priced country (United Kingdom € 458) diminished. As illustrated in Figure 3 the decrease of the average Greece,price Norway, was Francemainly and driven Switzerland.by The average price increase was driven andAustria. byWith regard to the price Germanyof a diagnostic test information is only from the European survey,where two countries reported prices: Austria reported anapproximate price of€ 110for Trastuzumab belongs to the group of high-cost cancer medicines: European countrieson have averageto pay € 609 perthe 150 mg vial includedwith powder of trastuzumab (year 2013). Figure 2 shows the price development of one vial trastuzumab 150 mg from 2005 until 2013. In 2005 the average price was € 641. Since 2005 the average price gradually decreased with some increasesin specific years (i.e. 2008 and 2012)to € 609 in 2013. It is visible that there were great differences between the countries: in 2005 the lowest priced country (the United Kingdom) margins. However, as shown in Figure 4, if margins are applied huge differences can be seen (as high high (as seen be can differences huge applied are margins if 4, Figure in shown as However, margins. Sweden). in 2% as low as and Italy in case the is it as 30% to up as Price developments PPP = pharmacy=PPP http://www.oenb.at/de/stat_ http://www.oenb.at/de/stat_melders/ ). AT = Austria, BE = Belgium, CH = Switzerland, DE = Switzerland, CH = Belgium, BE = Austria, AT ). ). Source: [33] as published by the European Central Bank ( Bank Central by the European as published of of May 2013 as published by the European Central Bank ( of May 2013 in non-Euro-countries (Denmark, Norway, Sweden, Switzerland exchangeand rate the UK) were converted to the monthlydatenangebot/zinssaetze/wechselkurse/wechselkurse.jsp 126 Figure 4. All price levels of 1 vial,AllpricetrastuzumabEuropean150mglevelsFigureten14. inof €countries, in June2013. purchasing price, PRP = pharmacy retail price. Finland, AT FR = France,= IT = Italy, NL = Austria,Netherlands, NO = Norway, DESE = Sweden. No =price informationGermany, for pharmacy DK = Denmark,purchasing and pharmacyEL= retail prices Greece,were available in FIBeglium, Spain,= Switzerland and the United Kingdom, as trastuzumab is applied in hospitals and therefore mark-ups are not regulated. Prices (exceptrefer in to 2005, June 2006 of and each2010 yearprices refer to December) and are mainly applied to for public hospitals. Prices to the monthly exchange rate rate exchange to the monthly Norway, = NO Netherlands, melders/datenangebot/zinssaetze/wechselkurse/wechselkurse.jsp = NL Italy, = IT France, = FR Finland, = FI Spain, = ES Greece, = EL Denmark, = DK Germany, = [33] Source: Wales. and England only = UK Sweden, = SE Figure 3. Unit ex-factory prices in € of 1 vial, 150 mg trastuzumab in fourteen European countries, 2005 and 2005 2013. countries, in € prices European in of fourteen 1 150 3. ex-factory Unit mg vial, trastuzumab Figure The were countries scaled in order for increasing 2013 prices. UK: price paid by the Health National Service. Prices refer to June of each year in (except 2005, 2006 and 2010 prices refer to and December) are mainly applied to for and the UK) converted were Switzerland Sweden, Norway, (Denmark, in Prices non-Euro-countries hospitals. public

Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 127 our study had difficulties to answer questions on funding or pricing of the diagnostic test as this is part of the medical service in hospitals and no nationwide information is available. This lack of knowledge is particularly critical since trastuzumab as well as other medicines sector are often not well coordinated as proven by the Pharmaceutical Health Information System (PHIS) project, a project funded by the European Commission [36]. This might lead to shifting of costs between the different sectors which could have as a consequence that tests are performed by hospitals but the eligibility sectorof is reimbursementnot given. in Our thestudy confirmedout-patient these outcomes as some of therespondents of be anotherbeideal modelbothelements as assessed bewouldsamethehaveinstitution, toby which could apply a common assessment tool for the ‘treatment package‘. However, none of the responding countries had this model as the diagnostic test was always administered in hospitals and therefore also funded through the hospital budget. mostcommonlythewhichmodelis In3,used model, funding splitwas between hospitalthe and the third party payer. Here the different funding streams of the in- and the out-patient decisions (e.g. in Cyprus the Pharmaceutical Services Department of the Ministry of Health is responsible for funding of the medication and the Medical Services Department for the diagnostic procedure). In a worst case scenario it could happen that e.g. the hospital takes thedecision tofund the test, but at national level the decision on reimbursing trastuzumab is not permitted due to budgetary constraints. modelInboth 2thetest andthe medicine paidistheforthirdby 265party This would payer. an ideal situation as the funding decision is taken by one institution. However, in practice there is a split in responsibilities between authorities in some Italy the countries.decision of funding ofFor trastuzumab instance,is taken at nationalin level, whereas the decision of funding the test is taken at hospital level, which is often the fundingregional the responsible for are Health level.countries Ministrydepartmentsdifferent of the within Or in other The results of the survey confirm previous perceptions of the challenge of assessing In model 1 the test as well as the medicine is funded by the hospital, which is in principal

3. 2. the treatment package of personalised medicine. The main reason trastuzumabfor and its diagnosticthis test are appliedchallenge at the interface ofis different fundingthat streams (as shown in the four models) which leads to multiple areas of conflicts: 1. medicine. In 2011, two predominant funding models for the ‘treatment package‘ trastuzumab diagnosticitsand identified:weretest funding hospitals1) by medicineboth for the test the and and 2) a combination of funds between hospital and third party payer. With respect to pricing studythedisplayed pricingthatfreethereis diagnosticthefor Europe;testinwhereas pricethe oftrastuzumab is regulated according nationalto pricing policies resulting in differences in the ex-factory price and a slight decline in overall price between 2005-2013. DISCUSSION This study showed that depending on the place hospitalfewandaincountries out-patientisitof day-clinics under treatmentthesupervision specialistsof – – in most countries it thefunding issources butalsothepricing procedures differentare the for the diagnostictest and the picture picture might not be complete. Ferrario and Kanavos point out that risk-sharing or further [40]. countries European some in rise the on are entry managed agreements The challenge of the interface is not only relevant for funding but also for pricing as This concept, known as managed entry agreements or risk-sharing schemes, gains more and and more gains schemes, risk-sharing or entry concept,managed agreements as This known Germany, Especially medicines. high-cost often and innovative for especially popularity more Italy, the Netherlands and the United Kingdom are known for being pioneers in [39]. However, this according to field the information from the European public authorities no such As survey. the of time the at test diagnostic its and trastuzumab for place in were agreements this information on such agreements is considered as confidentialand thus not shared, the as well as across sectors. The PHIS project coordinatingmentioned the some hospital national formularyinitiatives with such the as list of way theforward (e.g. out in thepatient Stockholm sectorCounty Council)as [37],a and possiblein a seminar improvingto the learninterface managementabout for medicines held in Stockholm in September 2012, further country examples manufacturers. were presented and [38]. payers party third between funding splitting suggests model last the Finally, used‘personalisedina medicines package‘ oftenare among high-cost medicines. This puts great pressure on hospital budgets, as these high costs are often not covered by the DRG systems, but require additional funding from third party payers (e.g. in the Netherlands).Hence, there is a great need for a common assessment tool for the treatment package

the so called AMNOG [43]. Further, in 2013 the Netherlands changed its policy of financialsharing the burden between hospitals and thirdmedicines party are now fully reimbursed by payers third party payers [31]. for high cost medicines. These 128 regulations regularly. Especially in times of limited budgets,economic as recession,it is countries the (e.g. case Greece,in the Portugal current strict price cuts and [42]. But also traditionally Spain) economically stable countries are are opting to regulate forced to implement medicine prices, e.g. Germany used to be a free pricing countryimplemented for regulationsmedicines linking pharmaceuticalbut in pricing 2011to addedit therapeutic benefit scores, to be identical to the list price (= ex-factory for price)which asdiscounts there might are be no negotiatedtherapeutic [36]. alternativesVogler and European co-authors countries illustrated selected that hospitalsin five nearly never granted discountsNevertheless, for it trastuzumabwas interesting [41]. to see, that our study showed of that trastuzumabthe unit ex-factory decreased price over time in decrease mostisthat pharmaceutical pricing policies countries.dynamicare aspublic authorities adjust pricing One of the reasons for this price different procedures are applied in the in- and the outpatient sector.formal Inpricing procedureshospital are foreseen settings as the hospital no price of the diagnostic or the medicine is often negotiated between hospital owners and suppliers on a confidential basis, leadingnon-publicationto and lacking of price information. Fortrastuzumab, it reimbursableis initially priced medicines, according to general in national ourpricing rules case often followed by price negotiations in hospitals. In the case of trastuzumab the actual hospital price is expected Other funding models e.g. funding by patients were not considered as in Europe – despite the high price of trastuzumab – use is always covered by public funds. 4.

Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 129 This This study adds to existing discussions on personalised medicines by raising the challenging A limitation of our study is that no country specific information on the price of the diagnostic the country of specificprice no information the that on isstudy ourlimitation ofA reimburse the treatment package of trastuzumab and its case accompanyingof trastuzumab and diagnostics.its diagnostic test,In all fundingthe models are exclusively based on public funding - might this be the state, a third party payer such social insurance or a public hospital (e.g. Ireland) specifically mentioned that in future changes in relation to the funding of high-cost of funding the to relation in changes future in that mentioned specifically Ireland) (e.g. be made. to have will diagnostics companion and medicine personalized as medicinessuch CONCLUSION The study highlights that European countries have opted for different funding models to definedguidelines or procedures for funding these medicines and the diagnostic procedures. The European Commission recommended in its 2011 conference on European perspectives in personalised medicine a close cooperation among Health Technology Agencies personalised in as continue to need discussions The Europe [44-45]. tools assessment to appropriate establish countries responding the of As some result, a importantrole. an play future in also will medicines but but also provides an illustrative example. In terms of pricing but also of funding the and medicine the test are very often considered as separate items. to Only a address few this countries have challenge started by of prescribing targeted and establishing cost-effective guaranteeing guidelines national (‘boards‘), disciplines advising committees with experts from different personalised medicine as well as economic evaluation. Norway, Sweden and Denmark as well as the United Kingdom might be mentioned as good practice examples. They have developed well a price of € 110 for the diagnostic test and Estonia a price of € 418). policies limited or missing of as well as gaps data resulting including systems funding dual of point for the treatment package ‘medicine and test‘. Our study not only confirmsthe results of the PHIS project, which displayed the knowledge gap between the in- and the out-patient sector, and € 167 (private health insurance). The same differences were observed inFISH the test: costs The of reported the costs (including material and personnel costs) varied (UK)between to € 495 in€ 220 the Netherlands. The reported costs from Ireland (€ 250) and Germany (€ 257, publicsocial health insurance and€ 398, private health insurance) werewithin this interval [28]. Even though we only had prices of two countries (Austria and Estonia), we came to theconclusion hugepricethattherearesamedifferences the for test same different in countries (Austria challengesfordiagnostics, because ifcumbersome coding systems andthe lack ofvalue-based arrangements [11]. Information on pricing of the diagnostic test is HER2-positve scarce, breastbut the cancer price testof a was studied by the Studies. Institute This for studyProspective indicatedTechnological that the costIVD and personnel of costs) as of immunohistochemistry2006 differed significantly in (IHC) Europe, rangingfrom test€ 103 in the (including United Kingdom to € 190 in Ireland, with Germany around € 127 (public social health insurance) test could be provided. Many countries replied that they had no information on the diagnostic Meckleyfindings of thewith linesupervision theunderin hospitals. outcomeisisof This it as test and Neumann, as they described that the existing pricing and reimbursement systems present In In addition, we would like to thank Prof. Anke Hövels from Utrecht University, Division of Further, the study provided additional knowledge to an area where information is scant: 130 Pharmacoepidemiology and Clinical Pharmacology, for giving input to the introduction of this paper. this of introduction the to input giving for Pharmacology, Clinical and Pharmacoepidemiology would like to thank the members of the Pharmaceuticalthemembers theofthankReimbursement Pricing andto wouldlike Information (PPRI) network and the network of (CAPR), Competent who provided answers Authoritiesto the survey as well as of took their time Pricingto answer clarifications. and Reimbursement Thanks also go to the Austrian Health Institute for providing price data on theirtrastuzumab Pharma Pricefrom Information (PPI) service. ACKNOWLEDGEMENTS Acknowledgements are given to the European Medicines Information Network on Pricing and Reimbursement of pharmaceuticals (EMINet) project, a project co-fundedCommission by(DG Enterprisethe and European Industry) for providing the results of the survey. Further, we but alsoregardingbutinterfacethe medicinesof medicaland devices. Traditionally pharmaceutical policies were focused on medicines alone and were often The limitedexample of howto European thecountries outdeal with patientthe treatment packagesector. of trastuzumab and its accompanying diagnostic test illustrates how competentpricing and reimbursement authorities have addressed this challenge for and have progressed pharmaceutical by developing solutions. Yet, a lot still needs to be done to refine these approaches. - and do not require a contribution of the manufacturer or the patient. Since trastuzumab is a high-cost medicine, this confirms the challenge of this treatment package for public payers. funding of care across sectors (a problem of the interface between in- and out-patient care)

Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1 Personalized medicine as a challenge for public pricing and reimbursement authorities 4.1

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43. 44.

