Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends

Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends PharmacoEconomics Open (2018) 2:109–123 https://doi.org/10.1007/s41669-017-0044-1 SYSTEMATIC REVIEW Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 1 1 2,3 • • Trevor Jozef Piatkiewicz Janine Marie Traulsen Tove Holm-Larsen Published online: 18 July 2017 The Author(s) 2017. This article is an open access publication Abstract the number of RSAs implemented and case studies have Objective Our objectives were to explore the changes in been steadily growing as evidence is becoming more the level of interest in risk-sharing agreements (RSAs) in readily available. The number of qualitative articles the EU during the last 15 years and the underlying reasons reporting and discussing the underlying reasons for these for these changes. changes in interest has largely fluctuated over the last Methods A systematic literature review was conducted 15 years. Despite these fluctuations, interest in RSAs using PubMed, Scopus, Web of Science, and Embase. remains high. Articles identified were divided into ‘quantitative articles’ used to establish the level of interest and ‘qualitative arti- cles’ used to identify the underlying trends in RSAs. Key Points for Decision Makers Results The literature search retrieved 2144 scientific arti- cles. Data were extracted from 238 articles. Of these, 100 There is a high level of interest in risk-sharing contained quantitative data and 138 contained qualitative agreements between payers, regulatory agencies, and data. The pace of articles being published about RSAs grew companies. significantly in 2015, which related to the increase in interest Underlying reasons for changes in the level of in and knowledge about RSAs. The underlying reasons for interest in risk-sharing agreements include (1) push the fluctuations were condensed into four overall themes: (1) for value-based pricing, (2) economic crisis and push for value-based pricing, (2) economic crisis and further further push to contain costs, (3) criticism of RSAs in push to contain costs, (3) criticism of RSAs in the real the real world, and (4) diversification of RSAs to fit world, and (4) diversification of RSAs to fit the purpose. the purpose. Conclusion The overall level of interest in RSAs in the EU has been increasing since 2000; therefore, articles reporting Increased reporting on pricing and reimbursement practices has led to an improved understanding of risk-sharing agreements. Electronic supplementary material The online version of this article (doi:10.1007/s41669-017-0044-1) contains supplementary material, which is available to authorized users. & Trevor Jozef Piatkiewicz tpiatkie@gmail.com 1 1 Introduction Section for Social and Clinical Pharmacy, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark According to ‘‘Health at a Glance: Europe 2014’’ [1], the aging population and longer life expectancies will increase Pharma Evidence, Farum, Denmark 3 the burden on healthcare systems in the coming years. In Nopia Research Group, Department of Urology, Ghent addition, decreasing odds of success in clinical trials as University Hospital, Ghent, Belgium 110 T. J. Piatkiewicz et al. well as new but expensive technologies have increased issue through a systematic literature review with an aim to drug prices. The increasing cost of healthcare is a major (1) track interest and changes in RSAs in the EU over the problem for most countries in the EU as they have main- last 15 years and (2) analyse the ‘how’ (the processes), the tained near-universal healthcare coverage [1]. New and ‘who’ (the stakeholders) and the ‘why’ (the circumstances) innovative approaches to pricing and reimbursement are that have contributed to these changes. needed if national healthcare payers are to be able to provide patients with access to new, innovative, and effective drugs while keeping within their limited budget 2 Methods [1–4]. Consequently, pharmaceutical manufacturers are being We conducted a systematic literature search and divided pressured to demonstrate real-world value for money selected articles into two groups: (1) quantitative articles to beyond that of the three traditional criteria of drug regu- explore changes in the level of interest and (2) qualitative lators: quality, efficacy, and safety [5, 6]. Many countries articles to explore the underlying reasons for the changes. are employing health technology assessment (HTA) agen- cies to evaluate on their behalf the real-world worth of new 2.1 Literature Search medicinal products [6]. However, the data available on the cost effectiveness of many new and innovative medicines, One author (TJP) performed an initial literature search to particularly in oncology, are severely lacking at the time of compose a list of searchable keywords. Grey literature product launch [7]. This can create a significant level of from Google, Google Scholar, and the official websites of uncertainty around a product’s performance in the real international organizations such as the World Health world, which in turn can cause delays in reimbursement Organization (WHO), the International Society for Phar- decisions by HTA agencies, resulting in potential revenue macoeconomics and Outcomes Research (ISPOR), and the loss by manufacturers [7]. Conversely, payers can poten- Organization for Economic Cooperation and Development tially risk reimbursing expensive medicines that have (OECD) were used. The decision to focus on EU member questionable benefits, and this can direct resources away states stemmed from the OECD’s yearly evaluation of EU from patients. member states and their healthcare spending rates and To address this issue, national healthcare payers, HTA because European health authorities have more leverage agencies, and the pharmaceutical industry found common than authorities in other countries to deny reimbursement ground in the form of formal arrangements. The aim has based on cost-effectiveness studies [1, 14, 15]. been to share the financial risks associated with new and The list of keywords and relevant databases were iden- innovative medicines when the value of a product is not tified in a three-step process. A number of keywords used fully observable at the time of its launch [7, 8]. These to define RSAs were identified through the above-men- agreements have many names and come in various forms, tioned initial literature review. Next, a list of databases was but the one characteristic they all have in common is the created that only searched for peer-reviewed articles. potential to enable patient access to new medicines that Keywords were then entered individually into each data- otherwise would not be available at the time of product base to validate the choice of keyword and database. With launch [9]. The most common names for these formal all predefined filters set (see the ‘‘Appendix’’ for an arrangements include risk-sharing agreements (RSAs), example), the number of ‘hits’ was taken into consideration payment by results (PbRs), patient access schemes (PAS), when selecting both the keywords and the databases. The or performance-based risk-sharing agreements (PBRSAs), following keywords and terms were retained and used in and the overarching concept is managed entry agreements the search: patient access scheme, pharmaceutical risk (MEAs) [7, 8, 10–13]. In this article, we use the term RSA sharing, risk sharing, risk sharing scheme, risk sharing to describe all of the above as it is the most often used in agreement, managed entry agreement, payment by result, the literature [14]. Years of debate and lack of consensus performance based risk sharing agreement, coverage with appear to have impeded the progress of RSAs; however, evidence development, and price volume agreement. today the term is accepted and well known in various The following databases were searched for peer-re- sectors of the healthcare system [15]. viewed literature: PubMed, Scopus, Web of Science, and Over the last 15 years, several articles have reported an Embase for all years leading up to January 2016. No increase in [12, 16–21] or discussed the implications of publication date filter was used so older articles were not RSAs [7, 22]. However, to the best of our knowledge, no overlooked. The search was limited to English-language article has evaluated the number of articles about RSAs articles. Only agreements or schemes relating to pharma- alongside the implications of their use to discuss the overall ceutical products were included; medical devices and trends in RSA development. This article addresses this diagnostic tools were excluded because pharmaceuticals Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 111 require a higher level of evidence for reimbursement. The where RSAs were implemented, examples of both suc- inclusion criteria specified that the title of the article cessful and failed RSA attempts, and other possible debates included or alluded to at least one of the searched words for or against their use. At this point, a synthesis, keeping and was about or relevant to the objective. The article had close to the original findings of each study, was created and to be related to pharmaceutical products; be conducted or integrated into a whole, forming a draft summary. published in and/or about EU member states; and/or The author TJP used a qualitative content analysis to involve the sale of pharmaceutical products (i.e. reim- identify recurrent themes and concepts retrieved from the bursement). The exclusion criteria included articles about draft summary. This process involved the use of inductive non-EU member states (e.g. USA, Australia, Asia, Israel, category development where themes and concepts were and Africa), capitation (monetary allocation to doctors, formed while summarizing and assessing the extracted physicians, nurses, and hospitals), vaccines, medical devi- information. These categories were deduced step by step ces, diagnostic tools, hospital financial schemes, and/or within a feedback loop wherein the categories were pure financial schemes. Additional exclusion criteria revised, eventually filtering out the main points of analysis included Medicaid or Medicare (as these pertain to the US [24, 25]. Saturation was reached when the analysis of data health system), administrative work with and without showed recurring themes and no new insights. The com- physicians, and/or needles and syringes. Abstract screening bination of the report on healthcare expenditure rates from was conducted by one author (TJP) using the same filtering the OECD [1] and the time-related themes identified in the criteria as used in the title screening and involved a more qualitative content analysis allowed for the possibility of a in-depth analysis of the article’s contents. historical interpretation of the political and economic The same author categorized articles as either quanti- pressures that led to the increased interest in RSAs in the tative or qualitative research using criteria based on Cres- EU. well’s [23] description of quantitative and qualitative methods: (1) quantitative methods ‘‘involve the process of collecting, analyzing, interpreting, and writing the results 3 Results of a study,’’ and (2) qualitative methods ‘‘are purposeful sampling, collection of open-ended data, analysis of text or 3.1 Trends in the Level of Interest in Risk-Sharing pictures, representation of information in figures and Agreements (RSAs) Over Time tables, and personal interpretation of the findings.’’ A simplified explanation of the differences between these two The systematic literature search retrieved 2144 scientific approaches is that quantitative articles collect and analyse articles; 641 remained after title screening, and 238 data in the form of numbers and qualitative articles collect remained after abstract review. Of these 238 articles, 100 and analyse data in the form of words [24]. Some articles contained quantitative data and 138 contained qualitative were described as mixed method reviews as they incor- data (Fig. 1). porated both qualitative and quantitative research; these The number of articles found for each year in the sys- articles were categorized as quantitative research. tematic review was used to create Fig. 2, which illustrates how publication rates varied by year. The 100 quantitative 2.2 Data Extraction and Qualitative Analysis articles were published at a steadily increasing rate between 2008 and 2015, and the 138 qualitative articles For each peer-reviewed article that passed both levels of fluctuated in a succession of waves as of 2009, increasing initial screening, two levels of data extraction were per- in 2015. This quantitative analysis helped identify an formed by one author (TJP). First, the summary informa- increasing level of interest in RSAs in the last 15 years tion (i.e. authors, title, abstract, and article classification) (Fig. 2). was extracted for all articles into an evidence table. Sec- ond, key concepts, data (i.e. numerical values), and sum- 3.2 Trends in Underlying Reasons for Change maries of findings presented for all articles were extracted, in Level of Interest Over Time forming the basis of the final evidence table. Information extracted from quantitative articles focused on the number From the evidence table for all articles (see the Electronic and/or type of RSAs investigated or tracked and the Supplementary Material for the complete table; examples country and specific years in which the RSAs took place. shown in Table 1), four overall time-related themes Information extracted from qualitative articles focused on emerged from the qualitative analysis: (1) push for value- the reasons for a shift towards value-based healthcare based pricing (VBP), (2) economic crisis and further push systems and the need to implement RSAs. Other key to contain costs, (3) criticism of RSAs in the real world, concepts included recommendations on how, when, and and (4) diversification of RSAs to fit the purpose. 