CHAPTER

General discussion 5

5 General discussion 137 . The Profiles were analyzed accordingto predefined 1 For this reason, we compared one of the most commonly used pricing public authorities in pricing and reimbursement in Europe and other countries [32]. The Pharmaceutical Pricing and Reimbursement (PPRI) network is a sustainable, self-funded network for

1 countries 24 applied EPR in 2010. Most countries had less than 10 countries in their referencebaskets, but this number ranged from one country to 26 countries. Higher income tendedcountries to include higher income countries in their basket, whereas generallylowerreferred tolower income regional incomecountries. the Taking averagecountries price of all countries in the basket as the basis to calculate the national price was the most common strategy (n = 8). specific PPRI (Pharmaceutical Pricing and Reimbursement Information) Pharma Profiles written by representatives of the PPRI Network criteria such as methodological differencesframework, in the Europe countries included with in respect the to referenceof the basket thereference price. and nationalAs theexpected, legalmany method differences of were found calculation waybetween of countriesimplementing asEPR the is a national competence. We found that of 28 analyzed European policies in Europe - external price referencing (EPR) - across 2.1 and European analyzed countries in inchapter chapter2.2 how national medicine prices EPR may is be definedaffected as by the this practice policy. of using the price(s) of ain medicineorder to inderive onea orbenchmark several or countriesreference price for the purposes of settingof orthe negotiationprice of the product in a given country [11]. In chapter 2.1 we reviewed the country- them have led to the studies in this thesis and are discussed in the following paragraphs: Firstly, despite efforts of exchanging best practice experiencespolicy-making among in Europeanthe field countries,of pharmaceutical pricing and reimbursement - as it is thehealth case care for in general - is still a national competence. Even if countries apply the same policy many differences exist, which influence medicine prices and other outcome measures in other European countries. ANALYSIS – WHY IS IT STILL NEEDED? Even though in recent years an increasing number of descriptions of national pharmaceutical systems, especially in developed countries such as Europe, Canada, Australia and the USA, are beingpublishedneedstill thereisregularfora up-to-date[1-10], pharmaceutical policy analysis to take account of the rapidly changing environment. Reasons are multifaceted and four of policies is addressed. Further, methodological and consumption challenges as well ofas policy data comparing are described medicinesand the policy pricesfindingsimplications are presented. Finally,of areas for allfuture research studyare identified. PHARMACEUTICAL PRICING AND REIMBURSEMENT POLICY DISCUSSION This concluding chapter discusses the benefits and limitations ofresearch on pharmaceutical pricing and reimbursement policy interventions to understand health policy. criticalIn specific,question the why there is a need to analyze pharmaceutical pricing and reimbursement Hence, Hence, findingsof previous

Various reports showed that EU price price EU that showed reports Various countries) with a 15% average price gap; and gap; price a with 15% average countries) 2 [13-15]. However, due such as to changes cuts policy price However, [13-15]. 3 In chapter 2.2 we looked at whether EPR leads to the desired effects of lower and stable Benelux countries: Belgium, the Netherlands and Luxembourg EU-15 countries = EU-15 EU Member States as of 1 January Austria, 1995: Belgium, Denmark, Finland, Germany, France, Greece, Ireland, Italy, Luxembourg, the Netherlands, Spain, Sweden, United Kingdom, Portugal. Kingdom, Sweden, United Spain, Netherlands, the Luxembourg, Italy, Ireland, Greece,

2 3 138 the European policy environment is diverse and changing over time, requiring regular monitoring of of monitoring regular requiring time, over changing and diverse is environment policy European the prices. medicine national on impact an have do changes policy these that and effects, the Thirdly, overall national economic trends such as the current economic require recession adjustments in of Europe existing policies. Short-term measures needed to be implemented to the prices between countries and selected products varied to varied a In extent. products the great and period, study selected the countries between prices a was price divergence seen which was driven only by two Germany (up countries, to 27% more countries other All average). the than cheaper 32% to (up Greece and average) the than expensive study. the in included countries the of average the around centered and prices stable relatively had of prices while time, over decreased or stable relatively remained medicines expensive less that of mind Prices in keep to makers policy for crucial therefore is It increase. to tended medicines expensive almost 40% level lower than almost the EU-15 as a consequence of the economic recession in many countries, the picture of medicine price in convergence Europe may have in changed. Therefore, chapter 2.3, we analyzed prices of ten medicines on-patent in fiveof years 15(2007-2011) European countries.The unit of analysis was the price in ex-factory € per defineddaily ratedose toindexed(exchange 2007).We found that policy analyses might already be outdated a few of years after their publication, as for it a occurred be few publication, of their outdated after already years might analyses policy Europe. in convergence price medicine of case the in example process the of result a as 1990s the of half second the in rapid more was medicines for convergence identified: were of countries two clusters 2000 from Starting [13-15]. convergence of EU monetary Benelux Italy, as (such France, EU the countries core prices had average which and Greece, Portugal and Spain, of States EU newer Member the cluster lowerprices. However, the large variation in price levels among countries using EPR confirmed that the price level is not only driven by EPR. This study however questionsalso on priceraised comparisons, methodological which will be discussed below. which area, changing andrapidly dynamic is an innovative, the offield pharmaceuticals Secondly, requires regular and adjustments of re-evaluations existing policies. medicine prices. The study aimed at examining prices, adjusting the for other impact factors that of may affect EPR price levels on such as on-patent sales volume, medicine exchangerates, gross domestic product (GDP) per capita, total pharmaceutical expenditure (TPE),pharmaceuticaltheofsizethe industryEuropeanand 14 countriesin 2008.2007Basedand theinon unit ex-factory prices in the European region (in €), scaled ranks per country and per product were calculated. The study showed that on average EPR as a pricing policy is associated with The methodology of EPR which impacts price determination has changed countriesin mostover theEuropean past 10 years (n = 19), showing that EPR is policy instill contrast to whatwidely some people usedbelieve [12].and a dynamic

5 General discussion 5 General discussion 139 We We analysed As this is a very timely topic, we explored in chapter 3.1 In In chapter 3.2 we performed a detailed evaluation of the impact of different policy measures as part of the treatment package. authoritiesEuropean27from countries Augustofas 2011. Further, Dataprice data (forthe years 2005 were obtained from a to 2013) of survey trastuzumab in the respective among European countries were surveyed competent and analyzed. We analyzed this European trend towards personalized medicines how Europeanin pricing and reimbursementchapter authorities deal with4.1, the common challengeby of how looking at to evaluate new and often expensive medicines which include medical qualitativedevices. descriptive data on national pharmaceutical pricing and funding policies applied to trastuzumab and its accompanying diagnostic test as an example of personalized medicines intended and possibly unintended effects of new policies or policy changes. neweffects changes. of or policy policies unintended possibly and intended Fourthly, new technologies such as highly specialized treatments - including often diagnostic referred tests to as personalized highest medicines priced medicines - putting additional are pressure on beingpublic funding developedof medicines. Hence, and policy-makers are are confronted among with essential the ethical questions such as how willingmuch is to a paysociety for new and innovative medicines if the available funds remain the same. medicines and increases in generic market share of major antipsychotic products. These findings findings These products. antipsychotic major of share market generic in increases and medicines can policies existing of adjustment the or policies new of implementation the that indicate clearly have positive effectsonpublic spending controlling in a short time period,but sometimes these policy changes may have unintended consequences such as higher out-of-pocket payments for patients which may lead is there a to a in needdecrease use. Therefore, to continuously monitor on on the consumption of antipsychotic medicines in Portugal and Finland during the time of the economic recession. We obtained monthly IMS sales data in medicines standard in Portugal units and Finland of for the antipsychotic period January 2007 to December 2011. We used an interrupted time series design to estimate changes in overall use and generic market shares by comparing pre-policy and post-policy levels antipsychotic and of use trends. overall We in found decreases that unintended, both likely slight, countries’ with policy associated were approaches Republic, Spain, Portugal) betweenimplemented 10 and 22 policy changes. Most policy changes schemes mark-up price payments, in out-of-pocket changes and included in 2010/2011 occurred and price cuts. All countries showed moderate increases in sales volumes (except Portugal and Greece, both showing slight declines after 2009), while sales value decreased in both country countries. lessstable economically declines in greater with groups, used used IMS Health data to analyze quarterly sales of products in the 10 therapeutic highest-selling classes in eight European countries, in IMS standard units (volume) and constant dollars (value). We presented sales growth rates, comparing economically stable versus less showed study Our countries. member stable OECD of plans consolidation fiscal 2012 on countries based classified that economically stable countries (Austria, Estonia, Finland) implemented between two seven policy and changes each, whereas economically less stable countries (Greece, Ireland, Slovak control control public spending on medicines. during countries by implemented were policies reimbursement and pricing pharmaceutical which the time of the economic recession and evaluated the correlation with medicines and sales changes in eight policy pharmaceutical described we review, literature a on Based countries. European Pharmaceutical policy analysis often studies the impact of implemented policies or For For these as four reasons well e.g. new as price other mechanisms reasons, evolving possible three major data sets were used: medicine price data, medicine sales data and pharmaceutical pricing and reimbursement policy data. We encountered several methodological challenges, which we summarized in 1Table and discuss in the following paragraphs. 140 divergent divergent between stakeholders, final recommendations of [18]. such countries research other should from thereforestudies be and experiences by supported and sensitivity political by guided policy changes. Verifying and quantifying the impact of such policyif researchers reformshave accessis to onlyreliable quantitativepossible and qualitative data over time. In this thesis Hence, Hence, assessment tools and methods research used to inform policy pharmaceutical decision- makers should be neutral, based on evidence, and no preempting conclusion should be drawn by the limiting scope of to questions one Such area. a method problem needs to research verify, is one process The analytical question. the research and - - quantify as as much possible describe, that expert requires knowledge in data and interpreting dialogue to with stakeholders insightful As on and data could be could conclusions. opinions be the results incomplete meaningful reach METHODOLOGICAL CHALLENGES IN PHARMACEUTICAL PRICING AND REIMBURSEMENT POLICY ANALYSIS embedded are policies reimbursement and pricing pharmaceutical leading introduction, the in outlined As provisions, legal as well as involved actors the of interests different many with framework a in to possible economic as well as information asymmetries and contradicting policy objectives. will be part of the agenda of international organizations such as the World Health Organization (WHO), (WHO), Organization Health World the as such organizations international of agenda the of part be will Commission European the (OECD), Development and Co-operation Economic for Organization the (EC) [12,16,17]. and the is and Bank. and World Evidence needed to the debate, public advocated fuel their discussions is area policy pharmaceutical the in decision-making based evidence therefore may have addressed some aspects of the problems occurring in this complex area. Butdecisions, suchother aswhether these medicines and diagnostics should bepaid for fromhospital or primary care budgets, may have a devastating effect on access. analysis. policy for pharmaceutical need is a there continuous agreements, entry as such managed and countries all in topic political a hot remain will discussions policy pharmaceutical Consequently, combined funding of both medicine and diagnostic test by third party payers was identified in the surveyed countries nor did the respondents from the competent authorities identifymanaged anyentry agreements. National pricing procedures are different for trastuzumab versus its diagnostic test, as most countries apply price control policies for trastuzumab but have free pricingforthediagnostic test. nineIncountries theprice trastuzumabof went down from2005 till 2013. The move to health technology assessment (HTA) that is occurring in many countries found that in 2011 testing and treatment mainly took place in hospitals or in specific day-careambulatory clinics. In the surveyed accompanying European diagnostic countriestest were funded eitherfrom hospital bothbudgets or medicines trastuzumab were fundedfrom andthe third party payers the such social insurances and the test from hospital budgets. Neither

5 General discussion 5 General discussion 141 Examples Unit of comparison Exchange rates Weighing of prices by volume Impact of timing of policy implementation on study design Collection of data on the policy context Sources of medicine price data Sources of medicine consumption data Collection of up-to-date policy data Sharing of information Price levels Summary of methodological challenges with respect to pharmaceutical pricing and reimbursement Using an international database such as the PPI serviceinternationalPPIprovidesadvantagesthean Usingindividually databaseas over such Another source of information would be to directly search for medicine price data price in for would be medicine national search to of directly source information Another The ability to compare medicine prices and consumption data across populations, Methodological challenges Understanding the policy context Validity and comparability of data Data availability and transparency of data Table Table 1. policy analysis looking at price trends over time (chapters 2.2 and 2.3). Constraints were that no information was provided on confidential discounts andrebates as well as that these data mainly cover the out-patient sector as medicines in the in-patient sector are often funded directly by regions or searching national price lists: data was provided innational currencyavailablegenericsin all for a alsooriginators butfor onlyEuropeancountriescomparable not and structured way across or converted to the €, additional information on were exchangedelivered, rates and andhistoric reimbursementprice data limits were available which was important for our research information needs to be provided. To comply with the EU Transparency Directive EU Member States States Member EU Directive Transparency EU the with comply To provided. be to needs information have to publish and provide public downloadable access to to links prices of database, medicines [25,26]. Most reimbursable EU available publicly as either list positive their provide States Member price NHS the in thenational published are (e.g. of in detail, level varyhowever lists These levels or informats. book price xls-files in differences currency, national specifications, national with [20]. language irregularly or annually to daily from ranging updating of frequency and Kingdom), United the in the Austrian Health Institute. Reasons for choosing this source of data were 1) accessibility thedata ofby the authors, 2)reliability asthe data have been collected aspart oflegal obligations [23] for the Austrian Pricing Committee [24] and 3) the PPI service became a point of reference for the European Commission and for many EU Member States. positive lists, which vary greatly as there are no common European requirements on which [19,20]. [19,20]. We identified two major medicine price databases for European countries: the EURIPID database [21], which is only accessible for public publiclyavailable Pharmaceuticalauthorities PriceInformation (PPI)serviceAustrian the by Health ofInstitute EU Member States, and the [22], which offers its service for freeto interested the parties. InAustrian the studies authoritiesin chapters 2.2, and 2.3 and with4.1 we used medicine costs price to data from all other geographic locations and over time requires standardized information from reliable sources The The capacity to perform cross-national medicine prices and medicine consumption An important aspect of all studies included in this thesis was to understand the dynamics of the the of dynamics the understand to was thesis this in included studies all of aspect important An With With respect to dispensing or medicine (prescription, consumption medicine sales) data no only available for members of the PPRI network. PPRI the members of for available only comparisons depends not only on the availability of reliable high-quality data but also on the 142 representatives of such public authorities, as Ministries party of Health payers, which representatives or are third responsible for pricing and reimbursement. In addition, the PPRI secretariat has established the possibility to confidentiallyexchange and share information betweenPPRI members on ad-hoc may information this Although discussions. policy national up-to-date reflecting questions policy further enhance the understanding of the policy context and the decision-making process, it is (PPRI) (PPRI) Network [32]. The PPRI network started as an EU-funded 2005 project from until 2007 and Europe in reimbursement and pricing in authorities public for network sustainable a as continues the and of other countries. Within scope the PPRI network country-specificreports, PPRIPharma Profiles,on national pricing and unique reimbursement is information systems sharing of and collecting the of European approach Member This published. States were and countries associated as the PPRI Pharma Profiles werewritten in a common structure with common terminology by changes changes were of key relevance for the performance of the studies. Potential sources for policy information range from peer-reviewed articles, to and grey literature country profiles published consultancy commercial or Organization Health World the as such organizations international by companies. However, these sources often do not provide insightful information to understand the national pharmaceutical policy context. Therefore, the main policy data source for all the studies included in this thesis was the Pharmaceutical Pricing and Reimbursement Information assess effects of policies on the individual patient or prescription level, but research questions such such questions research but level, prescription or patient individual the on policies of effects assess aggregation). of level the on (depending data these with assessed be can 3.2 and 3.1 chapter in as changes. policy national numerous the including environment policy reimbursement and pricing For this reason high-quality data on pricing and reimbursement policies as well as on policy prescribing data may prescribing differto[29]. analyses In a addition, cross-national great extenthampering quantitative data on medicine consumption is often expensive and difficult to obtain. For the purpose of the studies included in this thesis, we and received data wholesalers companies, from IMS pharmaceutical national Health. and IMS by multinational reports data from are generated international for source a was suitable very IMS data the that found We [31]. IMS Health to retailers the despite fact that comparisons, it data. IMS is not aggregated data may be therefore to useful are commercial (e.g. IMS Health), administrative (e.g. databases containing claims, prescription or prescription claims, containing databases (e.g. administrative IMS Health), (e.g. commercial are or records), dispensing publicly by operated suppliers agencies, or regulatory third party payers with States EUMember between exist differences great data, dispensing and prescription For [29]. more provide of data. to respect The traditionally anonymous countries public availability Nordic in information the public domain, while other countries such as Eastern European countries are of and definitions structures National [30]. availability data and public not as to used transparency individualhospitals For [27,28]. these reasons it remains a“black box” what hospitals and also in some cases third party payers actually pay for certain medicines [28]. EU are regulations in place to Sources vary foresee availability. transparent from databases that

5 General discussion 5 General discussion 143 To To examine the impact of implemented policies or changes of existing policies on health Further, it is especially crucial that an exact definition of the price per unit is given. In the studies studies the In given. is unit per price the of definition exact an that crucial especially is it Further, the the actual price out-of-pocket, generating an incentive for patients to request a medicine that is priced at or below the reference price. Such [42]. law a of implementation behavioral actual the start before often and gradually and also cultural changes happen accompanied by early involvement of all stakeholders, such as doctors and pharmacists, as well as as well as pharmacists, and doctors as such stakeholders, all of involvement early by accompanied a detailed methodology and positive perceptions of patients towards the System policy [40,41]. changes facilitate to intended are system price reference a of implementation the as such changes in price-sensitive; be more to them by encouraging health and providers in behaviors of patients a reference price system patients have to pay the difference betweenthe reference price and outcomes outcomes or on other such parameters as medicine prices or information consumption requires always not is this However, change. policy a or policy a of implementation the of time exact the on clear as political discussions on the implementation of a which policy, often implies adjustments of existing laws and regulations, may take up to guaranteeing a successful several implementation of years. a policy Among is a the transparent implementation key process elements of sets can create problems of matching the exact same medicine with each other. Another approach is is approach Another other. each with medicine same exact the matching of problems create can sets the is DDD The 2.3. chapter in did we which (DDD), dose daily defined per does price and unit the [38] calculate adults to in indication main its for used medicine a for day per dose average defined WHO or dosetheactual used recommended reflect [39].A that not when occurs necessarily challenge we which medicines, some for assigned been not have DDDs that is, DDD per price the calculating information. product the on based ourselves calculate and define to had therefore the European Central Bank for all studies; only in chapter 2.3 we indexed the exchange rate to the rate 2.3 the exchange we in only chapter indexed Bank for all studies; Central the European high with medicines for from account In2.2 chapter to we suggestions followed fluctuations. rate year 2007 for to exchange volume account sales their to according prices medicine weigh to literature access requires approach This [37]. scale of economics to according prices lower have which data volume different two linking and obtain to difficult is data as challenging is which data sales medicine to makers for countries applying EPR and referencing to the ‘artificial’ high list prices. list high ‘artificial’ the to referencing and EPR applying countries for makers in price for the included we this the thesis, medicine the collected same product, same strength, Crucial comparability. ensure to size pack same the if available, and, form pharmaceutical same the the bias may and time over exist fluctuations as rate exchange the is comparisons cross-national for of rate conversion monthly the used we €, the use not did a country case in reason, this For results. medicine was compared. Limitations of price data are that these data do not information include of price data are Limitations medicine was compared. on confidentialdiscounts or rebates after price negotiations betweenmanufacturers and third results the publishing through transparency, that belief the still is There hospitals. or payers party of confidentialprice negotiations betweenmanufacturers and third party payers or hospitals, would hamper the outcome of the negotiation process [36]. This does not only hamper cross- national research on medicine price comparison, but it is also an important aspect for policy- validity validity and of comparability these data For [33-35]. this wereason, compared medicine prices at as countries of basket a in medicines different of comparability guarantee to level price ex-factory and taxes vary but not worldwide only [34]. Only in Europe extent margins a distribution great to in the chapter prices 4.1 of all three price levels were as presented the prices of only one sample In summary, methodological challenges in pharmaceutical policy analysis are often related For this reason, it is especially important to have access to insightful national information Finally, it was not always clear whether countries implemented policies as a short-term We encountered this methodological challenge in chapters 3.1 in which we studied Health Health Organization and commissioned by the priorities for The for planning the report the program 2020 Horizon EU combined [46]. research European Commission, identified research highlighted among other topics the importance of investigating in cross-national research 144 POLICY IMPLICATIONS OF FINDINGS AND AVENUES FOR FUTURE RESEARCH In July 2013 the Priority Medicines Report for Europe and the World, a publication of the World e-mailgive room for discussion of challenges policy-makers face in their daily working routine. to availability and transparency of reliable comparability of anddata are necessary high-qualitywhen performing pharmaceutical data.policy analysis. Another In addition, keyaspect when performing validitycross-national pharmaceutical policy andanalysis understandisto the policy context which requires insight information on policy dynamics. on the ‘heart of the policy We reform’. found the qualitative data provided by the PPRI network to be very helpful. Of great value was the communication with PPRI members to verify certain policydetails understandandto country’sa characteristics, interpretorderinto policy a also or a medicine price correctly. In addition, we received insight information from PPRI members on the country’s culture, history and the “political temperature”. We recognize the value of such networking activities, as especially face-to-face meetings or exchange of ad-hoc questions via to the recessiontheadjustmentswere to existing ofpolicies changing countries (e.g.thebasket the of forexternal price referencing), which could beimplemented relatively quickly.While leading to desired short-term cost-containment, these policies might have substantial long-term effects on access to, use, and affordability of medicines and negative impacts on health[43-45]. analysis such as a pre / post interrupted time series analysis could not be performed in chapter we 3.1; decided to use descriptive analysis to understand trends of consumption over time. reaction to recession-related budgetary constraints or system changes. if For instance, policies in Finland, were the implementation long-term of plannedinternal reference pricing2009 was plannedin long before the recession [42]. Most of the observed policy changes related that the European countries were therefore hit then decided by that it thewas impossible economicto take the start recession of theone economic at point recessionin differentas time for times.all countries We assessing the impact rapid on implementationmedicines of sales. policies In duringaddition, the the economic recession and policiesdifferentinthe countries precludeddifferent attribution observedof changes timing any to single policy or of statistical comparisons of responses between countries. Therefore, a sophisticated statistical the impact of the recent economic recession. First of all,economic it crisiswas started.difficult toTherefore, definewe whenlooked the at developments (GDP) in pergross domesticcapita productsas well as unemployment rates over time. From these data it was evident

5 General discussion 5 General discussion 145 improvement improvement of on medicine prices and utilization data as adequate information on the pharmaceutical on the pharmaceutical information adequate We We already elaborated on the importance of availability of insightful national We haveshownsamethatpricesmedicinetheextentgreatWe amongof European stillavary to The ultimate goal of studying pharmaceutical pricing and reimbursement policies is to With respect to methodologies, much can be learned from international comparative The second important point is the availability of is point the availability important The second All studies included in this thesis already represent a firststep in answering several of the the 15 countries. This could have been caused by the several pricing policy measures that were implemented as a consequence of the recent economic recession. These developmentsthe factand that the ability to pay for medicines vary greatly in Europe [21] trigger discussions on ultimatelyimprove access [33]. Keeping this inmind several policy implications and avenues for future research can be formulated resulting from the experiences of this thesis. countries. Instead of the conventional wisdom that maymedicine converge prices[48], we of observedEuropean a countriesprice divergence driven by price changes in only two of studies in other research areas, such require qualitative as methods such as sociologicalinterviews with national and stakeholders, so economicas to put results studies,of research into context and to better which understand variations of mightoutcomes. understand issues of high prices and/or of poor affordability in the context of publicto systems then develop policies and interventions that can be applied to rectify these problems and years years to improve the situation of of availability insightful policy data: some European large-scale projects were launched to foster exchange between public are authorities but also initiatives to the transparent public by such of benefits the though even However, articles. or reports publishing is networks these of several of sustainability the level, European at as well as national at recognized [46]. funding limited to due stake at policy policy context. additional relevance key of see we further but policies, reimbursement and pricing pharmaceutical industry. pharmaceutical the of strength or size the or country a of wealth the as such information and the industry of level 2.2, in chapter of the for that size pharmaceutical instance illustrated We gross domestic product had an influenceon the price level. Muchhas been done in the last ten discussed discussed above. Inclusion of utilization data in a European price database has not been planned nor are there other plans to establish a role important European an play to State Member EU database each of responsibility the remains on It data. prescription medicine utilization including contain ideally should policy pharmaceutical everynational harmonization; and collection data in [47]. data price medicine and consumption medicine collect reliable to plan comprehensive a of new medicines such as personalized medicines for a small group of population. population. of group small a medicinesfor personalized new as of such medicines above mentioned research priority areas. While performing these critical studies factors we for identified future two successful studies in cross-country pricing comparisons and of reimbursement pharmaceutical policies. The first important point concerns the publicly available, transparent and comparable data of of pharmaceutical pricing and reimbursement policies. The the and policies reimbursement and report pricing of environment broader suggests the on focus which priorities several research impact the referencing, price external of effects the are those Among used. are that ‘tools’ specific and reimbursement pricing and issues around on medicine utilization of the economic recession The final point, which we would liketo highlight for futureresearch, is the trendtowards Another point is how the role of patients can be strengthened in pharmaceutical pricing In In this thesis the focus has been on analyzing well-established and widely applied policies more specialized and personalized medicines – either orphan medicinal products for patients with rare diseases or stratified medicines which include priortesting These for medicines targeted therapies. serve only a small group of patients and are often among the 146 highest 3.2 we found a decrease in use of antipsychotic drugs in Portugal due to the implementation of various policies including changes in co-payments. On the other hand in chapter 3.1 we could not find anyreal effects on use of the tenchanges top-sellingoccurred during the observation active period. substances as too many policy of-pocket the difference between thereference price and the actual anprice, incentive which for generatespatients to request a medicine that is priced at or below the referenceAnother price. possibility could be to explicitly indicat the whichprice was of done the in medicinePortugal, on to the make package,patients aware of Anotherthe aspect isthat somepolicy actualchanges such asincreases ofpatient priceco-payments mayhave of the product [32]. considerableconsequences for patients theto point ofunaffordability of medicines. In chapter and reimbursement policy making. In other regulatory science, parts civil society of representatives theare already formally pharmaceutical involved in the policy decision- making field,process. Whether e.g. it actually represents an added value to involveand patients reimbursementin pricing decisions is open to question [46], which require but patients tothe be more implementationprice-sensitive and of therefore morepolicies self-determined would be desirable. An example could be a reference price system, where patients have to pay out- offers another interesting opportunity for research in this field, especially harmonization of at licensing and EU reimbursement requirements level is initiatives being these where of attempted effects to the investigate overcome to important be will It Europe. across access of disparities medicines[56]. to access on impact actual their and advice) scientific HTA-EMA, parallel as (such high-cost medicines including value-based pricing models taking into account societal when evaluating costs the value of a treatment (e.g. the United Kingdom) or agreements risk-sharing The effectsbetweenof these new will need to Italy) [51-55]. payers approaches and industry (e.g. be determined and appropriate policy analysis methodologies including measurements e.g. on including bodies HTA of importance growing the also But defined. be to need will aspects societal their methodologies, procedures and knowledge on the access to market of novel medicines reqiured to pay a lower price as they are more sensitive to price than high-income users [50]. However, the concept of differential pricing limits the value of transparency, as it depends on confidential agreements within countries. such as external several price countries Recently, referencing. have explored alternative policies that link pricing and reimbursement decisions with sharing the financialrisk of selecting new, the need for differential pricing mechanisms and policies for Europe. The concept of Ramsey optimal pricing states that prices shouldelasticity: more price-sensitive users are differcharged alower price than users that areless sensitive across markets according to [49]. If applied the in demand practice, this would mean that users in lower income countries should be

5 General discussion 5 General discussion 147 . pharmaceutical pharmaceutical policies. Analyzing pharmaceutical pricing policy, and consumption data can be issues systems and policy health broader “lens”evaluate a and as used understand to The findings of pharmaceutical pricing and reimbursement policy analysis play a key role in helping helping in role key a play analysis policy reimbursement and pricing pharmaceutical of findings The to understand, interpret and evaluate the rapidly changing pharmaceutical policy environment. Many stakeholders findthat these studies are of importance as the results the more are efficientuse of used scarcepublic healthto care resources.The studies guide included in this thesis have shown that the current available data on pricing and policies reimbursement and medicine prices and consumption provide ample opportunities for studying cross-national variations in both sectors, such as joint reimbursement lists and joint therapeuticsin committeesScotland as occurs[57]. The introduction of policies accompaniedto by sound evaluationsimprove [58]. interface management should be FINAL CONCLUSIONS many countries, these sectors operate as separate worlds from a pricing and perspectivereimbursement [28]. Legal and organizational needs have to be addressed in order to reduce the duality in the system and to remove existing incentives for stakeholders to transfer treatments and patients between the two sectors. All stakeholders should be best incentivizedpoint to of definecare, the including pharmacotherapy, for patients from Researcha therapeuticis neededperspective. to explore the possibility of an implementation of policies applicable to priced medicines. An additional aspect is that these testing treatments or often other require screening prior methods genetic which add to the pharmacotherapiesoverall are cost often appliedof treatmentat the [20].interface Theseof the out-patient and whichhospital imply questionssectors of funding responsibilities between the two sectors. At the moment, in . . Does http:// http:// http://whocc.