112 T. J. Piatkiewicz et al. Fig. 1 Flowchart of systematic literature search and data extraction using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- analyses). RSA risk-sharing agreement, VBP value-based pricing 3.2.1 Push for Value-Based Pricing health authorities [26]. In theory, it was assumed this would encourage pharmaceutical companies to promote Our results suggest increasing demands from national proper utilization by physicians, thereby ensuring that healthcare payers in the early 2000s to have pharmaceuti- health authorities did not waste resources on treatments cals priced according to the benefits they offered as a that did not meet expectations in the real world [26]. We means to help allocate limited resources more efficiently as found no peer-reviewed articles that provided empirical healthcare costs increased [26]. This approach, known as evidence on RSAs between 2000 and 2003, possibly VBP, should balance the price of a new drug with the true because the discourses at the time were theoretical and value to patients [26]. As early as 2001, the idea of out- therefore lacking quantitative data. comes-based guarantees was beginning to be considered a At the same time, awareness of outcomes-based viable alternative pricing and reimbursement strategy, and schemes was growing as the UK National Institute for not merely a theory [26]. The initial idea of outcomes- Health and Care Excellence (NICE) approved beta inter- based guarantees was a scheme whereby if a drug failed to feron for multiple sclerosis (MS) where the base cost for meet predefined expectations, then the pharmaceutical the therapy ranged from £42,000 to £90,000 per quality- company would have to refund the costs of the drug to the adjusted life-year (QALY) gained [27, 28]. This approval Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 113 Fig. 2 Trends in risk-sharing agreement peer-reviewed articles are Pharmaceuticals Market Reorganization Act, DE Germany, EMA shown divided into the number of total (blue diamond), qualitative European Medicines Agency, NHS National Health Service, NICE (orange square), and quantitative (grey triangle) articles. Critical National Institute for Care and Excellence, HTA health technology events for price negotiation in Europe are labelled in grey boxes and assessment, IT Italy, PAS patient access scheme, PBRSA perfor- corresponding years are marked by orange arrows. The four overall mance-based risk sharing, PPRS Pharmaceutical Price Regulation themes and their corresponding timeframes are shown under the Scheme, RSA risk-sharing agreement, UK United Kingdom, VBP x axis in blue boxes. AIFA Italian Medicines Agency, AMNOG value-based pricing introduced one of the first novel RSAs in healthcare. Europe were tasked with measuring the cost effectiveness However, Sudlow and Counsell [29] raised doubt in their of new medicinal products before national healthcare article ‘‘Problems with UK government’s risk-sharing payers would reimburse the product [6]. Pharmaceutical schemes for assessing drugs for multiple sclerosis’’ as beta companies were now required to not only prove quality, interferon was approved without evidence of cost effec- efficacy, and safety but also to provide significant data on tiveness. This explains the spike in the number of quali- the cost effectiveness and budget impact of their new tative articles around 2003 and 2004 (Fig. 2). products, more commonly known as the ‘fourth hurdle’ [6]. The number of published articles dropped from 2005 to The change of power from regulators to payers became 2006 (Fig. 2) as data on the UK beta interferon RSA for even more important in 2008. MS were still lacking. The impact of the Italian Medicines One result of the economic crisis was that many coun- Agency (AIFA) in 2004 as the national authority respon- tries quickly introduced a wide variety of cost-containment sible for drug regulation in Italy is discussed further in the strategies to help curb pharmaceutical spending [1]. These following sections. In 2007 (Fig. 2) the number of quali- cost-containment strategies were more reactive than tative articles spiked as results of the UK’s RSA were proactive responses to the crisis and aimed to reduce the anticipated. At that time, many articles were questioning initial cost of new pharmaceuticals [1]. Cost containment whether such schemes were actually necessary [30–32]. was attempted by introducing international reference pricing (IRP), price cuts, compulsory rebates, the promo- 3.2.2 Economic Crisis and Further Push to Contain Costs tion of generics, increased co-payments, a more centralized public procurement system, and, lastly, a reduction in At the end of 2007 and the beginning of 2008, RSAs and coverage by excluding certain pharmaceuticals from HTAs were beginning to emerge in the UK. At this point, reimbursement [1]. In essence, the economic crisis of 2008 the push for value-based healthcare and pricing had sub- helped catalyse the implementation of VBP. One example stantial backing as healthcare resources were significantly of this was the new Pharmaceutical Price Regulation limited and budgets were cut. HTA agencies throughout Scheme (PPRS) that was passed in the UK, which formally 114 T. J. Piatkiewicz et al. Table 1 Example summary of articles with key characteristics for inclusion in systematic review. Qualitative and quantitative articles are presented to exemplify the categorization of articles retrieved from the systematic literature search presented in Fig. 1 References Key findings from abstracts Example of qualitative articles Claxton [30] The report by the OFT on the UK PPRS recommends the reform of the current scheme, which is a combination of profit and price controls, to one where price is based on the health benefits offered by a pharmaceutical. On closer examination, some of the more commonly expressed concerns about these proposals do not seem to be well founded. In principle, the OFT’s recommendations may contribute to allocative and dynamic efficiency in the NHS. However, some dangers exist, and the details of how it will be implemented are crucial. For example, VBP with an inappropriate threshold for cost effectiveness, or an inappropriate pricing structure, could lead to technologies being adopted at prices where their benefits, in terms of health outcome, do not offset the health displaced elsewhere in the NHS, a situation in which the NHS is damaged rather than improved by innovation. A failure to account for uncertainty and the value of evidence in negotiating prices and coverage could also undermine the evidence base for future NHS practice. Whatever view is taken, the OFT report will inevitably shape the scope of future policy debates about value, guidance, price, and innovation Thornton [32] The OFT report into the PPRS called for reform of the scheme, replacing existing profit and price controls with a system of VBP. The report argued that VBP would be much more effective than the current PPRS both at providing value for money for the NHS and giving pharmaceutical companies the right incentives to invest in drugs in the future. The report has sparked a widespread debate about drug pricing in the UK and has been controversial in some quarters. However, some of the more negative responses are based on fundamental misconceptions about the OFT recommendations. In particular, contrary to some claims, the recommended system would provide strong incentives for incremental innovation and the right balance of rewards for first-in-class and follow-on products. Nor, as is sometimes argued, would VBP have an adverse effect on investment in the UK. Certainly, real challenges lie ahead if VBP is to be implemented. These concern the definition of value, particularly where patient benefits differ significantly by subgroup or indication, and the level of resource required to implement VBP. The OFT report contains proposals for addressing each of these areas. Perhaps the most difficult challenge is the political one: securing acceptance for a reform package that would create winners and losers among pharmaceutical companies according to their success in producing valuable drugs. Ultimately, however, only a scheme that does precisely this can hope to meet the needs of patients, the NHS and innovative companies in the long run Towse [31] The OFT report on the UK PPRS recommends that when the current 5-year PPRS expires in 2010 it be replaced with VBP, which involves pre-launch centralized government price setting based on a cost-per-QALY threshold plus periodic ex post reviews. I examine the validity of the OFTs criticisms of the existing PPRS, review its proposals and propose an alternative way forward. I conclude that PPRS has performed well as a procurement bargain between industry and the UK government. However, it does not incentivize efficient relative prices. That is not its job. I identify a number of problems with the OFT proposals. I recommend that key elements of a reformed UK pharmaceutical environment for 2010 should include an expanded role for HTA but with companies retaining freedom to set prices at launch; HTA use targeted via a contingent value-of-information approach; a retained backstop PPRS, perhaps moving to an RPI-X type control; the use of RSAs and non-linear pricing arrangements; measures to ensure more effective therapeutic switching at local level; and measures to improve the take up of cost- effective treatments Ando et al. [73] The increasing use of risk-sharing in reimbursement decisions across major markets necessitates that key stakeholders understand the role of this concept in shaping drug development and regulatory decision making. The objective of this research was to examine global trends in RSAs since 1990 to provide a comprehensive understanding of the current and future impact of this fast-evolving concept. Primary research was conducted through 50 in-depth 45-minute telephone interviews in native languages. Subjects were carefully selected and represented payers, government agencies, and HTA organizations in nine markets (five in Europe; Australia, New Zealand, USA, and Canada) to understand their assessment of the role RSAs have or have not played in their respective markets, and whether they will do so in the future. This was complemented with secondary research of reimbursement decisions around the world based on a newly created database of RSAs around the world. In some countries such as the UK and Italy, for certain therapeutic areas such as oncology, these agreements almost act as a substitute for the normal reimbursement process, but primary research indicates that this practice faces significant resistance at many layers. Still, many other countries are seeking to understand the potential applicability of RSAs to their own market. Also, RSAs are being examined for their potential in several other therapeutic areas. While population- and patient-level agreements remain the most popular, we conclude that health outcomes-based arrangements are significantly on the rise, with 27 having been identified through the study in the markets that were studied, the majority of which were signed since 2007. Just over half were signed for oncology therapeutics. Outcomes-based agreements are becoming an increasingly important consideration to include in pricing models across the traditional development pathway for new molecules Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 115 Table 1 continued References Key findings from abstracts Towse and Garrison This article examines performance-based RSAs for pharmaceuticals from a theoretical economic perspective. We [22] position these agreements as a form of coverage with evidence development. New performance-based risk sharing could produce a more efficient market equilibrium, achieved by adjustment of the price post-launch to reflect outcomes combined with a new approach to the post-launch costs of evidence collection. For this to happen, the party best able to manage or to bear specific risks must do so. Willingness to bear risk will depend not only on ability to manage it but also on the degree of risk aversion. We identify three related frameworks that provide relevant insights: value of information, real option theory and money-back guarantees. We identify four categories of risk sharing: budget impact, price discounting, outcomes uncertainty and subgroup uncertainty. We conclude that a value-of- information real option framework is likely to be the most helpful approach for understanding the costs and benefits of risk sharing. A number of factors are likely to be crucial in determining whether performance-based agreements or RSAs are efficient and likely to become more important in the future: (1) the cost and practicality of post-launch evidence collection relative to pre-launch; (2) the feasibility of CED without a pre-agreed contract as to how the evidence will be used to adjust price, revenues or use, in which uncertainty around the pay-off to additional research will reduce the incentive for the manufacturer to collect the information; (3) the difficulty of writing and policing RSAs; (4) the degree of risk aversion (and therefore opportunity to trade) on the part of payers and manufacturers; and (5) the extent of transferability of data from one country setting to another to support CED in a risk-sharing framework. There is no doubt that in principle risk sharing can provide manufacturers and payers additional real options that increase overall efficiency. Given the lack of empirical evidence on the success of schemes already agreed and on the issues we set out above, it is too early to tell whether the recent surge of interest in these arrangements is likely to be a trend or only a fad Example of quantitative articles Carlson et al. [12] To identify and characterize publicly available cases and related trends for performance-based schemes, we performed a systematic review of performance-based schemes over the past 15 years (1996–2011) using publicly available databases and reports from colleagues and healthcare experts. These were categorized according to a previously published taxonomy of scheme types and assessed in terms of the underlying product and market attributes for each scheme. Macro-level trends were identified related to the timing of scheme adoption, countries involved, types of schemes, and product and market factors. Our search yielded in excess of 110 schemes. From this set, we identified 58 schemes that included a CED component, 25 that included a conditional treatment continuation component, 35 that included a performance-linked reimbursement component, and 37 that included a patient-level financial utilization component. Each type of scheme addresses fundamental uncertainties that exist when products enter the market. There has been a continued upward trend in terms of total schemes adopted per year and the number of countries with performance-based schemes in place. Despite the continued enthusiasm, challenges persist, including those related to (1) the cost and burden of implementation; (2) the need for consistent processes for scheme development, data collection, reporting, and evaluation; and (3) negotiating follow-on agreements after scheme initiation. Furthermore, the challenges faced differ by country, health system, and product. There is continued enthusiasm in many countries for using performance-based schemes for new medical products. Given the interest to date and the potential to meet the goals of interested stakeholders, these schemes may become a common element in healthcare coverage and reimbursement. However, significant challenges persist, and future studies are needed regarding the attitudes and perceptions of various stakeholders as well as evaluating the results and experiences with the schemes implemented thus far Ethgen [74] Our objective was to define an operational modelling framework intended to help the design of PBRS schemes. A time- to-event endpoint is used as a performance criterion. Such survival endpoints are commonly used in clinical studies, notably in oncology where PBRS schemes are gaining momentum. The framework is based on an open population model with a monthly cycle and 3-year time horizon from launch (i.e. when enrolment into the PBRS scheme starts). Entry into the model (i.e. the progressive arrival of new patients into the PBRS scheme) is determined by market diffusion assumptions and is modelled using a logistic function. Exit from the model (i.e. patients experiencing the event or dying from any cause) is determined by survival curves from clinical/epidemiological