http://www.oecd-ilibrary. . Accessed 14 August 2013. August 14 Accessed . . Accessed on 14 August 2013. 2013. August 14 on Accessed . Introduction to First Drug ed. Utilization Geneva, Organization2003:76-84. Switzerland: Research. World Health Rosian I, Vogler S, Stürzlinger H. Internationale Arzneimittelpreisvergleiche: Commissioned by Meta-Analyse. Available Pharmig. Vienna 2004; from: http://whocc.goeg.at/ competitiveness. Key messages from the European European the from messages Key competitiveness. Competitiveness Report. 2006. Available from: http://ec.europa.eu/enterprise/sectors/ict/files/ euro_comp_report_2006_en.pdf Kyle MK, Allsbrook Reimportation JS, Schulman Reduce KA. Price Prescription Drugs? Lessons Differencesfrom the European for Union. Health Serv Res. 2008 Aug;43(4):1308-24. doi: 10.1111/j.1475-6773.2008.00838.x. Epub 2008 Mar12. Cambridge Pharma 2006 Intelligence IMS 2005. Review Access Consulting. Market Pricing and Docteur E, policies Paris in a global V. market. Paris: OECD Health Pharmaceutical Policy pricing Studies; 2007. www.oecd.org/fr/els/systemes-sante/ Available from: pharmaceuticalpricingpoliciesinaglobalmarket. htm Paris V, Belloni Pricing. OECD A. Health Working Paper. Value 2013. No. in 63. Pharmaceutical Available from: org/social-issues-migration-health/value-in-pharmaceutical-pricing_5k43jc9v6knx-enAccessedAugust2013. 14 on Almarsdottir AB, Traulsen evaluating JM. pharmaceutical policy – Studying becoming a Pharm process. and consultative and policy the of part 30. Jun 2006 Epub Feb;28(1):6-12. 2006 Sci. World Sjöqvist BirkettF, D. Chaper 10. Drug Utilization. WHO WHO Pharmaceutical Collaborating Policies. Centre Reimbursement for and Pricing Pharmaceutical Pricing and from: Available Reimbursement 2013. July glossary. of as Updated version goeg.at/Glossary/ Seiter A. A Practical Approach to Pharmaceutical Policy. Directions in Development. The Bank, Washington World 2010. Available from: www-wds.worldbank.org/external/default/WDSContentServer/WDSP/IB/2010/06/22/000334955_20100622050742/Rendered/PDF/552030PUB0Phar10Box349442B01PUBLIC1.pdfAccessedAugust2013. 14 Competitiveness European Commission. European Report 2006: Economic reforms and

20. 14. 15. 16. 17. 18. 19. 11. 12. 13. Effect of a medication a copayment Effect increase in of Cochrane Database 2010;(8):CD008654. of Systematic doi: Reviews.CD008654. 10.1002/14651858. Carlsten A. Do policy changes in the pharmaceutical pharmaceutical the in changes policy Do A. Carlsten expenditures? drug affect schedule reimbursement and volume cost, of analysis series time Interrupted Health 1986-2002 Sweden in trend volume per cost 2006;79:231-243. Policy. Green CJ, Maclure M, Fortin Aaserud PM, M, Ramsay Bardal CR, S. Pharmaceuticaleffects of policies: restrictions on reimbursement. The Wladysiuk Wladysiuk M, A, Araszkiewicz Godman B, Szabert K, Barbui C, Poland: in Haycox choice A. antipsychotic Influence of atypical on patient co- payment implications once generic atypical are 1;9(2):101- Mar available. 2011 Policy. Health Econ Health Appl 10.2165/11318840-000000000-00000. doi: 10. K, C, Lönnroth K,MG, Sonesson Petzol Andersson veterans with schizophrenia. Am J Manag Care. 2007Jun;13(6 Pt2):335-46. Wagner AK, Ross-Degnan D, Gurwitz JH, Zhang GildenCoslerDB,L, Soumerai F, EffectNewSB. of York State regulatory action on benzodiazepine prescribing and hip fracture rates. Med.200716;146(2):96-103. AnnJan Intern Dec;30(12):2346-54. doi: 10.1377/hlthaff.2010.1296. doi: Dec;30(12):2346-54. Lu CY, Soumerai SB, prior Medicaid Ross-Degnana of impactsUnintended D, AS. Adams Zhang F, medicationsauthorizationaccesstofor policyon bipolarillness. Meddoi: Care.2010 Jan;48(1):4-9. 10.1097/MLR.0b013e3181bd4c10. LantzFC,Blow KL, M,Grazier ValensteinJE, Zeber PM. restriction and benzodiazepineuse in general practice.Ann Fam moderate 10.1370/afm.1319. Med.doi: 2012;10(1):42-9. decrease Goldman G, R,Wan Dirani J, Xia G, Joyce WB, Vogt in DP. Medicaid cost control measures second-generation antipsychotics led aimed to less use at of all antipsychotics.Health Aff (Milwood). 2011 2001Jul;16(4):227-33. exclusion The SB. Soumerai JE, Sabin KZ, Bambauer of benzodiazepine coverage in Medicare: simple steps for avoiding a public health crisis. Psychiatr Sep;56(9):1143-6. 2005 Serv. Hoebert JM, Souverein PC, AK, Mantel-Teeuwisse Leufkens HGM, van Dijk L. Reimbursement Barbui C, Campomori A, Mezzalira L, Lopatriello S, Cas RD, Garattini S. in Psychotropic Italy, drug 1984-99: use the Psychopharmacol.Clin Intreimbursementstatus. impact of a change in

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51. 150 50. 48. 49. 47. 46. 45. 44. 43.

5 General discussion

CHAPTER

Summary, Samenvatting, and Zusammenfassung 6

CHAPTER

Summary 6.1

Summary 6.1 157 ) we explain the pharmaceutical policy framework in which chapter 1 gives a descriptive overview of one of the most commonly used pricing policies Chapter 2 addresses the question as to how national pharmaceutical policies aim at In the introduction ( The goal of this thesis is to understand pharmaceutical pricing and reimbursement policies controlling public pharmaceutical spending chapter by 2.1 regulating medicine prices. In particular, policy makers have to take decisions and give reasons why constantlypharmaceutical needed. policyRaising analysispharmaceutical is expenditure as well as a changing pharmaceutical environment lead to the need for adjusting policy and making implementingis a national pharmaceuticalcompetence, the policies.pharmaceutical policy As environment in Europediverse is showing a variety of pricing and reimbursement policy methodologies. the Investigatingimpact of (differences in) national policies and policy changes is crucial for policy makersto understand whether public affordability and accessibilityto medicines is still guaranteed. in Europe: external price referencing (EPR). EPR is defined as the practice of using the price(s) of a medicine in one or several countries in order to forderive the a purposes benchmarkof settingor or reference negotiatingprice the price of the product in a chaptergiven country.we In thisreviewed the country-specific PPRI (PharmaceuticalInformation) PricingPharma Profiles written and byrepresentatives Reimbursementof the PPRI Network. The PPRI network is a sustainable, self-funded network for public authorities Europeotherandcountries. profilesThe in analyzed were accordingpredefinedto criteria as such pricing and reimbursement in methodological choices in Europe with respect to the national legal framework, the countries included in the reference basket and the methodexpected, of many differencescalculation wereof foundthe betweenreference countries price. as theAs is waya ofnational implementing competence. EPR We found that of 28 analyzedin 2010. MostEuropean countries countrieshad less than 24 10 appliedcountries in EPR their reference baskets, but this number ranged from one country to 26 countries. Higher income countries tended to include higherincome countries in their basket, whereas lower income countries generally referred to lower income regional countries, as there is product a (GDP) per relationshipcapita rank and between the average a rank of country’sthe reference countries gross in the domestic basket andtheir impact on medicines prices and consumption in Europe. The underlying basis for this thesis is pricing and reimbursement policy data in European countries, which are analyzeddescriptive asin well as through statistical methods by evaluating the impact of these policies on medicine prices and consumption, especially during the economic recession. SUMMARY The pharmaceutical policy environment is dynamic as new medicines are being developed and differentmedical needs arise, while diverse interests by stakeholders influence policy making. what medicines; of reimbursement and pricing to respect with noticeable especially are Tensions health plans may care view as necessary maintain equitable to access medicines, to industry may budgets care health public As innovation. and (R&D) development and research to inimical as view and adjust constantly to have makers policy limited are – expenditure pharmaceutical including – This environment. pharmaceutical changing the with cope to policies pharmaceutical implement recession. years the economic of last the during increased even pressure financial . However, due to policy dueto changes However, .such priceas consequence cuts aas theof 1 we assessed whether EPR leads to the desired effect of lower and more stable . Previous reports showed that European Union (EU) price convergence for chapter 2.2 The aspect of how national policies affect the overall medicine price level in European In chapter 2.3 France, Germany, Greece, Ireland, Italy, Luxembourg, the Netherlands, Portugal, Spain, Sweden,United Kingdom. EU-15 countries = EU Member States as of 1 January 1995: Austria, Belgium, Denmark, Finland,

1 158 economic recession in many countries, the picture of medicine price convergence in Europe may have changed. We received medicine price data from the Austrian Health Institute for ten on-patent medicines in five years (2007-2011) of 15 Europeanwas countries.the ex-factory price in The€ per defined unit daily dose (DDD, exchange ofrate indexedto analysis 2007). We found that the prices between countries and selected products varied to a great extent from as medicines was more rapid in the second half of the 1990s as a result of the process of EU monetaryEU of process the of result a as 1990s the of half second the in rapid more wasmedicines countries EU core identified: the were countriesof clusters two 2000 from Startingconvergence. (such as France, BeneluxItaly, countries) with a 15% average price gap; and the cluster of newer EU Member States and Spain, Portugal and Greece, which had average prices almost 40% lower level thantheEU-15 by EPR but also by pharmaceutical industry size. Substantial price differences among countries that apply EPR may be explained by different methodologies withrespect to countries the in a reference basket or theselection method for calculating the price. of countries and whether these policies lead to price convergence in across Europe is addressed applying EPR in a country was associated with a lower scaled rank (p=0.002). This persistedassociation after inclusion of total pharmaceutical expenditure per in capita the and finalGDP model. Theper assessmentcapita of therelationship between pharmaceuticalper 100,000 employmentinhabitants and the scaled ranks per country and product drivenonly concludednot price level therefore is the that We significant showed correlation (p=0.0063). a statistically price data (unit ex-factory prices level in €) from the Austrian Health Institute, which we used to calculate scaled ranks per country and per product. We analyzed the relationship between the scaled ranks and several explanatory variables (such as EPR, TPE per capita and GDP per capita) by a linear regression model. The median of the scaled ranks of the countries varied from as low as 0.23 in Italy to 0.83 in Denmark. Two of the countries that did not apply EPR (Germany Denmark) had theand highest scaled ranks. The unadjusted linear regression model confirmed that policy in contrast to what some people belief. medicineprices. Thestudyaimed examining at impacttheon-patent EPRonof medicine prices, adjustingaffectotherfactorsformay that price levelssales rates, GDP as volume, such exchange percapita, totalpharmaceutical expenditure (TPE), andofthesizepharmaceutical industry in14 European countries between 2007 and 2008. We received for 14 on-patent products medicine (Kendall’scorrelationrank tau:0.556263, p=0.0005331).averagethecountriespriceall ofTaking in the basket as the basis to calculate the national price was the most common strategy (n = 8). The methodology of EPR which impacts price determination has changed countriesin mostover theEuropean past 10 years (n = 19), showing that EPR is still widely used and a dynamic

Summary 6.1 Summary 6.1 159 while All countries showed moderate increases in sales volumes analyses which pharmaceutical pricing and reimbursement Chapter 3.1 Most policy changes occurred in 2010 (n=33/88) and 2011 (n=40/88) and presents a detailed evaluation of the impact of different policy measures on the Chapter 3.2 Chapter 3 focuses on how countries re-evaluate and adjust national policies in times of and to increases in generic market share of major antipsychotic products. In Finland quetiapine and risperidone experienced substantially increased generic year post-policy market compared to before, shares quetiapine: 6.80% (estimates[95% confidence intervals one (CI) 3.92%, recession. We obtained monthly IMS sales data in standard units of antipsychotic medicines in timeinterrupted an used We December2011. to periodJanuary 2007the for Finland Portugaland series design to estimate changes in overall use and generic market shares by comparing pre- policy and post-policy levels and trends. We found that both countries’ policy approaches were associated with slight, likely unintended, decreases in overall use of antipsychotic medicines Portugal (-11% in 2011). We concluded that countries’ responses to the recession differed.economicallypolicychangeslessimplementeddensityWe ofhigher by countries.stableobserved a Unexpectedly almost all countries showed moderate increases in pharmaceutical sales volume despite declines in sales value, especially in the less economically stable countries. economic the of time the during Finland and Portugal inmedicines antipsychotic of consumption included changes in out-of-pocket payments (n=16/88), changes in (n=13/88)price and pricemark-up cuts schemes(n=11/88). ranging from 1% (Greece and Portugal) to 3% (in Estonia, Ireland and Slovakaverage Republic);annual growth rates in sales value varied between -2% However, infrom 2009Portugal onwards to all 5% countriesin experiencedEstonia. decreases in sales value.declines The werelargest observed in Greece (negative year on year growth rate of -14% in 2010) and versusless stable countries classified based on 2012 fiscal consolidation plans of OECD member countries. Our study showed that economically stableimplemented between countries two and (Austria,seven policy Estonia,changes each, Finland)whereas economically less stablecountries (Greece, Ireland, Slovak Republic, Spain, Portugal)22 policy implemented changes. between 10 and economic recession. evaluatesand recessioneconomic the of time the duringcountries implementedby werepolicies the correlation with medicines sales in eight European countries. Based on a literature review, we described pharmaceutical policy changes and used IMS Health sales dataof productsto in analyze the 10 quarterlyhighest-selling therapeutic classes, in IMS standard units (volume)and constant dollars (value). We presented sales growth rates, comparing economically stable around the average of the countries included in the study. Prices of less expensive medicinesremained relatively stable or decreased over time, while prices of expensive medicines tended to increase. It is therefore crucial for policy makers to keep in mind that the environmentisdiverse and changing Europeanover time, requiring regular monitoring ofthe effects, policy and that these policy changes do have an impact on national medicine prices. low as an average price of € 1.3/DDD for sitagliptin in 2010-2012 to an average of € for221.5/DDD alemtuzumab in 2011. During the study period, a price divergence was seen which was only driven by two countries, Germany (up 27%to more expensive than the average) and Greece (up to 32% cheaper than the average). All other countries had relatively stable prices and centered We concluded that qualitative descriptive We analysed describes how European pricing chapter 4.1 Since 2005 the average price gradually decreased from € 641 contains a general discussion of the benefits and limitations chapter 5 The concluding In Europe, there is an increasing use of personalized medicines which require prior he example of trastuzumab and its accompanying diagnostic test highlights some problems of research on pharmaceutical pricing and reimbursement policywe interventions. advocate In firstly specific, for an improvementto ofpublicly dataavailable availabilitymedicine price andand transparencyconsumption withdata sources respect as well as of up-to-date 160 Themovehealthto technology assessment thatoccurring(HTA)is manyincountries mayhave addressed some aspects of the problems occurring in this complex area. But other decisions, such as whether these medicines and diagnostics should be paid for from hospital or primary care budgets may have a devastating effect on access. itsdiagnostic test, mostascountries applied pricecontrol policies fortrastuzumab buthadfree pricing for the diagnostic test. with some increases in specific years (i.e. 2008 and 2012)to € 609 in 2013. t of the interface between different funding streams(out-patient regard to andthe hospital)interface between but the alsomedicine with applied in combination with a medical device. surveyed European countries either both trastuzumab and the accompanying diagnostic test werefunded from hospital budgets (n=13) or medicines were funded by third party payers such social insurances and the test was funded from fundinghospital of budgetsboth the(n=14). medicine Neither and combineddiagnostic test by third partysurveyed payers was countries identified in nor the did the respondents managedentry agreements. National pricing from procedures weredifferent for trastuzumab versus the competent authorities identify any accompanying diagnostic test as an example of personalized medicines. Data fromwere obtaineda survey among competent authorities from 27 EuropeanFurther, countrieswe received as medicineof priceAugust data2011. (for the years 2005 respectiveto European countries 2013)from the Austrian Health of Institute. foundWe trastuzumabthat in 2011 testing in the and treatment mainly took place in hospitals or in specific day-care ambulatory clinics. In the genetic testing to guide their use which entail new challenges to policy to makers with pricingrespect and reimbursement. In and reimbursement specific, authorities deal with the increasing evaluate andand assess these common‘treatment packages’challenge which included of both new andhow often expensive to medicines as well as medical devices such as diagnostics. data on national pharmaceutical pricing and funding policies applied to trastuzumab and its of new policies or the adjustment of existing unintended havepolicies may changes policycan these sometimeshave but period, timepositive short a effectsin spending public on controlling decrease a to leadmaypatientsout-of-pockethigher whichconsequences paymentsforas such in use. Therefore, there is a need to continuously monitor intended and possibly effectsunintended of new policies or policy changes. 9.68%]; risperidone: 9.68%]; [95%11.13% CI 6.79%, The 15.48%]. policy interventions in Portugal resulted in a substantially increased generic market share for amisulpride (estimate one year post-policy genericrisperidone alreadydominatedthe 24.90%]; 21.01%, CI[95% before:22.95% compared to policytheinterventions. marketpriorto Thesefindings clearly implementationindicate the that

Summary 6.1 Summary 6.1 161 pharmaceutical policies. Analyzing pharmaceutical policy, pricing and consumption data canbe used as a “lens” to understand and evaluate broader health policy and systems issues. data on the policy context) to understand the context in which they are being Finally,implemented. avenues for future research such as exploring assessment methodologies with respect to new technologies such as personalized medicines and patient involvement are identifiedto eventually improve access to and affordability of medicines. The studies included in this thesis haveshowncurrentthattheavailable pricing dataonreimbursementand policies medicineand prices and consumption provide ample opportunities for studying cross-national variations in policy data; secondly for better validity and comparability priceof datalevels, in the specificunit of withcomparison,regard to exchange rates and forweighing a of pricestransparent by access volume; to and adequate information onthe impact nationalof timing of policypolicies implementation on(e.g. the study withdesign as wellrespect as the collection to of

CHAPTER

Samenvatting 6.2

Samenvatting 6.2 165 ) wordt het kader beschreven waarbinnen beleidsmakers geeft een overzicht van één van de meest toegepaste hoofdstuk 1 Hoofdstuk 2.1 In de introductie ( Hoofdstuk 2 gaat in op de vraag hoe nationale beleidsmaatregelen pogen de publieke Het doel van dit proefschrift is om op basis van beschikbare gegevens in Europa inzicht te uitgaven voor geneesmiddelen te te reguleren. controleren door prijsstelling van geneesmiddelen krijgen in het beleid rondom prijsstelling en vergoeding van geneesmiddelenvanditbeleid opprijzen enconsumptie vanengeneesmiddelen. deDeze gegevens zijn zowel invloedopeen beschrijvende manier als met behulp van statistische methoden geanalyseerd. De invloed van het beleid is vooral bestudeerd ten tijde van de recente economische recessie. beslissingen moeten nemen en farmaceutisch worden beleid continu te analyseren. redenen De toegenomen uitgaven aan geneesmiddelen aangegeven en waarom de het veranderende omgeving vragen nodigom bijstelling en implementatie is van farmaceutisch beleid. het Omdat beleidsvorming ten aanzien van prijsstelling en vergoeding van geneesmiddelen onder de nationale verantwoordelijkheid van lidstaten valt, is er in Europa een grote verscheidenheid aanbeleidmethoden en ditgebied.op Onderzoek naarimpactde van(verschillen in)nationale beleidsmaatregelen is cruciaal voor beleidsmakers betaalbaarheid om van en toegang tot geneesmiddelen vast voldoende is gewaarborgd. te kunnen stellen of publieke beleidsinstrumenten op het gebied van prijsvorming in Europa: externe prijsreferentie (EPR). EPR is het gebruik van de prijs van een geneesmiddel in een benchmarkof meerdere of landen om referentieprijszo een te verkrijgen voor een de ander prijsstelling land. of prijsonderhandeling Voor dit in vertegenwoordigers hoofdstuk van het PPRI zijn (‘Pharmaceutical zogenaamdePricing and Reimbursement landenprofielen, Information’)netwerk, bestudeerd. geschreven Het PPRI netwerk is een zichzelf door in stand houdend netwerk van publieke autoriteiten op het gebied van prijsstelling en vergoeding van geneesmiddelen in enkeleEuropa andere en landen. De profielen zijn onderzocht op gegevens met betrekkingtot EPR aan de hand van vooraf vastgestelde criteria, waaronder het wettelijk kader en methodologischekeuzeszoals het aantal referentielanden en de wijze waarop de referentieprijs wordt berekend. Zoals verwacht werden vele verschillen tussen Europese landen gevonden, omdat dit beleid SAMENVATTING Farmaceutisch beleid wordt Nieuwe vormgegeven geneesmiddelen in worden een ontwikkeld treden op, terwijl de en dynamischeverschillende belangen verschuivingenvan betrokken geneesmiddelenmarkt. partijen in het Met beleid name beïnvloeden.ten medische aanzien van prijsstelling noodzaak en vergoeding van op;geneesmiddelen treedt wat spanning vanuit het oogpunt toegang van tot geneesmiddelen de te waarborgen, volksgezondheid kan door wordt de farmaceutischebeschouwd gezien industrie als als worden noodzakelijk nadelig om voor voor onderzoek, de gezondheidszorg ontwikkeling – inclusief en farmaceutische innovatie. zorg beleidsmakers – Publiekehun beleid zijn continu beperkt. budgettenbijstellen en Daarom nieuw beleid moeten ontwikkelen om indeze veranderende te omgeving. spelenDe financiële druk ophiertoe is in de afgelopen jarentoegenomen door de economische recessie. . Eerdere . hoofdstuk2.3 hebben we bestudeerd of EPR leidt tot het gewenste effect van lagere hoofdstuk 2.2 De vraaghoenationaleDe beleidsmaatregelen hetprijsniveau Europeseinlanden beïnvloeden In Vanaf 2000Vanafkunnen twee clusters vanlanden wordenonderscheiden: hetcluster met“oude”de EU landen (o.a. Frankrijk, Italië en de Benelux) voor wie het verschil in prijs gemiddeld 15% was en het cluster van de nieuwe lidstaten en Spanje, Portugal en Griekenland, voor wie prijzen 166 waarop de referentieprijs wordt berekend. beantwoordinwordt prijsconvergentieEuropa intot leidtbeleid dit of en snelstoptradrapportenhethebbenaangetoond (EU)prijsconvergentieEuropese Uniedat de in tweededein helftjarennegentigvande alsgevolg vanhetproces vanmonetaire convergentie. uiteindelijke model. Ook werd een statistisch significanterelatie (p=0.0063) gevonden tussen het aantal werknemers in de farmaceutische industrie per 100,000 inwoners en deper rangordeland en per product. Daarom werd er geconcludeerd dat het prijsniveau niet alleenEPR doorwordt bepaald, maar ook door de omvang van de farmaceutischeDe grote industrie verschillenin een in land. prijsniveau tussen landen die EPR verklaard hebbendoor verschilleningevoerd in methodologie,wordt zoals de selectiemogelijk van referentielanden en de wijze zorg en BPP per hoofd van de bevolking is onderzocht met behulp van een lineair regressiemodel.lineaireen van behulponderzochtmet bevolkingis de van hoofd per BPP en zorg mediaanDe rangordevandevarieerde van0.23voor voorItalië Denemarken. 0.83 tot vanTwee de landen zonder EPR (Duitsland en Denemarken) hadden de hoogste plaats in de Hetongecorrigeerderangorde. lineaire regressiemodel bevestigde dathettoepassen vanEPReeninland was geassocieerd met een lagere rangorde (p=0.002). Deze associatie hield stand na correctie voor totale uitgaven aan farmaceutische zorg en BPP per hoofd van de bevolking in het aan farmaceutische zorg en omvang van de farmaceutische (fabrieksprijzenindustrie.in €per eenheid) werden van het Oostenrijkse Geneesmiddelprijzengezondheidsinstituut (‘Austrian HealthInstitute’) verkregen gepatenteerdevoor 14 geneesmiddelen. Dezeprijzen zijngebruikt om een geschaalde rangorde per land en per product te rangordeberekenen.en mogelijke verklarende variabelenDe zoals EPR relatieen totale uitgaven aan tussenfarmaceutische deze beleidsmaatregel is, in tegenstelling tot wat sommigen geloven. en stabielere geneesmiddelprijzen. Het onderzoek had prijzen tot van doel gepatenteerde de impact geneesmiddelen van te EPR bepalen op en in de 14 2008, Europese waarbij landen tussen er 2007 gecorrigeerd bepalen werd als voorverkoopvolume, wisselkoersen, andere BPP per factoren hoofd van die de bevolking, het totale prijsniveauuitgaven kunnen en lagere inkomenslanden van andere lagere inkomenslanden, bleek uit de gevonden relatie tussen de plaats van een land op basis van rangschikking van het bruto (BPP) binnenlandsen de product gemiddelde plaats van de referentielanden in deze rangschikking (Kendall’s correlationrank tau: 0.556263, p=0.0005331). De meeste landen bepaalden de referentieprijs door het gemiddelde van de prijzen in de referentielanden te berekenen (n=8). In de afgelopen jaargebruikte10de is methodologie landen10in aangepast wataangeeft datEPReendynamische eennationale verantwoordelijkheid vanis. de In2824 onderzochte Europese landen was EPR in 2010 ingevoerd als beleidsmaatregel. De meeste landen gebruikten prijzen van minder dan 10 anderereferentieprijslandendeom bepalen, te maaraantal ditvarieerde landen.26 ééntotvan Dat hogere inkomenslanden vooral prijzen van andere hogere inkomenslanden gebruikten

Samenvatting 6.2 Samenvatting 6.2 167 bestudeert welke Hoofdstuk 3.1 gemiddelde. Door nieuwe beleidsmaatregelen zoals 1 Hoofdstuk 3 richt zich op de vraag hoe landen hun nationale geneesmiddelenbeleid Griekenland, Ierland, Italië, Koninkrijk, Zweden Luxemburg, Nederland, Oostenrijk, Portugal, Spanje, Verenigd EU-15 = de 15 EU lidstaten op 1 januari 1995: België, Denemarken, Duitsland, Finland, Frankrijk,