studies and is modelled using a Weibull function. The model accommodates different treatment dosing schedules and performance levels (i.e. minimum survival times guaranteed). Multiple PBRS scenarios can be run and compared in terms of their operational and financial implications. Additionally, the effect of potential revisions of a PBRS scheme terms and conditions can also be examined as real-life information becomes available following scheme implementation (i.e. Bayesian updating). For example, assuming 1000 patients enrolled in a PBRS scheme, with a monthly dosing schedule and given diffusion (logistic alpha = 5.0; beta = 0.4) and survival (Weibull gamma = 0.7; k = 27.0) assumptions, the model predicts that 1937 (6970), 4050 (7861), and 9282 (4420) doses will be given to non- responding (responding) patients with 12, 18, and 24 months of minimum survival time guaranteed scenarios, respectively. This framework provides both payer and manufacturer with valuable insight into the operational and financial dimensions of the potential PBRS schemes they may contemplate as they negotiate patient access conditions. Both parties can better anticipate the implications of the schemes and better plan resources, logistics, and financial arrangements accordingly 116 T. J. Piatkiewicz et al. Table 1 continued References Key findings from abstracts Morel et al. [35] National payers across Europe have been increasingly looking into innovative reimbursement approaches, MEAs, to balance the need to provide rapid access to potentially beneficial OMPs with the requirements to circumscribe uncertainty, obtain best value for money, or ensure affordability. This study aimed to identify, describe, and classify MEAs applied to OMPs by national payers and to analyse their practice in Europe. To identify and describe MEAs, national HTAs and reimbursement decisions on OMPs across seven European countries were reviewed and their main characteristics extracted. To fill data gaps and validate the accuracy of the extraction, collaboration was sought from national payers. To classify MEAs, a bespoke taxonomy was implemented. Identified MEAs were analysed and compared by focusing on five key themes, namely by describing the MEAs in relation to drug targets and therapeutic classes, geographical spread, type of MEA applied, declared rationale for setting-up of MEAs, and evolution over time. 42 MEAs for 26 OMPs, implemented between 2006 and 2012 and representing a variety of MEA designs, were identified. Italy had the highest number of schemes (n = 15), followed by the Netherlands (n = 10), England and Wales (n = 8), Sweden (n = 5), and Belgium (n = 4). No MEA was identified for France and Germany because data were unavailable. Antineoplastic agents were the primary targets of MEAs. 55% of the identified MEAs were performance-based RSAs; the other 45% were financial-based. Nine of these 26 OMPs were subject to MEAs in two or three different countries, resulting in 24 MEAs. 60% of identified MEAs focused on conditions with a prevalence of\1 per 10,000. This study confirmed that a variety of MEAs were increasingly used by European payers to manage aspects of uncertainty associated with the introduction of OMPs in the healthcare system, and which may be of a clinical, utilization, or budgetary nature. Whether differences in the use of MEAs reflect differences in how ‘uncertainty’ and ‘value’ are perceived across healthcare systems remains unclear Ferrario and Kanavos MEAs are a set of instruments used to reduce the impact of uncertainty and high prices when introducing new [75] medicines. This study develops a conceptual framework for these agreements and tests it by exploring variations in their implementation in Belgium, England, the Netherlands, and Sweden and over time as well as their governance structures. Using publicly available data from HTA agencies and survey data from the European Medicines Information Network, a database of agreements implemented between 2003 and 2012 was developed. A review of governance structures was also undertaken. In December 2012 there were 133 active MEAs for different medicine indications across the four countries. These corresponded to 110 unique medicine indications. Over time, there has been a steady growth in the number of agreements implemented, with the highest number in the Netherlands in 2012. The number of new agreements introduced each year followed a different pattern. In Belgium and England it increased over time, whereas it decreased in the Netherlands and fluctuated in Sweden. Only 18 (16%) of the unique medicine–indication pairs identified were part of an agreement in two or more countries. England uses mainly discounts and free doses to influence prices. The Netherlands and Sweden have focused more on addressing uncertainties through CED and, Sweden has focussed on monitoring use and compliance with restrictions through registries. Belgium uses a combination of the above. Despite similar reasons being cited for MEA implementation, only in a minority of cases have countries implemented an agreement for the same medicine indication; when they do, a different agreement type is often implemented. Differences in governance across countries partly explain such variations. However, more research is needed to understand whether, for example, risk perception and/or notion of what constitutes a high price differs between these countries Tettamanti et al. [56] MAAs are vital to access the Italian market. MAAs, monitored by an AIFA registry, are divided into outcome-based (cost-sharing) and non-outcome-based (risk-sharing and payment-by-results) agreements. The objective is to understand the MAA adoption, evolution, and utilization variability among therapeutic areas. The desk-based research was carried out by integrating different information sources, from AIFA and Gazzette Ufficiali to regional HTA studies. Data were gathered for all the 82 products/indications belonging to an open registry signed up to a MAA since January 2006 up until April 2015. 59% of products/indications have an outcome-based MAA, 33% a non-outcome-based and 1% both. One-third of outcome-based and one-quarter of non-outcome-based MAAs have an additional volume agreement or spending cap. A maximum peak of 30 products/indications with MAA was recorded in 2014, compared with an annual average of 8. In 2006–2007, cost-sharing MAAs were predominantly adopted; in 2008–2011, outcome-based MAAs were negotiated in approximately half of the cases (57%), becoming, since 2012, the preferred conditional reimbursement scheme (78%). Focusing on antineoplastic products, leukaemia drugs have only non-outcome-based agreements; lymphoma, melanoma, breast, colorectal, and ovary cancer drugs have a prevalence of outcome-based agreements, whereas renal cell and lung cancer drugs have both. Throughout the years, there has been an increase in the adoption of MAAs as they are considered a valuable strategy to manage payer budget impact and drug clinical benefit uncertainties. Since their introduction, the choice of MAA schemes utilized has witnessed an evolution, with an increasing preference for outcome-based MAAs, though often applied together with additional financial saving schemes. Due to the model adoption variability of MAAs within the therapeutic areas, the study of their structure plays a key role in accessing the Italian market AIFA Italian Medicines Agency, CED coverage with evidence development, HTA health technology assessment, MAA market access entry agreements, MEA managed entry agreement, NHS National Health Service, OFT Office of Fair Trading, OMP orphan medicinal product, PBRS performance-based risk-sharing, PPRS pharmaceutical price regulation scheme, QALY quality-adjusted life-year, RPI-X, RSA risk-sharing agreement, VBP value-based pricing Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 117 introduced PAS as part of its legal framework in 2009 and this concern because of a lack of standardization for cost- was an important shift in the UK’s pricing and reim- effectiveness thresholds between and within different bursement framework [33]. The UK pushed its NHS to healthcare systems [4]. The inappropriate use of predefined consider the social value of medical treatments in an thresholds such as ICERs or QALYs resulted in appraisals attempt to solve the problem of inequity and to promote that were not always transparent or robust [4, 30, 38, 46]. innovation and a focus on underrepresented patient groups Cohen et al. [47] questioned the use of ICERs and/or [34]. Similarly, Germany approved the Pharmaceuticals QALYs as reimbursement parameters because cost effec- Market Reorganization Act (AMNOG) in 2011 whereby an tiveness only evaluates overall gains in health. Conversely, early benefit assessment became mandatory to obtain a budget-impact analysis with coverage with evidence reimbursement. This can be viewed as a formal move to development (CED) takes into account the healthcare VBP [35]. The policy shifts in the pricing and reimburse- budget as a whole; therefore, Cohen et al. [48] suggested ment practices of these two countries helped signal the end this was more important than a cost-effectiveness analysis of the era of free pricing in some of Europe’s largest in reimbursement decision making. markets [36]. As shown in Fig. 2, the sudden spike in qualitative All these pressures on the healthcare budget forced articles published in 2009 and 2010 was the result of payers to discuss how to properly balance costly medica- attempts by numerous authors to characterize and define tions with the population’s needs while simultaneously RSAs. For example, McCabe et al. [11] proposed a making coverage decisions while uncertain of the out- framework for defining and evaluating risk-sharing comes [37]. Furthermore, the evaluation of cost effective- schemes. In addition, Carlson et al. [18] attempted to cat- ness with incremental cost-effectiveness ratios (ICERs) egorize and examine PBRSAs by performing a review and/or QALYs of all new drug applicants was a costly and using public search databases. Their search yielded 14 time-consuming task. As a remedy, national payers intro- performance-linked reimbursement schemes, ten condi- duced HTA agencies to act as an intermediary and make tional treatment continuation schemes, and 34 CED recommendations on their behalf [30, 38]. schemes; 36 of the 53 PBRSAs took place in the EU [18]. HTA agencies became more important as authors such Confidence in the viability of PBRSAs was waning as as McCabe et al. [4], Lucas et al. [39], and Chawla et al. there were still not enough concrete examples of successful [40] discussed how manufacturers increased their produc- schemes to fundamentally alter reimbursement policies tion of drugs that surpassed the acceptable cost-effective- [15, 46]. In 2010, Towse and Garrison [22] and Towse [49] ness measurements (e.g. cost per QALY or ICER) even acknowledged the lack of empirical evidence for successful though the main reasoning behind rejection by NICE was a RSAs and tried to define RSAs based on previous defini- drug with an ICER[£30,000 per QALY. Chawla et al. [40] tions. In 2011, the number of qualitative articles published reported that HTA agencies usually have two options to dropped substantially. For this period, the most that could reach an agreement about a drug’s price and reimburse- be said is that enthusiasm for the use of RSAs in many ment status: (1) to reduce the initial cost of the treatment countries continued [12], as the number of quantitative (financial discount) to meet the cost-effectiveness ratio and articles being published grew steadily. (2) to enter into a PBRSA (outcomes-based) to overcome any uncertainty the payer may have regarding the product’s 3.2.4 Diversification of RSAs to Fit the Purpose real-world performance. Although Chawla et al. [40] sug- gested that RSAs do not guarantee a positive recommen- As of 2013, there were 148 identified PBRSAs, with a dation by HTA agencies, other authors agreed that the majority implemented between 2007 and 2011 [18]. As increase in the use of RSAs, especially for new oncology shown in Fig. 3 [18], the rate at which new RSAs were therapies, appeared to indicate that reimbursement was still being implemented levelled out. Although the number of very possible as long as both parties share the financial drugs with RSAs attached to them plateaued in 2012–2013, risks while the company has time to demonstrate the value the majority of the new schemes were financial based, of their drug [41–45]. demonstrating a shift away from PBRSAs to minimize administrative burden [16–18]. 3.2.3 Criticism of the Use of RSAs in the Real World According to Spoors et al. [17] and Pritchett et al. [50], it was clear that difficulties with the implementation and The shift to VBP came with its own set of problems. evaluation of PBRSAs, mostly in the UK, had shifted the According to McCabe et al. [4], payers were at risk of focus to the more simplified financial-based RSAs. As an jeopardizing their own healthcare system if medicines example of this, Briceno and Seoane-Vazquez [51] deemed cost effective during product launch were in fact reviewed 207 NICE drug appraisals between September not as cost effective in the real world. The authors raised 2001 and September 2014 and determined that more than 118 T. J. Piatkiewicz et al. Fig. 3 Number of performance-based arrangements by year. Hybrid evidence development, CTC conditional treatment continuation, FU arrangements included the following: PLR|CTC: 2; PLR|FU: 1; financial/utilization, PLR performance-linked reimbursement Fig- PLR|CTC|FU: 12; CED|PLR: 2; CED|PLR|FU: 1. CED coverage with ure obtained from Carlson et al. [18] 45% of the appraisals published after 2010 included a from 2006 to 2015. More than half of the therapies (59%) confidential discount from the company to the NHS. This had a PBRSA, 33% were financial-based, and 1% used study highlighted that most high-cost drugs achieved a both schemes [56]. According to the data, PBRSAs slowly positive evaluation from NICE only if a simple discount replaced financial-based RSAs over the years and consti- was offered through a PAS [51, 52]. Although the UK tuted 78% of the total schemes [56]. The authors concluded primarily preferred discounts, PBRSAs were also suc- that one reason for the change to PBRSAs was that the cessful. Sumra and Walters [53] reported on one such case AIFA relied heavily on their extensive online patient- in their article ‘‘A long term analysis of the clinical and monitoring registries [50]. The AIFA monitoring registries cost effectiveness of glatiramer acetate from the UK mul- allow for the continuous evaluation of pharmaceuticals in tiple sclerosis risk sharing scheme.’’ This study involved clinical practice and may in fact allow for quicker access to the creation of a model for the clinical and cost effec- medicines and promotion of innovation at affordable prices tiveness of glatiramer acetate (GA) using 6 years’ worth of [57]. Fasci et al. [58] presented an example of this in their data from the UK Multiple Sclerosis Risk-Sharing article ‘‘Conditional Agreements for Innovative Therapies Scheme and a 20-year time horizon [53]. Based on their in Italy: The Case of Pirfenidone’’ when an RSA was put in model, the authors concluded that the long-term efficacy place for pirfenidone in the treatment of idiopathic pul- and cost effectiveness of GA was greater than estimated monary fibrosis to gain reimbursement in 2013. By the time during the planning of the RSA [53]. Giovannoni et al. [54] of price renegotiation, new data from phase III clinical conducted a follow-up review and reported that this posi- trials and clinical practice were used to support the cost– tive review allowed for the price to increase following the benefit profile of pirfenidone [58]. According to this article, agreed upon amount at the start of the RSA 6 years prior. the evidence allowed the AIFA to overcome their previous In light of successful PBRSAs such as this, Antonanzas uncertainties about the benefits of the drug and to remove et al. [55] determined that financial-based RSAs were the RSA while still covering the reimbursement costs [58]. preferred by payers when non-responding patients bore a Eastern Europe has also seen an increase in the number small impact on the overall health budget but—when the of published articles pertaining to their experiences with cost was high—a PBRSA was preferred only if there was a RSAs. Similar to the UK’s position on the adequate use of low monitoring burden. RSAs, a systematic literature review and expert analysis by In Italy, RSAs became a standard procedure to access Kolasa et al. [59] determined that PBRSAs were better the Italian Market, and a recent study by Tettamanti et al. suited for real-world application when dealing with [56], the AIFA, and local resources assessed 82 therapies uncertainties surrounding cost effectiveness, and financial- Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 119 based RSAs were deemed more appropriate for budgeting processes [7, 22]. However, details of and results from and cost containment. Since cost-effectiveness and budget- RSAs that were originally not publically available are now impact analyses have become a requirement in most beginning to emerge [52, 65], enabling this study. healthcare systems for setting the reimbursement of highly This study shows that, in the early 2000s, predominantly innovative drugs, Zizalova et al. [60] in the Czech Republic qualitative articles were being published because evidence recently evaluated whether or not these costs matched for the number of RSAs implemented was essentially non- those in the real world. They concluded that estimated existent as no RSA scheme had been introduced at the costs were exceeded by 31–332% in five cases [60]. In six time. Our study identified that initially, in 2000, only a few other cases, real costs did not achieve the estimations, authors and healthcare institutions were discussing the use running from 12 to 91% under the estimated costs. This of RSAs in the EU, although a lack of articles published in study concluded that cost estimations for highly innovative this time span could have been the result of delays in the drugs, although required in budget-impact analysis, did not publication process. Nonetheless, it was evident that the contribute to a reasonable decision and had no real prac- increased need for alternative pricing and reimbursement tical impact [60]. In Hungary, an analysis on the cost of strategies for market access has led to a significant increase treatment with new antiviral therapies for hepatitis C virus in interest in RSAs. However, with this increased level of (HCV) by Kocsis et al. [61] was submitted to the HTA interest, our study has identified valid arguments and agency, which found that the introduction of these new questions surrounding their use by both advocates and drugs placed a financial strain on payers. As such, RSAs opponents of RSAs. appear to be a promising solution for balancing payer Our study shows that, after the economic crisis in uncertainty with the market access for new medicines in 2007–2008, both the discussion and the implementation of Eastern Europe [61, 62]. RSAs increased significantly. As a result, the number of As many healthcare systems faced budget constraints RSAs increased as more evidence was collected and pre- and pressures by the year 2015, difficulties in making sented as quantitative articles. In addition, fluctuations choices about what treatments to fund remained. According were seen in the number of qualitative articles published as to Focsa [63], there is a willingness to pay a fair price for the viability, budget impact, and sustainability of RSAs new drugs and the benefits they potentially can offer, but was discussed and debated. In the following years, a sub- many current healthcare systems do not have the necessary stantial number of both qualitative and quantitative peer- infrastructure and evaluation processes. Patient monitoring reviewed articles were published, providing invaluable data has the potential to pave the way for accurate RSAs that and information about how many RSAs were being put in directly link patient benefits with the cost of the treatment place and the results of some older schemes. These articles [63]. Dranitsaris et al. [64] concluded that VBP and RSAs also reaffirmed the issues being dealt with by national could allow for earlier access to new treatments, improved healthcare payers as pharmaceutical expenditure continued transparency in pricing, the inclusion of multiple stake- to increase significantly across many OECD countries [66]. holders, the recognition of highly innovative therapies, and Several articles have concluded there is no ‘one size fits all’ a more predictable return on investments for or perfect method of risk sharing, and it should only be manufacturers. used when the standard conditions of access are hindered by uncertainty about cost effectiveness [2, 5, 46]. Addi- tional studies have shown that special considerations must 4 Discussion be made as to the appropriateness of an RSA, its objectives, and whether or not staff and IT systems are available to To address the uncertainty surrounding RSAs, our study support the administrative burden [2, 5, 46]. identified four time-related themes that explain the under- We identified several countries that have largely influ- lying reasons for the fluctuating levels of interest in RSAs enced policies surrounding RSA use. These include the over the past 15 years. UK, Italy, France, Germany, and—more recently—Eastern The growing interest in the use of RSAs among phar- Europe. We would like to note that the UK has played a maceutical companies and healthcare institutions in the EU very important role as it was one of the first countries to over the past 15 years has emphasized the knowledge gap implement an RSA and has maintained very detailed in the literature between what is publicly known and what records. In addition, RSAs have been implemented in many is actually practiced, partially due to a lack of transparency countries in the EU in accordance with each countries’ own from both parties [7, 22]. As a result, empirical evidence evaluation, governance, reporting, and evidence-collection and validated success stories have been lacking in past practices [50]. As such, many countries have had different years, and this has led to substantial debates about the results and outcomes when implementing RSAs, and sustainability of alternative pricing and reimbursement manufacturers must consider each country and their 120 T. J. Piatkiewicz et al. implementation processes as key indicators when deciding can lower the cost of a product without changing the global on the use of RSAs [50]. However, differences in HTA list price, meaning that a negative impact on a company’s assessment criteria have led to a noticeable difference in revenue could be avoided [68]. As an example, the PBRSA drug benefit evaluations, recommendations, and overall for bortezomib in the UK allows the list price to be access to several EU markets for each drug [67]. unchanged, while the NHS can be refunded for non-re- Although RSAs continue to emerge in many EU coun- sponding patients [68]. This refund allows the net price per tries, Neumann et al. [14], Carlson et al. [15, 68], and unit of drug to be less than the price listed [68]. Ultimately, Towse and Garrison [15] have discussed and identified it is predicted that IRP will cease to exist as the demand for some of the most notable barriers to their implementation VBP is increasing where payers and HTA agencies are as being (1) transaction and administrative costs; (2) lim- requiring more evidence to make reimbursement decisions itations to online tracking systems; (3) identifying and [68, 72]. agreeing on scheme details such as clinical endpoints, and Our review found that RSAs are continuing to emerge as price negotiations, etc.; (4) IRP; and (5) the lack of trust many countries are engaged in new pricing and reim- between payers, manufacturers, and healthcare providers. bursement strategies, although barriers to RSAs have been Crinson [69] researched a combination of these barriers extensively documented [71]. RSAs for high-priced spe- in one of the first case studies on the results of an RSA cialty drugs have a place in the future as more personalized conducted in 2004 and proposed that the NHS was medicines and better technology for identifying patient unsuccessful in its attempt to control the cost of beta responses are being developed. RSAs have evolved and interferon. Suggested reasons for this were the clinical transformed immensely since their original conception and needs of the patients, the prescribing activities of the implementation in the early 2000s. It is assumed they will doctors, and even the pharmaceutical company’s reluctance be primarily financial-based schemes in the coming years to lower its profit margin [69]. By March 2003, fewer in the EU, but a transition back to performance-based patients than planned had entered the RSA scheme and not schemes could occur in the near future. Technology for the thousands needed before November 2004 [70]. Many of patient tracking and monitoring is improving and may the initial problems were delays in setting up the proper match the needs of both the national healthcare payers and infrastructure for the RSA, securing promised funding, and the pharmaceutical industry. Conversely, RSAs may no a lack of specialist doctors and nurses to run the clinics longer be viable as pharmaceutical companies become [70]. However, these delays were to be expected with such better at creating and gathering data on the value of their a new and innovative scheme and needed to be overcome product. In doing so, they will build strong cases, lowering in the ensuing years [70]. the chances of rejection by HTA agencies. A clear under- Although RSAs play an important role in the collection standing of factors influencing the adoption, implementa- of real-world data, improved patient tracking and moni- tion, and sustainability of and learning around RSAs are toring technology may be required for the efficient use of necessary for further implementation strategies, while risk sharing in a performance-based model. However, the ongoing evaluation of RSAs is essential and needs to be limitations of digital tracking systems are becoming less of reported in peer-reviewed articles. an issue in some countries, as well as for manufacturers, as Despite obtaining valuable data about the current use they are increasing their monitoring registries and imple- and perception of RSAs, there were limitations to this menting new and improved tracking systems to keep pace research. The systematic review may not have found all with modern healthcare needs [71]. relevant sources pertaining to RSAs because, before a RSAs are now used as a means to circumnavigate cost- standardized definition and taxonomy were established, effectiveness barriers and IRP, when in fact HTA agencies RSAs had various names that are no longer used, and many should be viewed as business partners instead of as barriers countries used their own terminology in their own lan- or hurdles to overcome. Alternative pricing and reim- guage. Non-English articles were excluded because of bursement strategies such as RSAs may be the way forward language limitations among the people conducting the as traditional pricing and reimbursement methods are no research. In addition, article publication dates are not longer viable. All EU member states except for the UK and always related to the exact year the content was written Sweden apply a form of IRP because VBP is more com- about because of publication time requirements. This may plicated [72]. However, IRP offers payers a means of also be responsible for the lack of published articles in the pricing a pharmaceutical that is not in line with optimal years 2000–2003. Another reason for the lack of informa- welfare-maximizing pricing [72]. Both manufacturers and tion lies in the fact that the overall process of pricing and payers are now engaged in RSAs as they are trying to find reimbursement is classified and not transparent in many payment models where the real price will differ from the countries, and therefore it is difficult to obtain detailed list price. [72]. An RSA or confidential discount to payers reports and procedures to not only replicate but also to Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 121 learn from. The number of peer-reviewed articles being ((((((((‘‘patient access scheme’’[All Fields] OR published each year may not completely reflect the level of ((‘‘pharmacy’’[MeSH Terms] OR ‘‘pharmacy’’[All Fields] interest in RSAs because this can be considered single OR ‘‘pharmaceutical’’[All Fields] OR ‘‘dosage for- channel reporting and does not reflect all channels of lit- ms’’[MeSH Terms] OR (‘‘dosage’’[All Fields] AND ‘‘for- erature. The level of interest in RSAs may vary between ms’’[All Fields]) OR ‘‘dosage forms’’[All Fields]) AND manufacturers and payers as they are not directly repre- (‘‘risk’’[MeSH Terms] OR ‘‘risk’’[All Fields]) AND shar- sented by peer-reviewed articles. In spite of these limita- ing[All Fields])) OR ‘‘risk sharing scheme’’[All Fields]) tions, we feel that the depth and breadth of this study OR ‘‘risk sharing agreement’’[All Fields]) OR ‘‘managed (based on valuable data) makes a considerable contribution entry agreement’’[All Fields]) OR ‘‘risk sharing’’[All to our knowledge of the field. Fields]) OR ‘‘payment by result’’[All Fields]) OR ‘‘cover- age with evidence development’’[All Fields]) OR (perfor- mance[All Fields] AND based[All Fields] AND (‘‘risk’’[MeSH Terms] OR ‘‘risk’’[All Fields]) AND shar- 5 Conclusion ing[All Fields] AND agreement[All Fields])) OR ‘‘price volume agreement’’[All Fields] AND ((hasabstract[text] Information gathered in this systematic review indicates AND ‘‘loattrfull text’’[sb]) AND English[lang]) that the current level of interest in RSAs in the EU is high Filters: Abstract, Full text, English. and has been increasing since 2000. 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Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends

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PharmacoEconomics Open (2018) 2:109–123 https://doi.org/10.1007/s41669-017-0044-1 SYSTEMATIC REVIEW Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 1 1 2,3 • • Trevor Jozef Piatkiewicz Janine Marie Traulsen Tove Holm-Larsen Published online: 18 July 2017 The Author(s) 2017. This article is an open access publication Abstract the number of RSAs implemented and case studies have Objective Our objectives were to explore the changes in been steadily growing as evidence is becoming more the level of interest in risk-sharing agreements (RSAs) in readily available. The number of qualitative articles the EU during the last 15 years and the underlying reasons reporting and discussing the underlying reasons for these for these changes. changes in interest has largely fluctuated over the last Methods A systematic literature review was conducted 15 years. Despite these fluctuations, interest in RSAs using PubMed, Scopus, Web of Science, and Embase. remains high. Articles identified were divided into ‘quantitative articles’ used to establish the level of interest and ‘qualitative arti- cles’ used to identify the underlying trends in RSAs. Key Points for Decision Makers Results The literature search retrieved 2144 scientific arti- cles. Data were extracted from 238 articles. Of these, 100 There is a high level of interest in risk-sharing contained quantitative data and 138 contained qualitative agreements between payers, regulatory agencies, and data. The pace of articles being published about RSAs grew companies. significantly in 2015, which related to the increase in interest Underlying reasons for changes in the level of in and knowledge about RSAs. The underlying reasons for interest in risk-sharing agreements include (1) push the fluctuations were condensed into four overall themes: (1) for value-based pricing, (2) economic crisis and push for value-based pricing, (2) economic crisis and further further push to contain costs, (3) criticism of RSAs in push to contain costs, (3) criticism of RSAs in the real the real world, and (4) diversification of RSAs to fit world, and (4) diversification of RSAs to fit the purpose. the purpose. Conclusion The overall level of interest in RSAs in the EU has been increasing since 2000; therefore, articles reporting Increased reporting on pricing and reimbursement practices has led to an improved understanding of risk-sharing agreements. Electronic supplementary material The online version of this article (doi:10.1007/s41669-017-0044-1) contains supplementary material, which is available to authorized users. & Trevor Jozef Piatkiewicz tpiatkie@gmail.com 1 1 Introduction Section for Social and Clinical Pharmacy, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark According to ‘‘Health at a Glance: Europe 2014’’ [1], the aging population and longer life expectancies will increase Pharma Evidence, Farum, Denmark 3 the burden on healthcare systems in the coming years. In Nopia Research Group, Department of Urology, Ghent addition, decreasing odds of success in clinical trials as University Hospital, Ghent, Belgium 110 T. J. Piatkiewicz et al. well as new but expensive technologies have increased issue through a systematic literature review with an aim to drug prices. The increasing cost of healthcare is a major (1) track interest and changes in RSAs in the EU over the problem for most countries in the EU as they have main- last 15 years and (2) analyse the ‘how’ (the processes), the tained near-universal healthcare coverage [1]. New and ‘who’ (the stakeholders) and the ‘why’ (the circumstances) innovative approaches to pricing and reimbursement are that have contributed to these changes. needed if national healthcare payers are to be able to provide patients with access to new, innovative, and effective drugs while keeping within their limited budget 2 Methods [1–4]. Consequently, pharmaceutical manufacturers are being We conducted a systematic literature search and divided pressured to demonstrate real-world value for money selected articles into two groups: (1) quantitative articles to beyond that of the three traditional criteria of drug regu- explore changes in the level of interest and (2) qualitative lators: quality, efficacy, and safety [5, 6]. Many countries articles to explore the underlying reasons for the changes. are employing health technology assessment (HTA) agen- cies to evaluate on their behalf the real-world worth of new 2.1 Literature Search medicinal products [6]. However, the data available on the cost effectiveness of many new and innovative medicines, One author (TJP) performed an initial literature search to particularly in oncology, are severely lacking at the time of compose a list of searchable keywords. Grey literature product launch [7]. This can create a significant level of from Google, Google Scholar, and the official websites of uncertainty around a product’s performance in the real international organizations such as the World Health world, which in turn can cause delays in reimbursement Organization (WHO), the International Society for Phar- decisions by HTA agencies, resulting in potential revenue macoeconomics and Outcomes Research (ISPOR), and the loss by manufacturers [7]. Conversely, payers can poten- Organization for Economic Cooperation and Development tially risk reimbursing expensive medicines that have (OECD) were used. The decision to focus on EU member questionable benefits, and this can direct resources away states stemmed from the OECD’s yearly evaluation of EU from patients. member states and their healthcare spending rates and To address this issue, national healthcare payers, HTA because European health authorities have more leverage agencies, and the pharmaceutical industry found common than authorities in other countries to deny reimbursement ground in the form of formal arrangements. The aim has based on cost-effectiveness studies [1, 14, 15]. been to share the financial risks associated with new and The list of keywords and relevant databases were iden- innovative medicines when the value of a product is not tified in a three-step process. A number of keywords used fully observable at the time of its launch [7, 8]. These to define RSAs were identified through the above-men- agreements have many names and come in various forms, tioned initial literature review. Next, a list of databases was but the one characteristic they all have in common is the created that only searched for peer-reviewed articles. potential to enable patient access to new medicines that Keywords were then entered individually into each data- otherwise would not be available at the time of product base to validate the choice of keyword and database. With launch [9]. The most common names for these formal all predefined filters set (see the ‘‘Appendix’’ for an arrangements include risk-sharing agreements (RSAs), example), the number of ‘hits’ was taken into consideration payment by results (PbRs), patient access schemes (PAS), when selecting both the keywords and the databases. The or performance-based risk-sharing agreements (PBRSAs), following keywords and terms were retained and used in and the overarching concept is managed entry agreements the search: patient access scheme, pharmaceutical risk (MEAs) [7, 8, 10–13]. In this article, we use the term RSA sharing, risk sharing, risk sharing scheme, risk sharing to describe all of the above as it is the most often used in agreement, managed entry agreement, payment by result, the literature [14]. Years of debate and lack of consensus performance based risk sharing agreement, coverage with appear to have impeded the progress of RSAs; however, evidence development, and price volume agreement. today the term is accepted and well known in various The following databases were searched for peer-re- sectors of the healthcare system [15]. viewed literature: PubMed, Scopus, Web of Science, and Over the last 15 years, several articles have reported an Embase for all years leading up to January 2016. No increase in [12, 16–21] or discussed the implications of publication date filter was used so older articles were not RSAs [7, 22]. However, to the best of our knowledge, no overlooked. The search was limited to English-language article has evaluated the number of articles about RSAs articles. Only agreements or schemes relating to pharma- alongside the implications of their use to discuss the overall ceutical products were included; medical devices and trends in RSA development. This article addresses this diagnostic tools were excluded because pharmaceuticals Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 111 require a higher level of evidence for reimbursement. The where RSAs were implemented, examples of both suc- inclusion criteria specified that the title of the article cessful and failed RSA attempts, and other possible debates included or alluded to at least one of the searched words for or against their use. At this point, a synthesis, keeping and was about or relevant to the objective. The article had close to the original findings of each study, was created and to be related to pharmaceutical products; be conducted or integrated into a whole, forming a draft summary. published in and/or about EU member states; and/or The author TJP used a qualitative content analysis to involve the sale of pharmaceutical products (i.e. reim- identify recurrent themes and concepts retrieved from the bursement). The exclusion criteria included articles about draft summary. This process involved the use of inductive non-EU member states (e.g. USA, Australia, Asia, Israel, category development where themes and concepts were and Africa), capitation (monetary allocation to doctors, formed while summarizing and assessing the extracted physicians, nurses, and hospitals), vaccines, medical devi- information. These categories were deduced step by step ces, diagnostic tools, hospital financial schemes, and/or within a feedback loop wherein the categories were pure financial schemes. Additional exclusion criteria revised, eventually filtering out the main points of analysis included Medicaid or Medicare (as these pertain to the US [24, 25]. Saturation was reached when the analysis of data health system), administrative work with and without showed recurring themes and no new insights. The com- physicians, and/or needles and syringes. Abstract screening bination of the report on healthcare expenditure rates from was conducted by one author (TJP) using the same filtering the OECD [1] and the time-related themes identified in the criteria as used in the title screening and involved a more qualitative content analysis allowed for the possibility of a in-depth analysis of the article’s contents. historical interpretation of the political and economic The same author categorized articles as either quanti- pressures that led to the increased interest in RSAs in the tative or qualitative research using criteria based on Cres- EU. well’s [23] description of quantitative and qualitative methods: (1) quantitative methods ‘‘involve the process of collecting, analyzing, interpreting, and writing the results 3 Results of a study,’’ and (2) qualitative methods ‘‘are purposeful sampling, collection of open-ended data, analysis of text or 3.1 Trends in the Level of Interest in Risk-Sharing pictures, representation of information in figures and Agreements (RSAs) Over Time tables, and personal interpretation of the findings.’’ A simplified explanation of the differences between these two The systematic literature search retrieved 2144 scientific approaches is that quantitative articles collect and analyse articles; 641 remained after title screening, and 238 data in the form of numbers and qualitative articles collect remained after abstract review. Of these 238 articles, 100 and analyse data in the form of words [24]. Some articles contained quantitative data and 138 contained qualitative were described as mixed method reviews as they incor- data (Fig. 1). porated both qualitative and quantitative research; these The number of articles found for each year in the sys- articles were categorized as quantitative research. tematic review was used to create Fig. 2, which illustrates how publication rates varied by year. The 100 quantitative 2.2 Data Extraction and Qualitative Analysis articles were published at a steadily increasing rate between 2008 and 2015, and the 138 qualitative articles For each peer-reviewed article that passed both levels of fluctuated in a succession of waves as of 2009, increasing initial screening, two levels of data extraction were per- in 2015. This quantitative analysis helped identify an formed by one author (TJP). First, the summary informa- increasing level of interest in RSAs in the last 15 years tion (i.e. authors, title, abstract, and article classification) (Fig. 2). was extracted for all articles into an evidence table. Sec- ond, key concepts, data (i.e. numerical values), and sum- 3.2 Trends in Underlying Reasons for Change maries of findings presented for all articles were extracted, in Level of Interest Over Time forming the basis of the final evidence table. Information extracted from quantitative articles focused on the number From the evidence table for all articles (see the Electronic and/or type of RSAs investigated or tracked and the Supplementary Material for the complete table; examples country and specific years in which the RSAs took place. shown in Table 1), four overall time-related themes Information extracted from qualitative articles focused on emerged from the qualitative analysis: (1) push for value- the reasons for a shift towards value-based healthcare based pricing (VBP), (2) economic crisis and further push systems and the need to implement RSAs. Other key to contain costs, (3) criticism of RSAs in the real world, concepts included recommendations on how, when, and and (4) diversification of RSAs to fit the purpose. 