1 (n=11/88). In alle landen werden kleine stijgingen in de jaarlijksekleinestijgingenlandendeverkoopvolumeswerdenalle in In waargenomen, (n=11/88). variërend van 1% in Griekenland en Portugal tot 3% in Estland, Ierland en Slowakije. De jaarlijkse verkoopcijfers in dollars varieerden daarentegen van -2% in Portugal tot +5% in Estland. Vanaf 2009 lieten alle landen echter een waargenomen in dalingGriekenland (negatief groeipercentage in van in -14% 2010) en Portugal uitgaven (-11% in zien. De grootste dalingen werden consolidatieplannen van de OECD lidstaten in 2012. Economisch stabiele landen bleken twee tot zeven veranderingen in het farmaceutisch beleid te hebben doorgevoerd, terwijl de minder stabiele landen elk tussen de 10 en 22 veranderingen doorvoerden. De meeste veranderingen vonden plaats in 2010 (n=33/88) en 2011 (n=40/88) en behelsden bijdrage veranderingen (n=16/88), veranderingen in in het de systeem eigenvan ‘mark ups’ (n=13/88) en prijsverlagingen geneesmiddelenconsumptie. Gegevens over de veranderingen in het beleid zijn op basis van literatuuronderzoek verkregen en IMS Health data zijn gebruikt om verkoopcijfers per kwartaal in standaard units (volume) en dollars (uitgaven) van de tien meest verkochte productgroepen (therapeutische klassen) te analyseren. economisch stabiele De (Estland, Finland en Oostenrijk) groeipercentages en minder stabiele landen werden (Griekenland, vergelekenIerland, Slowakije, tussen Spanje, Portugal), waarbij stabiliteit werd bepaald op basis van de fiscale monitoren van de effecten van beleidsmaatregelen noodzakelijk. herevalueren en bijstellen tijdens de economische recessie.Europese acht doorgeneesmiddelen van vergoeding en prijsstelling rondom beleidsmaatregelen landen zijn geïmplementeerd tijdens de economische recessie en of er een correlatie is met het gemiddelde). De overige landen hadden relatief stabielehet gemiddelde geneesmiddelprijzenprijsniveau lagen. Prijzendie van derond goedkopere geneesmiddelen bleven relatief stabiel of namen af in de tijd, terwijl prijzen van dure geneesmiddelen omhoog leken te gaan. Dit onderzoek laat zien dat het voor Europese beleidsmakers van groot belangrealiseren is dat om de zich vorming te van beleid plaatsvindt in een diverse en datdynamische omgeving veranderingen en in beleid een effect hebben op nationale prijsstellingen. Dit maakt het landen. De in dit onderzoek gebruikte prijs was de fabrieksprijs (DDD),in waarbij € de wisselkoersenper op ‘defined2007 waren dailygeïndexeerd. Er dose’ werden grote prijsverschillen gevonden tussen landen en producten. De gemiddeldesitagliptine in prijs 2010-2012 varieerdetot €221.5/DDD van voor €1.3/DDDalemtuzumab in voor2011. De prijsconvergentieoptrad gedurende die de onderzoeksperiode werd door slechts twee landen bepaald; (meer Duitslanddan 27% hogere prijzen dan het gemiddelde) en Griekenland (tot 32% goedkoper dan bijna 40% lager waren dan het EU-15 prijsverlagingen tijdens de economische recessie kan dit beelddit echter onderzoek zijn veranderd. zijn Voor prijsgegevens ontvangen van tien gepatenteerde het geneesmiddelen Oostenrijks voor een periode gezondheidsinstituut van vijf jaar (2007-2011) van in 15 Europese beschrijft daarom hoe Europese autoriteiten omgaan met deze geeft een gedetailleerde analyse weer van de impact van verschillende Hoofdstuk 4.1 In Europa wordt een toename gezien van de zogenaamde individualisering van Hoofdstuk Hoofdstuk 3.2 In de onderzochte landen werden zowel vanuit het ziekenhuisbudget trastuzumab gefinancierd (n=13) als of werd het geneesmiddel het gefinancierd door bijbehorende diagnosticumeen derde partij als de zorgverzekeraar terwijl het diagnosticum werd gefinancierd vanuit 168 voorbeeld genomen. Deze gegevens zijn verkregen via een onderzoekautoriteiten onder de van bevoegde 27 Europese landen bijbehorendeprijsstelling van trastuzumab in verkregen via het Oostenrijks gezondheidsinstituut augustus 2011. Daarnaast voor zijn de gegevens periode over 2005-2013. de Uit patiënten dit in onderzoek 2011 bleek vooral dat binnen het ziekenhuizen testen en en gespecialiseerde behandelen van dagcentra plaatsvond. bepaald door het (genetische) profiel vanautoriteitenvoorvergoeding prijsstellingen detotbetrekking metuitdagingenbijzondere brengen patiënt. Deze ‘personalised’ geneesmiddelen met zich mee. uitdagingen en hoe zij de behandelcombinaties van een en vaak een nieuw medisch en hulpmiddelduur geneesmiddelzoals een diagnostische test over beoordelen. de Hierbijprijsstelling zijn en gegevensvergoeding van trastuzumab en het bijbehorende diagnosticum als positief positief effect kunnen hebben op de korte termijn uitgaven deze maatregelen tegelijkertijd onbedoelde aan neveneffectenkunnen hebben geneesmiddelen, zoals hogere eigen maar bedoelde de noodzakelijk dat het is Daarom leiden. kunnen gebruik het in daling een tot die bijdragen monitoren. te continue beleidsmaatregelen aangepaste of nieuwe van onbedoelde en effecten geneesmiddelen(‘personalised medicine’), waarbij de toepassing van het geneesmiddel wordt risperidon risperidon (11.13%, 95% BI waargenomen 6.79-15.48%) als de periode voor de invoering van de beleidsmaatregelen werd vergeleken met het jaar erna. leidden Detot een behoorlijke beleidsmaatregelen stijging in van het Portugal generieke marktaandeel van amisulpride (22.95%, maar 95% niet BI van 21.01%-24.90%) risperidon, omdat voor dat antipsychoticum de generieke versies de markt al domineerden. Deze bevindingen laten zien dat dergelijke maatregelen een de de trend in gebruik van antipsychotica en veranderingen in het marktaandeel antipsychotica voor en na de van introductie van te beleidsmaatregelen bepalen. Er werd gevonden generieke ongewenste, vermoedelijk kleine, tot leidden landen beide in beleidsmaatregelen gekozen de dat dalingen in het gebruik van antipsychotica en een stijging in het generieke marktaandeel van de meest gebruikte antipsychotica. In Finland werden aanzienlijke stijgingen in het generieke marktaandeel van quetiapine (6.80%, 95% betrouwbaarheidsinterval (BI) 3.92%-9.68%) en geneesmiddelen, vooral in de economisch minder stabiele landen. beleidsmaatregelen op het gebruik van antipsychotica in Portugal en economische recessie. Gegevens over Finland het maandelijks gebruik van gedurende deze middelen in de standaard units van werden verkregen IMS Health voor de periode januari 2007 tot en met december 2011. Een ‘interrupted time series’ analyse werd uitgevoerd om veranderingen in het niveau van en 2011). Dit onderzoek toonde aan dat landen verschillend reageren op de economische recessie, waarbij economisch minder stabiele landen meer beleidsmaatregelen implementeerden. lichte stijging De van het geneesmiddelengebruik in volume was een onverwachte bevinding, die in vrijwel alle landen werd waargenomen en die plaatsvond ondanks een daling in uitgaven aan

Samenvatting 6.2 Samenvatting 6.2 169 bevat een algemene bespreking van de voordelen en hoofdstuk 5 Het afsluitende variaties in farmaceutisch beleid tussen landen te bestuderen. Het analyserengegevens kan vanfungeren als eendergelijke “venster” om algemene aspecten van beleid en systemen in de gezondheidszorg te kunnen begrijpen en evalueren. voor toekomstig onderzoek geïdentificeerd,zoals het verkennen van beoordelingsmethoden voor nieuwe technologieën waaronder ‘personalised’ geneesmiddelen en de rol van patiënten in dit proces, wat uiteindelijk van kan geneesmiddelen. leiden tot De een onderzoeken betere beschikbaregegevens inover beleidsmaatregelen toegangaanzienten vanprijsstelling vergoedingen van dit tot proefschrift en betaalbaarheid laten geneesmiddelen, zien geneesmiddelprijzen dat en gebruiksgegevens de vele mogelijkheden momenteel bieden om prijsniveaus en eenheden, wisselkoersen en het verschillen wegen in van verkoopvolumes; prijzen en om tenslotte te tot corrigerentransparantie voor vaninformatie overen nationale toegangbeleidsmaatregelen tot(bijvoorbeeld adequateover de exacte timing in verband met het mogelijke effect op de onderzoeksopzet) omdeze zo maatregelen de nationale worden context genomen waarbinnen beter te begrijpen. Daarnaast worden mogelijkheden beperkingen van onderzoek naar interventies op het gebied van prijsstelling en vergoedingen van geneesmiddelen. We roepen ten eerste op tot een betere (publieke) beschikbaarheid en transparantie van gegevens over prijsstelling en consumptie van geneesmiddelendate gegevens tenen aanzien up-to-van genomen beleidsmaatregelen; ten tweede tot betere validiteit en vergelijkbaarheid van dergelijke gegevens, met name met betrekking tot gebruikte tussen verschillende geldstromen binnen de gezondheidssector (intramuraal en extramuraal). Het toepassen van ‘health technology assessment’landen gebeurt, komt tegemoet (HTA), aan sommige aspecten zoals van de problemen die in indit complexe een toenemend aantalveld optreden. Maar andere beslissingen, zoals bijbehorende diagnostica uit moeten welk worden betaald, budget kunnen deze mogelijk een geneesmiddelen vernietigend hebben effectop de en toegang tot ‘personalised’ geneesmiddelen. om de prijs van trastuzumab te reguleren, terwijl voor het diagnosticum een vrije prijsstelling gemiddeldetrastuzumabDegeleidelijkgold.€609vanprijs2005vanaf wastot €641gedaald van in2013, waarbij er kleine verhogingen zichtbaar waren in sommige jaren (bijvoorbeeld 2008 en 2012). Dit voorbeeld van trastuzumab en het bijbehorende diagnosticum belicht verscheidene problemen die kunnen optreden bij het vaststellen geneesmiddelvan en deeen bijbehorend prijsmedisch hulpmiddel,en maar ook problemende in de vergoeding‘interface’ van een het ziekenhuisbudget (n=14). In geen enkel diagnosticum land door werdende zorgverzekeraar zowel gefinancierd het en ook geneesmiddel werdenzogenaamde entry als agreements’ ‘managedniet het gerapporteerd. De nationale procedures voor prijsstelling verschilden voortrastuzumab en het bijbehorende diagnosticum; de meeste landen kenden mechanismen

CHAPTER

Zusammenfassung 6.3

173 Kapitel 2.1 Kapitel ) beschreiben wir den arzneimittelpolitischen Rahmen, in Kapitel 1 In der Einleitung ( Zielsetzung dieser Dissertation ist es arzneimittelpreis- sowie erstattungspolitische Kapitel Kapitel 2 beschäftigt sich mit der Frage, ob die Regulierung von Arzneimittelpreisen eine Maßnahmen und deren Einflusserfassen. auf Informationen Arzneimittelpreise zu Arzneimittelpreise Maßnahmen und und der –verbrauch -verbrauch Arzneimittelpreisbildung in in den aufbereitet Europa und mittels und statistischer europäischen Methoden analysiert. zu –erstattung, Ländern wurden dazu deskriptiv ZUSAMMENFASSUNG arzneimittelpolitischeDas dynamisch:UmfeldistLaufend Arzneimittel neuewerden entwickelt, um den Bedarf am medizinischen Fortschritt zu Interessendecken, der Akteurewährend auf die sich Ausgestaltung die der Arzneimittelsystemekontroversiellen auswirkt. Spannungen treten vor allem im Bereich Arzneimttelpreisfestsetzungwelche die öffentliche und Verwaltung für Erstattung grundlegend erachten, auf: um einen gerechten Maßnahmen, Zugang zu Arzneimitteln zu gewährleisten, mag die pharmazeutische Industrie als negativ für Forschung und Entwicklung sowie für Tatsache, dass Innovation die öffentlichen Gesundheitsausgaben einschätzten. – inklusive der Aufgrund Arzneimittelausgaben – dieser limitiert sind, Dynamik müssen Entscheidungsträger und ständig Anpassungen der und NeueinführungenpolitischenMaßnahmen vornehmen. Finanzkrise,Durchdievon währendletztender fünf Jahre,hat sich dieser finanzielle Druck auf die öffentlichen Budgets sogar noch verstärkt. Dämpfung der öffentlichen Arzneimittelausgaben bewirken kann. Dazu wird einführend in in einführend wird Dazu kann. bewirken Arzneimittelausgaben öffentlichen der Dämpfung welchemEntscheidungsträger agieren, undbegründen, warum eseinen fortwährenden Bedarf arzneimittelpolitischenAnalysedesder an Umfeldsgibt.SteigendeArzneimittelausgaben sowie ein sich schnell veränderndes arzneimittelpolitisches Umfeld erfordern neue bzw. geänderteMaßnahmen. Die Ausgestaltung der Arzneimittelsysteme in liegt der Verantwortung in der der EU-Mitgliedstaaten, Europäischen Union und Arzneimittelpreisbildungs- die unterschiedlicheund –erstattungssysteme Ausgestaltung ist eine derFolge davon. Die Untersuchung des Einflusses der Einführung und Anpassungzentraler Bedeutung von für Entscheidungsträger/innen, Maßnahmen um die öffentliche in Finanzierung von und diesem Bereichden Zugang ist zu Arzneimitteln langfristig von zu gewährleisten. ein deskriptiver Überblick über eine der am häufigsten verwendeten Preisfestsetzungsmaßnahmen Preisfestsetzungsmaßnahmen verwendeten häufigsten am der eine über Überblick deskriptiver ein in Europa gegeben: der internationale Preisvergleich (in englischer Literatur als external price referencing, EPR bekannt); bei dieser Methodik wird der der Preise in Preis anderen Referenzländern eines festgesetzt. In diesem Arzneimittels Kapitel analysierten auf wir die Basis PPRI- Länderberichte (PPRI = Pharmaceutical Pricing and Reimbursement Information), welche Vertreter/innen von des PPRI-Netzwerkes geschrieben wurden, auf Informationen hinsichtlich des Einsatzes von EPR. Das PPRI-Netzwerk ist ein Behörden, nachhaltiges, die für selbstfinanziertes die Netzwerk Arzneimittelpreisfestsetzung und von -erstattung in Europa zuständig Die sind. PPRI-Länderberichte wurden anhand von definiertenüber Kriterien, wie die etwa Vorgangsweise hinsichtlich Informationen der nationalen gewählten gesetzlichen Rahmenbedingungen, Referenzländer der und des erwartet, gewählten wurden unzählige Unterschiede in der Ausgestaltung Preisfestsetzungsverfahrens und der Umsetzung von EPR analysiert. in Wie analysiert. Frühere Studien zeigten eine bei Preiskonvergenz Arzneimitteln untersuchen wir, ob EPR den erwünschten Effekt, niedrigere und stabilere Kapitel Kapitel 2.3 Kapitel 2.2 Der Aspekt, wie nationale politische Maßnahmen das Arzneimittelpreisniveau in den In Währungspreiskonvergenz. Währungspreiskonvergenz. Seit 2000 verlief die Preiskonvergenz unterschiedlich zwischen der Gruppe der ersten EU-Mitgliedstaaten (wie Frankreich, Italien und die Beneluxländer) mit einer durchschnittlichen Preisschere von 15% und der Gruppe der neueren EU-Mitgliedsländer sowie 174 der Vergleichsländer oder der Berechnung des Preises), zurückzuführen sein. europäischen Ländern beeinflussen und ob sie zu wurde in einer Preiskonvergenz in Europa führen, in Europa in der ersten Hälfte der 1990er-Jahre als Konsequenz der gesamteuropäischen einen möglichen Zusammenhang zwischen der Anzahl der pharmazeutischen pro 100.000 Einwohner/innenUnternehmen und der Skalierung pro Land und Produkt zeigte eine statistisch signifikanteKorrelation (p =0.0063). Daraus folgerten wir, dass das Preisniveau nicht nur von EPR,sondern auch von der Relevanz der pharmazeutischen Industrie in einem Land beeinflusst erheblichenist.DiePreisunterschiede Ländern,anwendeten,zwischenwelchedenEPRkönnten auf die unterschiedlichen methodischen Ansätze, welche die Länder wählten (z. B. hinsichtlich Faktoren mittels eines linearen Länder reichte Regressionsmodells. von 0,23 Der in Median Italienanwenden (Deutschland bis der und 0,83 Dänemark), Skalierungenwiesen in den Dänemark.höchsten der Wert ZweiRegressionsmodells auf. Dank der des konnten linearen Länder, wir die nachweisen, nicht variablenEinschlussstatistischeder Zusammenhang nachführt.Derblieb 0.002) dass = EPR Preisniveau(p EPR zu einem tendenziell niedrigeremArzneimittelausgaben pro Kopf und BIP pro Kopf bestehen. Die Auswertung im Hinblick auf undGröße der pharmazeutischen Industrie europäischenin 14 Ländern inden Jahren 2007 und 2008 zu analysieren. Wir erhielten dafür Preisdaten von 14 (auf patentgeschützten Ebene Arzneimitteln des Fabrikabgabepreises in €) Österreich GmbH, von mit welchen wir eine Skalierung dem pro Land und pro Produkt wissenschaftlichenerrechneten. Wir Institut Gesundheit analysierten die Beziehung zwischen den Skalierungen und den verschiedenen beschriebenen kontinuierlich kontinuierlich verändert (n = 19). Trotz manch gegenteiliger Methodik Preisfestsetzung. zur dynamische sehr zugleich und verbreitete Meinung bleibt EPR eine stark Preise zu erzielen, bewirkt. Ziel der Studie war es,patentgeschützter die Auswirkungen von ArzneimittelEPR auf die Preise unter Umsatzvolumen der untersuchten Berücksichtigung Produkte, Wechselkurs, BIP pro Kopf, Arzneimittelausgaben von zusätzlichen Faktoren wie wohingegen wohingegen einkommensschwache Länder umgekehrt referenzierten. zu Dies einkommensschwachen ist Länder auf den Kopf und Zusammenhang der zwischen durchschnittlichen Anzahl Bruttoinlandsprodukt der (BIP) Referenzländer Korrelation tau: 0.556263, p-value pro zurückzuführen = 0.0005331). Am häufigsten (n (Kendall’s = 8) wurdeder rank Preis in einem ermittelt. Die EPR-Methodik, welche in Vergleichsländern allen des Preises Land als Durchschnitt sich auf die Arzneimittelpreise in anderen Ländern auswirkt, hat sich in den letzten 10 Jahren den den Ländern gefunden. Von 24 der 28 untersuchten Länder wenden EPR an (im Jahr 2010). Die meisten Länder hatten weniger als 10 wobei Vergleichsländer, sich hier eine Länder große einkommensstarke dass Bandbreite nachweisen, konnten Wir zeigte. Länder 26 zu bis Land einem von dazu tendierten, andere einkommensstarke Länder in ihrem Referenzländerkorb aufzunehmen,