112 T. J. Piatkiewicz et al. Fig. 1 Flowchart of systematic literature search and data extraction using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- analyses). RSA risk-sharing agreement, VBP value-based pricing 3.2.1 Push for Value-Based Pricing health authorities [26]. In theory, it was assumed this would encourage pharmaceutical companies to promote Our results suggest increasing demands from national proper utilization by physicians, thereby ensuring that healthcare payers in the early 2000s to have pharmaceuti- health authorities did not waste resources on treatments cals priced according to the benefits they offered as a that did not meet expectations in the real world [26]. We means to help allocate limited resources more efficiently as found no peer-reviewed articles that provided empirical healthcare costs increased [26]. This approach, known as evidence on RSAs between 2000 and 2003, possibly VBP, should balance the price of a new drug with the true because the discourses at the time were theoretical and value to patients [26]. As early as 2001, the idea of out- therefore lacking quantitative data. comes-based guarantees was beginning to be considered a At the same time, awareness of outcomes-based viable alternative pricing and reimbursement strategy, and schemes was growing as the UK National Institute for not merely a theory [26]. The initial idea of outcomes- Health and Care Excellence (NICE) approved beta inter- based guarantees was a scheme whereby if a drug failed to feron for multiple sclerosis (MS) where the base cost for meet predefined expectations, then the pharmaceutical the therapy ranged from £42,000 to £90,000 per quality- company would have to refund the costs of the drug to the adjusted life-year (QALY) gained [27, 28]. This approval Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 113 Fig. 2 Trends in risk-sharing agreement peer-reviewed articles are Pharmaceuticals Market Reorganization Act, DE Germany, EMA shown divided into the number of total (blue diamond), qualitative European Medicines Agency, NHS National Health Service, NICE (orange square), and quantitative (grey triangle) articles. Critical National Institute for Care and Excellence, HTA health technology events for price negotiation in Europe are labelled in grey boxes and assessment, IT Italy, PAS patient access scheme, PBRSA perfor- corresponding years are marked by orange arrows. The four overall mance-based risk sharing, PPRS Pharmaceutical Price Regulation themes and their corresponding timeframes are shown under the Scheme, RSA risk-sharing agreement, UK United Kingdom, VBP x axis in blue boxes. AIFA Italian Medicines Agency, AMNOG value-based pricing introduced one of the first novel RSAs in healthcare. Europe were tasked with measuring the cost effectiveness However, Sudlow and Counsell [29] raised doubt in their of new medicinal products before national healthcare article ‘‘Problems with UK government’s risk-sharing payers would reimburse the product [6]. Pharmaceutical schemes for assessing drugs for multiple sclerosis’’ as beta companies were now required to not only prove quality, interferon was approved without evidence of cost effec- efficacy, and safety but also to provide significant data on tiveness. This explains the spike in the number of quali- the cost effectiveness and budget impact of their new tative articles around 2003 and 2004 (Fig. 2). products, more commonly known as the ‘fourth hurdle’ [6]. The number of published articles dropped from 2005 to The change of power from regulators to payers became 2006 (Fig. 2) as data on the UK beta interferon RSA for even more important in 2008. MS were still lacking. The impact of the Italian Medicines One result of the economic crisis was that many coun- Agency (AIFA) in 2004 as the national authority respon- tries quickly introduced a wide variety of cost-containment sible for drug regulation in Italy is discussed further in the strategies to help curb pharmaceutical spending [1]. These following sections. In 2007 (Fig. 2) the number of quali- cost-containment strategies were more reactive than tative articles spiked as results of the UK’s RSA were proactive responses to the crisis and aimed to reduce the anticipated. At that time, many articles were questioning initial cost of new pharmaceuticals [1]. Cost containment whether such schemes were actually necessary [30–32]. was attempted by introducing international reference pricing (IRP), price cuts, compulsory rebates, the promo- 3.2.2 Economic Crisis and Further Push to Contain Costs tion of generics, increased co-payments, a more centralized public procurement system, and, lastly, a reduction in At the end of 2007 and the beginning of 2008, RSAs and coverage by excluding certain pharmaceuticals from HTAs were beginning to emerge in the UK. At this point, reimbursement [1]. In essence, the economic crisis of 2008 the push for value-based healthcare and pricing had sub- helped catalyse the implementation of VBP. One example stantial backing as healthcare resources were significantly of this was the new Pharmaceutical Price Regulation limited and budgets were cut. HTA agencies throughout Scheme (PPRS) that was passed in the UK, which formally 114 T. J. Piatkiewicz et al. Table 1 Example summary of articles with key characteristics for inclusion in systematic review. Qualitative and quantitative articles are presented to exemplify the categorization of articles retrieved from the systematic literature search presented in Fig. 1 References Key findings from abstracts Example of qualitative articles Claxton [30] The report by the OFT on the UK PPRS recommends the reform of the current scheme, which is a combination of profit and price controls, to one where price is based on the health benefits offered by a pharmaceutical. On closer examination, some of the more commonly expressed concerns about these proposals do not seem to be well founded. In principle, the OFT’s recommendations may contribute to allocative and dynamic efficiency in the NHS. However, some dangers exist, and the details of how it will be implemented are crucial. For example, VBP with an inappropriate threshold for cost effectiveness, or an inappropriate pricing structure, could lead to technologies being adopted at prices where their benefits, in terms of health outcome, do not offset the health displaced elsewhere in the NHS, a situation in which the NHS is damaged rather than improved by innovation. A failure to account for uncertainty and the value of evidence in negotiating prices and coverage could also undermine the evidence base for future NHS practice. Whatever view is taken, the OFT report will inevitably shape the scope of future policy debates about value, guidance, price, and innovation Thornton [32] The OFT report into the PPRS called for reform of the scheme, replacing existing profit and price controls with a system of VBP. The report argued that VBP would be much more effective than the current PPRS both at providing value for money for the NHS and giving pharmaceutical companies the right incentives to invest in drugs in the future. The report has sparked a widespread debate about drug pricing in the UK and has been controversial in some quarters. However, some of the more negative responses are based on fundamental misconceptions about the OFT recommendations. In particular, contrary to some claims, the recommended system would provide strong incentives for incremental innovation and the right balance of rewards for first-in-class and follow-on products. Nor, as is sometimes argued, would VBP have an adverse effect on investment in the UK. Certainly, real challenges lie ahead if VBP is to be implemented. These concern the definition of value, particularly where patient benefits differ significantly by subgroup or indication, and the level of resource required to implement VBP. The OFT report contains proposals for addressing each of these areas. Perhaps the most difficult challenge is the political one: securing acceptance for a reform package that would create winners and losers among pharmaceutical companies according to their success in producing valuable drugs. Ultimately, however, only a scheme that does precisely this can hope to meet the needs of patients, the NHS and innovative companies in the long run Towse [31] The OFT report on the UK PPRS recommends that when the current 5-year PPRS expires in 2010 it be replaced with VBP, which involves pre-launch centralized government price setting based on a cost-per-QALY threshold plus periodic ex post reviews. I examine the validity of the OFTs criticisms of the existing PPRS, review its proposals and propose an alternative way forward. I conclude that PPRS has performed well as a procurement bargain between industry and the UK government. However, it does not incentivize efficient relative prices. That is not its job. I identify a number of problems with the OFT proposals. I recommend that key elements of a reformed UK pharmaceutical environment for 2010 should include an expanded role for HTA but with companies retaining freedom to set prices at launch; HTA use targeted via a contingent value-of-information approach; a retained backstop PPRS, perhaps moving to an RPI-X type control; the use of RSAs and non-linear pricing arrangements; measures to ensure more effective therapeutic switching at local level; and measures to improve the take up of cost- effective treatments Ando et al. [73] The increasing use of risk-sharing in reimbursement decisions across major markets necessitates that key stakeholders understand the role of this concept in shaping drug development and regulatory decision making. The objective of this research was to examine global trends in RSAs since 1990 to provide a comprehensive understanding of the current and future impact of this fast-evolving concept. Primary research was conducted through 50 in-depth 45-minute telephone interviews in native languages. Subjects were carefully selected and represented payers, government agencies, and HTA organizations in nine markets (five in Europe; Australia, New Zealand, USA, and Canada) to understand their assessment of the role RSAs have or have not played in their respective markets, and whether they will do so in the future. This was complemented with secondary research of reimbursement decisions around the world based on a newly created database of RSAs around the world. In some countries such as the UK and Italy, for certain therapeutic areas such as oncology, these agreements almost act as a substitute for the normal reimbursement process, but primary research indicates that this practice faces significant resistance at many layers. Still, many other countries are seeking to understand the potential applicability of RSAs to their own market. Also, RSAs are being examined for their potential in several other therapeutic areas. While population- and patient-level agreements remain the most popular, we conclude that health outcomes-based arrangements are significantly on the rise, with 27 having been identified through the study in the markets that were studied, the majority of which were signed since 2007. Just over half were signed for oncology therapeutics. Outcomes-based agreements are becoming an increasingly important consideration to include in pricing models across the traditional development pathway for new molecules Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 115 Table 1 continued References Key findings from abstracts Towse and Garrison This article examines performance-based RSAs for pharmaceuticals from a theoretical economic perspective. We [22] position these agreements as a form of coverage with evidence development. New performance-based risk sharing could produce a more efficient market equilibrium, achieved by adjustment of the price post-launch to reflect outcomes combined with a new approach to the post-launch costs of evidence collection. For this to happen, the party best able to manage or to bear specific risks must do so. Willingness to bear risk will depend not only on ability to manage it but also on the degree of risk aversion. We identify three related frameworks that provide relevant insights: value of information, real option theory and money-back guarantees. We identify four categories of risk sharing: budget impact, price discounting, outcomes uncertainty and subgroup uncertainty. We conclude that a value-of- information real option framework is likely to be the most helpful approach for understanding the costs and benefits of risk sharing. A number of factors are likely to be crucial in determining whether performance-based agreements or RSAs are efficient and likely to become more important in the future: (1) the cost and practicality of post-launch evidence collection relative to pre-launch; (2) the feasibility of CED without a pre-agreed contract as to how the evidence will be used to adjust price, revenues or use, in which uncertainty around the pay-off to additional research will reduce the incentive for the manufacturer to collect the information; (3) the difficulty of writing and policing RSAs; (4) the degree of risk aversion (and therefore opportunity to trade) on the part of payers and manufacturers; and (5) the extent of transferability of data from one country setting to another to support CED in a risk-sharing framework. There is no doubt that in principle risk sharing can provide manufacturers and payers additional real options that increase overall efficiency. Given the lack of empirical evidence on the success of schemes already agreed and on the issues we set out above, it is too early to tell whether the recent surge of interest in these arrangements is likely to be a trend or only a fad Example of quantitative articles Carlson et al. [12] To identify and characterize publicly available cases and related trends for performance-based schemes, we performed a systematic review of performance-based schemes over the past 15 years (1996–2011) using publicly available databases and reports from colleagues and healthcare experts. These were categorized according to a previously published taxonomy of scheme types and assessed in terms of the underlying product and market attributes for each scheme. Macro-level trends were identified related to the timing of scheme adoption, countries involved, types of schemes, and product and market factors. Our search yielded in excess of 110 schemes. From this set, we identified 58 schemes that included a CED component, 25 that included a conditional treatment continuation component, 35 that included a performance-linked reimbursement component, and 37 that included a patient-level financial utilization component. Each type of scheme addresses fundamental uncertainties that exist when products enter the market. There has been a continued upward trend in terms of total schemes adopted per year and the number of countries with performance-based schemes in place. Despite the continued enthusiasm, challenges persist, including those related to (1) the cost and burden of implementation; (2) the need for consistent processes for scheme development, data collection, reporting, and evaluation; and (3) negotiating follow-on agreements after scheme initiation. Furthermore, the challenges faced differ by country, health system, and product. There is continued enthusiasm in many countries for using performance-based schemes for new medical products. Given the interest to date and the potential to meet the goals of interested stakeholders, these schemes may become a common element in healthcare coverage and reimbursement. However, significant challenges persist, and future studies are needed regarding the attitudes and perceptions of various stakeholders as well as evaluating the results and experiences with the schemes implemented thus far Ethgen [74] Our objective was to define an operational modelling framework intended to help the design of PBRS schemes. A time- to-event endpoint is used as a performance criterion. Such survival endpoints are commonly used in clinical studies, notably in oncology where PBRS schemes are gaining momentum. The framework is based on an open population model with a monthly cycle and 3-year time horizon from launch (i.e. when enrolment into the PBRS scheme starts). Entry into the model (i.e. the progressive arrival of new patients into the PBRS scheme) is determined by market diffusion assumptions and is modelled using a logistic function. Exit from the model (i.e. patients experiencing the event or dying from any cause) is determined by survival curves from clinical/epidemiological studies and is modelled using a Weibull function. The model accommodates different treatment dosing schedules and performance levels (i.e. minimum survival times guaranteed). Multiple PBRS scenarios can be run and compared in terms of their operational and financial implications. Additionally, the effect of potential revisions of a PBRS scheme terms