Zusammenfassung 6.3 Zusammenfassung 6.3 175 analysiert, welche Kapitel Kapitel 3.1 aufwiesen. Jedoch das Muster der europäischen Preiskonvergenz Preiskonvergenz europäischen der Muster das Jedoch aufwiesen. 1 Kapitel Kapitel 3 sich beschäftigt mit der Frage, wie Länder während der ihre Finanzkrise nationalen EU-15 EU-15 Länder = EU Mitgliedschaft seit 1. Jänner 1995: Belgien, Dänemark, Deutschland, Finnland, Frankreich, Griechenland, Großbritannien, Irland, Italien, Luxemburg, Niederlande, Portugal, Spanien, Schweden, Österreich. Schweden, Spanien, Portugal, Niederlande, Luxemburg, Italien, Irland, Großbritannien, Griechenland,

1 Die meisten Maßnahmen Die wurden 2010 Maßnahmen meisten (n = 33/88) und 2011 (n = 40/88) gesetzt und inkludierten Änderungen bei den (n = 16/88),Zuzahlungen Änderungen der Abgeltung der Vertriebsakteure (n = 13/88) und Preiskürzungen (n Irland = (Estland, 3% bis Portugal) und 11/88). Alle (Griechenland 1% von Länder Bandbreite der in wiesen Arzneimittelumsatzes einen Portugal moderaten in Anstieg -2% des zwischen Wachstumsrate durchschnittliche jährliche die während auf, Slowakei) und Dollar). Dabei stellten wir die Steigerungsraten der Arzneimittelumsätze in wirtschaftlich stabilen in wirtschaftlich der wir Dabei Arzneimittelumsätze Dollar). stellten die Steigerungsraten Ländern denen in wirtschaftlich weniger stabilen Ländern gegenüber – dass zeigte, die Studie der Unsere 2012. Kategorisierung in Änderungen OECD-Finanzplanung der Basis auf erfolgte sieben Gruppen beiden diese bis zwei zwischen Österreich) Finnland, (Estland, Länder stabile wirtschaftlich (Griechenland, Länder stabile weniger wirtschaftlich während vornahmen, Maßnahmen poltischen einführten. Maßnahmen, 22 und 10 zwischen mehr, weitaus Portugal) und Spanien Slowakei, Irland, Arzneimittelpreisfestsetzungs- und -erstattungsmaßnahmen während der eingeführt und Finanzkrise -erstattungsmaßnahmen Arzneimittelpreisfestsetzungs- wurden und untersucht deren den auf Literaturrecherche; einer basierte der Maßnahmen Die möglichen Auflistung Ländern. europäischen Einfluss auf Verbrauch quartalsweisen den über den Health-Daten IMS mittels wir analysierten Arzneimittelverbrauch Arzneimittelkonsum „Standards in IMS-Messgröße der (in acht Klassen therapeutischen meistverkauften 10 den in Produkte gehaltenen aller konstant in wertmäßig auch als mengenmäßig sowohl Einheiten, standardisierte / Units“ Grund ist es für politische sehr Entscheidungsträger/innen wichtig, sich in Erinnerung zu rufen, dass das politische Umfeld sehr divers ist und sich mit der Zeit Arzneimittelpreise. Maßnahmen,die der etwaauf Auswirkungen der Überprüfung verändert; regelmäßige dies erfordert eine Maßnahmen im Bereich Arzneimittelpolitik angepasst haben. für für Alemtuzumab in 2011. Die Preisabweichungen wurden während des Untersuchungszeitraums durch nur zwei Länder – Deutschland mit fast 27% teureren Preisen als der Griechenland Durchschnitt mit und fast 32% niedrigeren Preisen als der Durchschnitt – getrieben. Alle anderen Länder wiesen relativ stabile Preise auf und waren um den Durchschnittswert aller in der Studie aufgenommenen Länder angesiedelt. Preise von preiswerteren Produkten blieben relativ stabil diesem Aus stiegen. eher Produkten hochpreisigen von Preise Zeit, der mit während sanken bzw. Arzneimitteln Arzneimitteln aus 15 Ländern über fünf Jahre hinweg analysiert. (2007-2011) Die Preise erhielten wir vom wissenschaftlichen Institut erheblich Gesundheit Tagesdosis(in als in englischer Literatur Fabriksabgabepreis defined € daily pro definierterdose, variierte Preis Der Österreich Wechselkurs. bezogenen GmbH; 2007 Jahr das untersucht auf einem und wurde bezeichnet) DDD der zwischen den Ländern und den ausgewählten Produkten: vom niedrigsten Durchschnittspreis von € 1,3/DDD für Sitagliptin in 2010-2012 zu einem Höchstdurchschnittspreis von € 221,5/DDD Spanien, Portugal und Griechenland, welche einen durchschnittlichen Preis von fast 40% unterhalb unterhalb 40% fast von Preis durchschnittlichen einen welche Griechenland, und Portugal Spanien, EU-15-Durchschnittspreises des könnte sich, aufgrund der durch die Finanzkrise eingeführten Maßnahmen wie Preiskürzungen geändert haben. Um dieser Frage nachzugehen, haben wir Preise von zehn patentgeschützten widmet sich daher insbesondere der Frage, Frage, der insbesondere daher sich widmet Kapitel 4.1 Kapitel stellt eine detaillierte Analyse der Auswirkungen der unterschiedlichen im Rahmen der unterschiedlichen der Auswirkungen Analyse detaillierte eine stellt In In den letzten Jahren verzeichnet Europa eine steigende Nutzung von personalisierten Kapitel 3.2 Kapitel eingesetzt werden. eingesetzt Daten wurden einer Umfrage bei den Behörden in zuständigen allen damals 27 EU-Mitgliedstaaten vom August 2011 entnommen. Zusätzlich erhielten wir Preisdaten (von den Jahren 2005-2013) von Trastuzumab in den jeweiligen Ländern vom wissenschaftlichen 176 wie wie Behörden in Ländern europäischen mit der oft und Evaluierung schwierigen Bewertung des der „Behandlungspakets“ personalisierten Arzneimittel, welches häufig hochpreisige und neue Arzneimittel sowie Medizinprodukte umfassen, umgehen. Dazu zeigten wir und die für dabei Tests als diagnostischen eingesetzten ein Trastuzumab Beispiel für Medizin personalisierte auf, und in Erstattung welche den zur Ländern Strategien europäischen Arzneimittelpreisfestsetzung Aus Aus diesem Grund Maßnahmen. besteht politischen eingeführten ein der Konsequenzen kontinuierlicher unerwünschten Bedarf der sowie erwünschten an regelmäßigen Überprüfungen der Voraussetzung als Therapie die über Entscheidung zur Test genetischen einen welche Arzneimitteln, und im auf Dies Hinblick vorsehen. Arzneimittelpreisfestsetzung bringt neue Herausforderungen Entscheidungsträger/innen. für -erstattung Einführung der Maßnahme verglichen mit einem Jahr danach: 22,95% [95% KI 21,01%, 24,90%]); das das 24,90%]); 21,01%, KI [95% 22,95% danach: Jahr einem mit verglichen Maßnahme der Einführung Ergebnisse Diese dominiert. Markt den Intervention der vor bereits hat Risperidone von Generikum kurzfristig einen Maßnahmen politischen von Anpassung bzw. Einführung die dass deutlich, zeigten positiven Einfluss auf Kostendämpfung haben kann, jedoch diese manchmal zu unerwarteten und können. auswirkten möglicherweise unerwünschten Verbrauch Auswirkungen, sinkenden wie einem in höheren wiederum sich Zuzahlungen welche für kann, führen Patienten/ Patientinnen sowie sowie einem Anstieg des Generikaanteils führten. In Finnland stiegen die Generikaanteile der Wirkstoffe Quetiapine und Risperidone (Schätzungen vom im Maßnahme zu führten verglichen mit Portugal Jahr in einem Interventionen Die Jahr vor danach: 15,48%]). Quetiapine: 6,79%, KI 6,80% der [95% [95% 11,13% (KI) Konfidenzintervall Einführung Risperidone: der 9,68%]; 3,92%, der vor Jahr im vom (Schätzungen Amisulpride von Generikaanteiles des Anstieg erheblichen einem (wiederum die von IMS-Health verwendete Maßeinheit der „Standard Units“) von Antipsychotika in in Antipsychotika von Units“) „Standard der Maßeinheit verwendete IMS-Health von die (wiederum statistisches ein wendeten Wir 2011. Dezember bis 2007 Jänner von Zeit der in Finnland und Portugal den und Gesamtverbrauch mengenmäßigen beim Änderungen mögliche um an, von Zeitfolgenmodell Einführung der nach und vor Entwicklung die insbesondere und analysieren zu Generikaanteilen zu Länder beider Herangehensweisen die dass zeigten, Ergebnisse Die vergleichen. zu Maßnahmen von des Rückgang einem unerwarteten wenngleich geringen, Antipsychotika Gesamtverbrauchs weniger stabilen Ländern eingeführt. Unerwartet war jedoch, dass fast alle Länder einen moderaten moderaten einen Länder alle fast dass jedoch, war Unerwartet eingeführt. Ländern stabilen weniger Anstieg aufwiesen, des während der Arzneimittelumsatzes mengenmäßigen wertmäßige Absatz Ländern). stabilen weniger wirtschaftlich den in (v. a. sank in und Portugal auf von Maßnahmen den Antipsychotika Verbrauch eingeführten der Finanzkrise Einheiten“ „standardisierten in Umsatzdaten monatliche IMS-Health von erhielten Wir dar. Finnland und 5% in Estland schwankte. Seit 2009 erfahren allerdings alle Länder Rückgänge des wertmäßigen wertmäßigen des Rückgänge Länder alle allerdings erfahren 2009 Seit schwankte. Estland in 5% und Wachstumsrate jährliche negative (eine Griechenland in wurden Rückgänge größten Die Absatzes. schließen so – somit reagierten Länder Die beobachtet. 2011) in (-11% Portugal und 2010) in 14% von wirtschaftlich von wurden Maßnahmen mehr Tendenziell Finanzkrise. die auf unterschiedlich – wir

Zusammenfassung 6.3 Zusammenfassung 6.3 177 beinhaltet eine Diskussion der Vor- und Nachteile der Erforschung Schlusskapitel 5 Das Möglichkeiten für länderübergreifende Analysen bieten. Desweiteren kann von die Erforschung arzneimittelpolitischen Maßnahmen, Arzneimittepreisen dienen, um das Gesundheitssystem sowie im Allgemeinen besser zu verstehen und Verbrauch zu evaluieren. auch dazu wie zum Beispiel einerseits die personalisierte ErforschungMedizin undandererseits eineaktivere Beteiligung vonPatienten/Patientinnen, neuer Bewertungsmethoden im um damit Hinblick den Zugang und die Leistbarkeit von Arzneimitteln auf zu verbessern. Die Studien dieser Dissertation zeigen, dass die derzeitig verfügbaren Daten über Arzneimittelpreisfestsetzungs- und Erstattungsmaßnahmen sowie über Arzneimittelpreise und –verbrauch eine Vielzahl an verbundenen Datenvergleichbarkeit v. a. im Hinblick auf Maßgrößen, Arzneimittelstufen, der Wechselkursproblematik vergleichbarer und einer möglichen mengenmäßigen Gewichtung von Preisen. Darüber hinaus setzen wir für eine Verbesserung des Zugangs zu entsprechenden Länderinformationen über Politikmaßnahmen (z. B. um politischen dieRahmen bei zeitlicheder Einführung einer Dimension Maßnahme beim sowie Studiendesign bestmöglich den zu berücksichtigen) ein. Schlussendlich skizzierten wir mögliche zukünftige Forschungsgebiete, negativ auf den Zugang zu diesem personalisierten Arzneimittel auswirken könnte. könnte. auswirken Arzneimittel personalisierten diesem zu Zugang den auf negativ von arzneimittelpolitischen Datenverfügbarkeit und die Trends. damit verbundene geringe Transparenz von Arzneimittelpreisen, Wir Verbauchsdaten und empfehlen aktuellen Informationen einerseits überDes weiteren die sehen Politikmaßnahmen wir die die zu Notwendigkeit verbessern. für eingeschränkte eine bessere Datenvalidität und der damit Arzneimittel und Arzneimittel auf. Medizinprodukt Eine leisten, verstärkte Bewertung (in von Beitrag Gesundheitsleistungen einen kann bezeichnet) HTA Assessment, Technology Health als Literatur englischer um anzugehen. Dennoch diese bleibt die Herausforderungen Gefahr bestehen, dass bestimmte diagnostischer und Arzneimittel von Finanzierung ausschließliche eine (z. B. Finanzierungsmodelle sich Bereich) für den niedergelassenen der Zahler seitens oder aus dem Krankenhausbudget Tests erlaubten jedoch freie Preisbildung für den den (d. h. Test selbst konnten Preis jedoch Preisbildung freie die erlaubten Unternehmen untersuchten meisten den in Trastuzumab von Preis durchschnittliche der sank 2005 Seit festlegen). sank Im Schnitt gab. Preiserhöhungen und 2012) (2008 Jahren es in wenigen wenngleich Ländern, er von € 641 im Jahr 2005 auf € 609 in 2013. Die dieser für Ergebnisse beispielhaft Trastuzumab und seinem Test diagnostischen Studie durchgeführten zeigten erhebliche der Schwierigkeiten an Finanzierung Sektor der und sowie niedergelassener Nahtstelle Spitalsbereich auch zwischen öffentlichen Zahlern (entweder oder Sozialversicherung nationaler und Gesundheitsdienst) die Finanzierung gemeinsame Eine getragen. = 14) (n Krankenhausbudget dem aus Test den für Kosen für und Medikament Test seitens der Hand öffentlichen ist aus keinem der Länder weiteres untersuchten Ein Agreements“. Entry „Managed wie Finanzierungsmodelle neue wenig ebenso bekannt; den für als Preisregulierung unterschiedliche eine Medikament das für dass war, Studie der Ergebnis Test zum Einsatz kam: so für setzten die Trastuzumab, meisten Länder Preiskontrollmaßnahmen Institut Gesundheit Österreich GmbH. dass Die Österreich zeigten, Institut Gesundheit im Ergebnisse Jahr 2011 sowohl der Test als auch die Therapie hauptsächlich im Spital bzw. in verabreicht wurden. Tagesklinken In den untersuchten europäischen Ländern wurden entweder sowohl Test als auch vonden wurden fürdas Medikament (n =Kosten die oder 13), Medikament finanziert aus dem Krankenhausbudget

CHAPTER

Addendum 7

CHAPTER

Acknowledgements 7.1

Acknowledgements 7.1 183 Finally, I Finally, want to personal express and my deep professional this gratitude to of my frustrations family and and problems friends for unavoidable sharing the the as joy well as of achievements my strength. and support continuous his for father my thank to like would I particular, In journey. I am grateful for all the contributions this work. of In my particular, collaboratorsI would andlike to co-authorsthank the to pharmaceuticalIMS theHealth sales Institutedata body as for well of providingas for me givingwith me the opportunity fellowshipto atcomplete the IMS Institutean for Healthcareacademic Informatics. the Pharmaceutical Pricing and Reimbursement Information (PPRI) network. The PPRI network meetings with the opportunity to present my work were of great value. I would therefore like to express my sincere thanks to all members of the PPRI network. During my PhD program I fellowship had at the Harvard extraordinary Medical opportunity School professional to with mentorship has inspired me complete deeply Anita and will shape my future career. Wagner an and academic Dennis Ross-Degnan. Their I would also like to express my thanks to Claudiacritical mindHabl and (Gesundheither enthusiasm Österreichfor policyGmbH). analysis Her have shaped this work. headIn of the Departmenther of HealthpositionEconomics sheas also supportedme byenabling aflexible and supportive work environment. membersof the with professional haddiscussions the I waswork my inspirationAnothermajorof Learningfrom her as aco-worker and throughout the PhD program as well as her dedication of leading the Pharmaceutical Pricing and Reimbursement Information (PPRI) network has been an inspiration to me. I am deeply grateful to Kees throughout the PhD de program as well as for his Joncheerevaluable contributions to the research (WHO) papers. for his encouragement and guidance that inspired me to start with my professional PhD and Bert’s inspiration box”“to while think writingout myof PhDthe thesis as well as Aukje’s faith in memotivation, and whichmy gave workme theand courage her to finalizepositive this achievement. I therefore feel honored that I had the privilege of working with and learning from you. Further, I am deeply thankful for the support of Sabine Vogler (Gesundheit Österreich GmbH). ACKNOWLEDGEMENTS I would like to express my sincere thanks to Bert Leufkens (Utrecht University), Richard Laing(WHO) and Aukje Mantel-Teeuwisse (Utrecht throughout University)the PhD program. for It was theirRichard’s enthusiasm guidancefor pharmaceutical andpolicy analysis support

CHAPTER

List of co-authors 7.2

List of co-authors 7.2 187 Fang Zhang DepartmentPopulationof Medicine, Harvard Medicine SchoolHarvardand Pilgrim HealthCare Institute, Boston, USA Vienna, Austria Anita K. Wagner DepartmentPopulationof Medicine, Harvard Medicine SchoolHarvardand Pilgrim HealthCare Institute, Boston, USA Vienna, Austria Silvia Valkova IMS Institute for Healthcare Informatics, Pennsylvania, USA Sabine Vogler Department of Health Economics, Gesundheit Österreich GmbH / Austrian Health Institute, Dennis Ross-Degnan DepartmentPopulationof Medicine, Harvard Medicine SchoolHarvardand Pilgrim HealthCare Institute, Boston, USA Leonhard Seyfang Department of Health Economics, Gesundheit Österreich GmbH / Austrian Health Institute, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of PharmacoepidemiologyClinical Pharmacology, Utrechtand University, Utrecht, the Netherlands Aukje K. Mantel-Teeuwisse Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of PharmacoepidemiologyClinical Pharmacology, Utrechtand University, Utrecht, the Netherlands Vienna, Austria Richard LaingO. Department of Essential Medicines and Pharmaceutical Policies, World Geneva,Health Switzerland Organization, Bert G.M. Leufkens Regional Office for Europe, World HealthOrganization, Copenhagen, Denmark Jaime Espin Andalusian School of Public Health / Escuela Andaluza de Salud Pública, Granada, Spain Claudia Habl Department of Health Economics, Gesundheit Österreich GmbH / Austrian Health Institute, AFFILIATIONS DURING THE CONDUCTANCE OF THE RESEARCH THE OF CONDUCTANCE THE DURING AFFILIATIONS Kees de Joncheere Department of Essential Medicines and Pharmaceutical Policies, World Geneva,Health Switzerland (sinceOrganization, May 2012)

CHAPTER

List of publications 7.3

List of publications 7.3 191 South Med Rev. 2011;4(2):22-32. Soziale Sicherheit. 2013;9:414-429. Vogler S, Leopold C, Zuidberg C, Habl C. Medicines discharged in household garbage. Analysis of a pharmaceutical waste sample in the city of Vienna. Submitted for publication. countries in response to the global financial crisis. Leopold C, Vogler S, Erfahrungen Habl aus internationaler Sicht. Soziale Sicherheit. C. 2008;11:614-23. Was macht ein erfolgreiches Vogler S, Habl C, Leopold ReferenzpreissystemC. Arzneimittel – wer zahlt? Erstattung aus und Selbstbeteiligung in der – erweiterten EU. Soziale Sicherheit. 2006;9:411-8. arzneimittelpolitische Trends in Europa. Vogler S, Zimmermann N, Leopold C, Habl C, MedicinesMazag J. for Discounts Hospitaland Rebates Use Granted in for Five Health European Economics Journal. 2013;5:1-10. Countries. The Open Pharmacoeconomics & Vogler S, Zimmermann N, Leopold C, de Joncheere K. Pharmaceutical policies in European and Portugal: interrupted time series analyses. Submitted for publication. SCIENTIFIC PUBLICATIONS NOT INCLUDED IN THIS THESIS Leopold C, Vogler S, Piesnegger J, Bucsics A. Aktuelle Heilmittelausgaben und Leopold C, Mantel-Teeuwisse AK, Vogler S, Valkova S, de Joncheere, Wagner AK, Ross-Degnan D, Laing RO. Impact of pharmaceutical policy measures implemented in respond to the 2008 recession on medicine consumption in Europe. Submitted for publication. Leopold S, Zhang F, Mantel-Teeuwisse AK, Vogler S, Valkova S, Ross-DegnanImpact of D, pharmaceuticalWagner policyAK. interventions on sales of antipsychotic medicines in Finland countries. Health Policy. 2013;112(3): 209-216 http://dx.doi.org/10.1016/j.healthpol.2013.08.012. http://dx.doi.org/10.1016/j.healthpol.2013.08.012. 209-216 2013;112(3): Policy. Health countries. Leopold C, Vogler S, Habl challenge C, for Mantel-Teeuwissepublic pricing AK, and reimbursement Espin authorities J. – countries Personalized a (including surveyIceland medicineandamong Norway) 27 on as Europeanthe example a of trastuzumab. Health PolicyOct 25. DOI:10.1016/j.healthpol.2013.09.018.2013 [Epub ahead of print]. Leopold C, Mantel-Teeuwisse AK, Seyfang L, Vogler S, HG. de Impact Joncheereof external K, price heading referencingLaing on Europe RO, medicineIs Leufkens prices RO. – a Laing price comparisonHGM, European countries.among South Leufkens Med14 Rev. 2012;5(2):34-41. K, Joncheere de S, Vogler AK, Mantel-Teeuwisse C, Leopold European Western 15 among comparison price A medicines? on-patent for level price common a to SCIENTIFIC PUBLICATIONS INCLUDED IN THIS THESIS Leopold C, Vogler S, Mantel-Teeuwisse AK, de Joncheere K, Leufkens HG, Laing R. Differences in external price referencing in Europe: a descriptive overview. Health Policy. 2012;104(1):50- 60. DOI: 10.1016/j.healthpol.2011.09.008. Submitted for publication. 192 Vogler S, Leopold C, Zimmermann N, Habl C, de Joncheere K. The Pharmaceutical Pricing and ReimbursementInformation (PPRI) initiative experiences– fromengaging withpharmaceutical policy makers.

List of publications 7.3

CHAPTER

About the author 7.4

About the author 7.3 197 obtained a master degree in International Business Relations from the Upon graduation of her PhD thesis in January 2014, she will continue her academic interest In September 2009 Christine started her professional PhD under the umbrella of the in in pharmaceutical policy analysis by working as planned a The post-doctoral Pharmaceutical Boston. Policy Research in Medicine Population of Department the in School Medical Harvard at fellow Health facilitate to strategies regional of impacts and processes the assessing on focus will project Latin medicinesin American countries. expensive innovative, of Assessments (HTA) Technology had the opportunity to take sabbatical leave from her position at the Austrian Health Institute furtherto enhance on her ForPhD. this reason she completed an academic fellowship in Global Health Research at the IMS Institute for Healthcare Informatics in Pennsylvania (July – August 2012) as well as a Harvard Medical School Fellowship in Pharmaceutical Policy Research at Departmentthe of Population Medicine in Boston (September – November 2012). Institute, which is in charge of developing a national action plan for rare diseases in Austria. Utrecht World Health Organization (WHO) Collaborating Centre for Pharmaceutical Policy and DivisionRegulation,Pharmacoepidemiologytheofbasedat whichis Clinicaland Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands. In 2012 she from Bocconi University in Milan, Italy, in 2004. Since 2005 she works for the AustrianInstitute, Health Department of Health Economics. analysisat Hernational, European and international worklevel. She is a leading member of focusesthe European on pharmaceutical Pharmaceutical system Pricing and Reimbursement Information (PPRI) network and she co-leads the WHO Collaborating Centre for Pharmaceutical Policy Analysis at the Austrian Health Institute. Further, she is the co-leader of the National Centre for Rare Diseases at the Austrian Health ABOUT THE AUTHOR Christine Leopold completingby specializedhealthcarethen inShe2002. Austrian Applied UniversitySciencein of postgraduatea masterdegreeInternational in Health CareManagement, Economics Policyand