and conditions can also be examined as real-life information becomes available following scheme implementation (i.e. Bayesian updating). For example, assuming 1000 patients enrolled in a PBRS scheme, with a monthly dosing schedule and given diffusion (logistic alpha = 5.0; beta = 0.4) and survival (Weibull gamma = 0.7; k = 27.0) assumptions, the model predicts that 1937 (6970), 4050 (7861), and 9282 (4420) doses will be given to non- responding (responding) patients with 12, 18, and 24 months of minimum survival time guaranteed scenarios, respectively. This framework provides both payer and manufacturer with valuable insight into the operational and financial dimensions of the potential PBRS schemes they may contemplate as they negotiate patient access conditions. Both parties can better anticipate the implications of the schemes and better plan resources, logistics, and financial arrangements accordingly 116 T. J. Piatkiewicz et al. Table 1 continued References Key findings from abstracts Morel et al. [35] National payers across Europe have been increasingly looking into innovative reimbursement approaches, MEAs, to balance the need to provide rapid access to potentially beneficial OMPs with the requirements to circumscribe uncertainty, obtain best value for money, or ensure affordability. This study aimed to identify, describe, and classify MEAs applied to OMPs by national payers and to analyse their practice in Europe. To identify and describe MEAs, national HTAs and reimbursement decisions on OMPs across seven European countries were reviewed and their main characteristics extracted. To fill data gaps and validate the accuracy of the extraction, collaboration was sought from national payers. To classify MEAs, a bespoke taxonomy was implemented. Identified MEAs were analysed and compared by focusing on five key themes, namely by describing the MEAs in relation to drug targets and therapeutic classes, geographical spread, type of MEA applied, declared rationale for setting-up of MEAs, and evolution over time. 42 MEAs for 26 OMPs, implemented between 2006 and 2012 and representing a variety of MEA designs, were identified. Italy had the highest number of schemes (n = 15), followed by the Netherlands (n = 10), England and Wales (n = 8), Sweden (n = 5), and Belgium (n = 4). No MEA was identified for France and Germany because data were unavailable. Antineoplastic agents were the primary targets of MEAs. 55% of the identified MEAs were performance-based RSAs; the other 45% were financial-based. Nine of these 26 OMPs were subject to MEAs in two or three different countries, resulting in 24 MEAs. 60% of identified MEAs focused on conditions with a prevalence of\1 per 10,000. This study confirmed that a variety of MEAs were increasingly used by European payers to manage aspects of uncertainty associated with the introduction of OMPs in the healthcare system, and which may be of a clinical, utilization, or budgetary nature. Whether differences in the use of MEAs reflect differences in how ‘uncertainty’ and ‘value’ are perceived across healthcare systems remains unclear Ferrario and Kanavos MEAs are a set of instruments used to reduce the impact of uncertainty and high prices when introducing new [75] medicines. This study develops a conceptual framework for these agreements and tests it by exploring variations in their implementation in Belgium, England, the Netherlands, and Sweden and over time as well as their governance structures. Using publicly available data from HTA agencies and survey data from the European Medicines Information Network, a database of agreements implemented between 2003 and 2012 was developed. A review of governance structures was also undertaken. In December 2012 there were 133 active MEAs for different medicine indications across the four countries. These corresponded to 110 unique medicine indications. Over time, there has been a steady growth in the number of agreements implemented, with the highest number in the Netherlands in 2012. The number of new agreements introduced each year followed a different pattern. In Belgium and England it increased over time, whereas it decreased in the Netherlands and fluctuated in Sweden. Only 18 (16%) of the unique medicine–indication pairs identified were part of an agreement in two or more countries. England uses mainly discounts and free doses to influence prices. The Netherlands and Sweden have focused more on addressing uncertainties through CED and, Sweden has focussed on monitoring use and compliance with restrictions through registries. Belgium uses a combination of the above. Despite similar reasons being cited for MEA implementation, only in a minority of cases have countries implemented an agreement for the same medicine indication; when they do, a different agreement type is often implemented. Differences in governance across countries partly explain such variations. However, more research is needed to understand whether, for example, risk perception and/or notion of what constitutes a high price differs between these countries Tettamanti et al. [56] MAAs are vital to access the Italian market. MAAs, monitored by an AIFA registry, are divided into outcome-based (cost-sharing) and non-outcome-based (risk-sharing and payment-by-results) agreements. The objective is to understand the MAA adoption, evolution, and utilization variability among therapeutic areas. The desk-based research was carried out by integrating different information sources, from AIFA and Gazzette Ufficiali to regional HTA studies. Data were gathered for all the 82 products/indications belonging to an open registry signed up to a MAA since January 2006 up until April 2015. 59% of products/indications have an outcome-based MAA, 33% a non-outcome-based and 1% both. One-third of outcome-based and one-quarter of non-outcome-based MAAs have an additional volume agreement or spending cap. A maximum peak of 30 products/indications with MAA was recorded in 2014, compared with an annual average of 8. In 2006–2007, cost-sharing MAAs were predominantly adopted; in 2008–2011, outcome-based MAAs were negotiated in approximately half of the cases (57%), becoming, since 2012, the preferred conditional reimbursement scheme (78%). Focusing on antineoplastic products, leukaemia drugs have only non-outcome-based agreements; lymphoma, melanoma, breast, colorectal, and ovary cancer drugs have a prevalence of outcome-based agreements, whereas renal cell and lung cancer drugs have both. Throughout the years, there has been an increase in the adoption of MAAs as they are considered a valuable strategy to manage payer budget impact and drug clinical benefit uncertainties. Since their introduction, the choice of MAA schemes utilized has witnessed an evolution, with an increasing preference for outcome-based MAAs, though often applied together with additional financial saving schemes. Due to the model adoption variability of MAAs within the therapeutic areas, the study of their structure plays a key role in accessing the Italian market AIFA Italian Medicines Agency, CED coverage with evidence development, HTA health technology assessment, MAA market access entry agreements, MEA managed entry agreement, NHS National Health Service, OFT Office of Fair Trading, OMP orphan medicinal product, PBRS performance-based risk-sharing, PPRS pharmaceutical price regulation scheme, QALY quality-adjusted life-year, RPI-X, RSA risk-sharing agreement, VBP value-based pricing Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 117 introduced PAS as part of its legal framework in 2009 and this concern because of a lack of standardization for cost- was an important shift in the UK’s pricing and reim- effectiveness thresholds between and within different bursement framework [33]. The UK pushed its NHS to healthcare systems [4]. The inappropriate use of predefined consider the social value of medical treatments in an thresholds such as ICERs or QALYs resulted in appraisals attempt to solve the problem of inequity and to promote that were not always transparent or robust [4, 30, 38, 46]. innovation and a focus on underrepresented patient groups Cohen et al. [47] questioned the use of ICERs and/or [34]. Similarly, Germany approved the Pharmaceuticals QALYs as reimbursement parameters because cost effec- Market Reorganization Act (AMNOG) in 2011 whereby an tiveness only evaluates overall gains in health. Conversely, early benefit assessment became mandatory to obtain a budget-impact analysis with coverage with evidence reimbursement. This can be viewed as a formal move to development (CED) takes into account the healthcare VBP [35]. The policy shifts in the pricing and reimburse- budget as a whole; therefore, Cohen et al. [48] suggested ment practices of these two countries helped signal the end this was more important than a cost-effectiveness analysis of the era of free pricing in some of Europe’s largest in reimbursement decision making. markets [36]. As shown in Fig. 2, the sudden spike in qualitative All these pressures on the healthcare budget forced articles published in 2009 and 2010 was the result of payers to discuss how to properly balance costly medica- attempts by numerous authors to characterize and define tions with the population’s needs while simultaneously RSAs. For example, McCabe et al. [11] proposed a making coverage decisions while uncertain of the out- framework for defining and evaluating risk-sharing comes [37]. Furthermore, the evaluation of cost effective- schemes. In addition, Carlson et al. [18] attempted to cat- ness with incremental cost-effectiveness ratios (ICERs) egorize and examine PBRSAs by performing a review and/or QALYs of all new drug applicants was a costly and using public search databases. Their search yielded 14 time-consuming task. As a remedy, national payers intro- performance-linked reimbursement schemes, ten condi- duced HTA agencies to act as an intermediary and make tional treatment continuation schemes, and 34 CED recommendations on their behalf [30, 38]. schemes; 36 of the 53 PBRSAs took place in the EU [18]. HTA agencies became more important as authors such Confidence in the viability of PBRSAs was waning as as McCabe et al. [4], Lucas et al. [39], and Chawla et al. there were still not enough concrete examples of successful [40] discussed how manufacturers increased their produc- schemes to fundamentally alter reimbursement policies tion of drugs that surpassed the acceptable cost-effective- [15, 46]. In 2010, Towse and Garrison [22] and Towse [49] ness measurements (e.g. cost per QALY or ICER) even acknowledged the lack of empirical evidence for successful though the main reasoning behind rejection by NICE was a RSAs and tried to define RSAs based on previous defini- drug with an ICER[£30,000 per QALY. Chawla et al. [40] tions. In 2011, the number of qualitative articles published reported that HTA agencies usually have two options to dropped substantially. For this period, the most that could reach an agreement about a drug’s price and reimburse- be said is that enthusiasm for the use of RSAs in many ment status: (1) to reduce the initial cost of the treatment countries continued [12], as the number of quantitative (financial discount) to meet the cost-effectiveness ratio and articles being published grew steadily. (2) to enter into a PBRSA (outcomes-based) to overcome any uncertainty the payer may have regarding the product’s 3.2.4 Diversification of RSAs to Fit the Purpose real-world performance. Although Chawla et al. [40] sug- gested that RSAs do not guarantee a positive recommen- As of 2013, there were 148 identified PBRSAs, with a dation by HTA agencies, other authors agreed that the majority implemented between 2007 and 2011 [18]. As increase in the use of RSAs, especially for new oncology shown in Fig. 3 [18], the rate at which new RSAs were therapies, appeared to indicate that reimbursement was still being implemented levelled out. Although the number of very possible as long as both parties share the financial drugs with RSAs attached to them plateaued in 2012–2013, risks while the company has time to demonstrate the value the majority of the new schemes were financial based, of their drug [41–45]. demonstrating a shift away from PBRSAs to minimize administrative burden [16–18]. 3.2.3 Criticism of the Use of RSAs in the Real World According to Spoors et al. [17] and Pritchett et al. [50], it was clear that difficulties with the implementation and The shift to VBP came with its own set of problems. evaluation of PBRSAs, mostly in the UK, had shifted the According to McCabe et al. [4], payers were at risk of focus to the more simplified financial-based RSAs. As an jeopardizing their own healthcare system if medicines example of this, Briceno and Seoane-Vazquez [51] deemed cost effective during product launch were in fact reviewed 207 NICE drug appraisals between September not as cost effective in the real world. The authors raised 2001 and September 2014 and determined that more than 118 T. J. Piatkiewicz et al. Fig. 3 Number of performance-based arrangements by year. Hybrid evidence development, CTC conditional treatment continuation, FU arrangements included the following: PLR|CTC: 2; PLR|FU: 1; financial/utilization, PLR performance-linked reimbursement Fig- PLR|CTC|FU: 12; CED|PLR: 2; CED|PLR|FU: 1. CED coverage with ure obtained from Carlson et al. [18] 45% of the appraisals published after 2010 included a from 2006 to 2015. More than half of the therapies (59%) confidential discount from the company to the NHS. This had a PBRSA, 33% were financial-based, and 1% used study highlighted that most high-cost drugs achieved a both schemes [56]. According to the data, PBRSAs slowly positive evaluation from NICE only if a simple discount replaced financial-based RSAs over the years and consti- was offered through a PAS [51, 52]. Although the UK tuted 78% of the total schemes [56]. The authors concluded primarily preferred discounts, PBRSAs were also suc- that one reason for the change to PBRSAs was that the cessful. Sumra and Walters [53] reported on one such case AIFA relied heavily on their extensive online patient- in their article ‘‘A long term analysis of the clinical and monitoring registries [50]. The AIFA monitoring registries cost effectiveness of glatiramer acetate from the UK mul- allow for the continuous evaluation of pharmaceuticals in tiple sclerosis risk sharing scheme.’’ This study involved clinical practice and may in fact allow for quicker access to the creation of a model for the clinical and cost effec- medicines and promotion of innovation at affordable prices tiveness of glatiramer acetate (GA) using 6 years’ worth of [57]. Fasci et al. [58] presented an example of this in their data from the UK Multiple Sclerosis Risk-Sharing article ‘‘Conditional Agreements for Innovative Therapies Scheme and a 20-year time horizon [53]. Based on their in Italy: The Case of Pirfenidone’’ when an RSA was put in model, the authors concluded that the long-term efficacy place for pirfenidone in the treatment of idiopathic pul- and cost effectiveness of GA was greater than estimated monary fibrosis to gain reimbursement in 2013. By the time during the planning of the RSA [53]. Giovannoni et al. [54] of price renegotiation, new data from phase III clinical conducted a follow-up review and reported that this posi- trials and clinical practice were used to support the cost– tive review allowed for the price to increase following the benefit profile of pirfenidone [58]. According to this article, agreed upon amount at the start of the RSA 6 years prior. the evidence allowed the AIFA to overcome their previous In light of successful PBRSAs such as this, Antonanzas uncertainties about the benefits of the drug and to remove et al. [55] determined that financial-based RSAs were the RSA while still covering the reimbursement costs [58]. preferred by payers when non-responding patients bore a Eastern Europe has also seen an increase in the number small impact on the overall health budget but—when the of published articles pertaining to their experiences with cost was high—a PBRSA was preferred only if there was a RSAs. Similar to the UK’s position on the adequate use of low monitoring burden. RSAs, a systematic literature review and expert analysis by In Italy, RSAs became a standard procedure to access Kolasa et al. [59] determined that PBRSAs were better the Italian Market, and a recent study by Tettamanti et al. suited for real-world application when dealing with [56], the AIFA, and local resources assessed 82 therapies uncertainties surrounding cost effectiveness, and financial- Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 119 based RSAs were deemed more appropriate for budgeting processes [7, 22]. However, details of and results from and cost containment. Since cost-effectiveness and budget- RSAs that were originally not publically available are now impact analyses have become a requirement in most beginning to emerge [52, 65], enabling this study. healthcare systems for setting the reimbursement of highly This study shows that, in the early 2000s, predominantly innovative drugs, Zizalova et al. [60] in the Czech Republic qualitative articles were being published because evidence recently evaluated whether or not these costs matched for the number of RSAs implemented was essentially non- those in the real world. They concluded that estimated existent as no RSA scheme had been introduced at the costs were exceeded by 31–332% in five cases [60]. In six time. Our study identified that initially, in 2000, only a few other cases, real costs did not achieve the estimations, authors and healthcare institutions were discussing the use running from 12 to 91% under the estimated costs. This of RSAs in the EU, although a lack of articles published in study concluded that cost estimations for highly innovative this time span could have been the result of delays in the drugs, although required in budget-impact analysis, did not publication process. Nonetheless, it was evident that the contribute to a reasonable decision and had no real prac- increased need for alternative pricing and reimbursement tical impact [60]. In Hungary, an analysis on the cost of strategies for market access has led to a significant increase treatment with new antiviral therapies for hepatitis C virus in interest in RSAs. However, with this increased level of (HCV) by Kocsis et al. [61] was submitted to the HTA interest, our study has identified valid arguments and agency, which found that the introduction of these new questions surrounding their use by both advocates and drugs placed a financial strain on payers. As such, RSAs opponents of RSAs. appear to be a promising solution for balancing payer Our study shows that, after the economic crisis in uncertainty with the market access for new medicines in 2007–2008, both the discussion and the implementation of Eastern Europe [61, 62]. RSAs increased significantly. As a result, the number of As many healthcare systems faced budget constraints RSAs increased as more evidence was collected and pre- and pressures by the year 2015, difficulties in making sented as quantitative articles. In addition, fluctuations choices about what treatments to fund remained. According were seen in the number of qualitative articles published as to Focsa [63], there is a willingness to pay a fair price for the viability, budget impact, and sustainability of RSAs new drugs and the benefits they potentially can offer, but was discussed and debated. In the following years, a sub- many current healthcare systems do not have the necessary stantial number of both qualitative and quantitative peer- infrastructure and evaluation processes. Patient monitoring reviewed articles were published, providing invaluable data has the potential to pave the way for accurate RSAs that and information about how many RSAs were being put in directly link patient benefits with the cost of the treatment place and the results of some older schemes. These articles [63]. Dranitsaris et al. [64] concluded that VBP and RSAs also reaffirmed the issues being dealt with by national could allow for earlier access to new treatments, improved healthcare payers as pharmaceutical expenditure continued transparency in pricing, the inclusion of multiple stake- to increase significantly across many OECD countries [66]. holders, the recognition of highly innovative therapies, and Several articles have concluded there is no ‘one size fits all’ a more predictable return on investments for or perfect method of risk sharing, and it should only be manufacturers. used when the standard conditions of access are hindered by uncertainty about cost effectiveness [2, 5, 46]. Addi- tional studies have shown that special considerations must 4 Discussion be made as to the appropriateness of an RSA, its objectives, and whether or not staff and IT systems are available to To address the uncertainty surrounding RSAs, our study support the administrative burden [2, 5, 46]. identified four time-related themes that explain the under- We identified several countries that have largely influ- lying reasons for the fluctuating levels of interest in RSAs enced policies surrounding RSA use. These include the over the past 15 years. UK, Italy, France, Germany, and—more recently—Eastern The growing interest in the use of RSAs among phar- Europe. We would like to note that the UK has played a maceutical companies and healthcare institutions in the EU very important role as it was one of the first countries to over the past 15 years has emphasized the knowledge gap implement an RSA and has maintained very detailed in the literature between what is publicly known and what records. In addition, RSAs have been implemented in many is actually practiced, partially due to a lack of transparency countries in the EU in accordance with each countries’ own from both parties [7, 22]. As a result, empirical evidence evaluation, governance, reporting, and evidence-collection and validated success stories have been lacking in past practices [50]. As such, many countries have had different years, and this has led to substantial debates about the results and outcomes when implementing RSAs, and sustainability of alternative pricing and reimbursement manufacturers must consider each country and their 120 T. J. Piatkiewicz et al. implementation processes as key indicators when deciding can lower the cost of a product without changing the global on the use of RSAs [50]. However, differences in HTA list price, meaning that a negative impact on a company’s assessment criteria have led to a noticeable difference in revenue could be avoided [68]. As an example, the PBRSA drug benefit evaluations, recommendations, and overall for bortezomib in the UK allows the list price to be access to several EU markets for each drug [67]. unchanged, while the NHS can be refunded for non-re- Although RSAs continue to emerge in many EU coun- sponding patients [68]. This refund allows the net price per tries, Neumann et al. [14], Carlson et al. [15, 68], and unit of drug to be less than the price listed [68]. Ultimately, Towse and Garrison [15] have discussed and identified it is predicted that IRP will cease to exist as the demand for some of the most notable barriers to their implementation VBP is increasing where payers and HTA agencies are as being (1) transaction and administrative costs; (2) lim- requiring more evidence to make reimbursement decisions itations to online tracking systems; (3) identifying and [68, 72]. agreeing on scheme details such as clinical endpoints, and Our review found that RSAs are continuing to emerge as price negotiations, etc.; (4) IRP; and (5) the lack of trust many countries are engaged in new pricing and reim- between payers, manufacturers, and healthcare providers. bursement strategies, although barriers to RSAs have been Crinson [69] researched a combination of these barriers extensively documented [71]. RSAs for high-priced spe- in one of the first case studies on the results of an RSA cialty drugs have a place in the future as more personalized conducted in 2004 and proposed that the NHS was medicines and better technology for identifying patient unsuccessful in its attempt to control the cost of beta responses are being developed. RSAs have evolved and interferon. Suggested reasons for this were the clinical transformed immensely since their original conception and needs of the patients, the prescribing activities of the implementation in the early 2000s. It is assumed they will doctors, and even the pharmaceutical company’s reluctance be primarily financial-based schemes in the coming years to lower its profit margin [69]. By March 2003, fewer in the EU, but a transition back to performance-based patients than planned had entered the RSA scheme and not schemes could occur in the near future. Technology for the thousands needed before November 2004 [70]. Many of patient tracking and monitoring is improving and may the initial problems were delays in setting up the proper match the needs of both the national healthcare payers and infrastructure for the RSA, securing promised funding, and the pharmaceutical industry. Conversely, RSAs may no a lack of specialist doctors and nurses to run the clinics longer be viable as pharmaceutical companies become [70]. However, these delays were to be expected with such better at creating and gathering data on the value of their a new and innovative scheme and needed to be overcome product. In doing so, they will build strong cases, lowering in the ensuing years [70]. the chances of rejection by HTA agencies. A clear under- Although RSAs play an important role in the collection standing of factors influencing the adoption, implementa- of real-world data, improved patient tracking and moni- tion, and sustainability of and learning around RSAs are toring technology may be required for the efficient use of necessary for further implementation strategies, while risk sharing in a performance-based model. However, the ongoing evaluation of RSAs is essential and needs to be limitations of digital tracking systems are becoming less of reported in peer-reviewed articles. an issue in some countries, as well as for manufacturers, as Despite obtaining valuable data about the current use they are increasing their monitoring registries and imple- and perception of RSAs, there were limitations to this menting new and improved tracking systems to keep pace research. The systematic review may not have found all with modern healthcare needs [71]. relevant sources pertaining to RSAs because, before a RSAs are now used as a means to circumnavigate cost- standardized definition and taxonomy were established, effectiveness barriers and IRP, when in fact HTA agencies RSAs had various names that are no longer used, and many should be viewed as business partners instead of as barriers countries used their own terminology in their own lan- or hurdles to overcome. Alternative pricing and reim- guage. Non-English articles were excluded because of bursement strategies such as RSAs may be the way forward language limitations among the people conducting the as traditional pricing and reimbursement methods are no research. In addition, article publication dates are not longer viable. All EU member states except for the UK and always related to the exact year the content was written Sweden apply a form of IRP because VBP is more com- about because of publication time requirements. This may plicated [72]. However, IRP offers payers a means of also be responsible for the lack of published articles in the pricing a pharmaceutical that is not in line with optimal years 2000–2003. Another reason for the lack of informa- welfare-maximizing pricing [72]. Both manufacturers and tion lies in the fact that the overall process of pricing and payers are now engaged in RSAs as they are trying to find reimbursement is classified and not transparent in many payment models where the real price will differ from the countries, and therefore it is difficult to obtain detailed list price. [72]. An RSA or confidential discount to payers reports and procedures to not only replicate but also to Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends 121 learn from. The number of peer-reviewed articles being ((((((((‘‘patient access scheme’’[All Fields] OR published each year may not completely reflect the level of ((‘‘pharmacy’’[MeSH Terms] OR ‘‘pharmacy’’[All Fields] interest in RSAs because this can be considered single OR ‘‘pharmaceutical’’[All Fields] OR ‘‘dosage for- channel reporting and does not reflect all channels of lit- ms’’[MeSH Terms] OR (‘‘dosage’’[All Fields] AND ‘‘for- erature. The level of interest in RSAs may vary between ms’’[All Fields]) OR ‘‘dosage forms’’[All Fields]) AND manufacturers and payers as they are not directly repre- (‘‘risk’’[MeSH Terms] OR ‘‘risk’’[All Fields]) AND shar- sented by peer-reviewed articles. In spite of these limita- ing[All Fields])) OR ‘‘risk sharing scheme’’[All Fields]) tions, we feel that the depth and breadth of this study OR ‘‘risk sharing agreement’’[All Fields]) OR ‘‘managed (based on valuable data) makes a considerable contribution entry agreement’’[All Fields]) OR ‘‘risk sharing’’[All to our knowledge of the field. Fields]) OR ‘‘payment by result’’[All Fields]) OR ‘‘cover- age with evidence development’’[All Fields]) OR (perfor- mance[All Fields] AND based[All Fields] AND (‘‘risk’’[MeSH Terms] OR ‘‘risk’’[All Fields]) AND shar- 5 Conclusion ing[All Fields] AND agreement[All Fields])) OR ‘‘price volume agreement’’[All Fields] AND ((hasabstract[text] Information gathered in this systematic review indicates AND ‘‘loattrfull text’’[sb]) AND English[lang]) that the current level of interest in RSAs in the EU is high Filters: Abstract, Full text, English. and has been increasing since 2000. Therefore, the number of quantitative articles reporting the number of RSAs implemented and case studies has been growing steadily as evidence is becoming more readily available. The number References of qualitative articles reporting and discussing the under- lying reasons for these changes in interest has generally 1. OECD/EU. Health at a Glance: Europe 2014. Paris: OECD fluctuated over the last 15 years. Despite these fluctua- Publishing; 2014. tions, the overall level of interest in RSAs remains high 2. Adamski J, Godman B, Ofierska-Sujkowska G, Osinska B, Her- holz H, Wendykowska K, et al. Risk sharing arrangements for and continues to grow. pharmaceuticals: potential considerations and recommendations for European payers. BMC Health Serv Res. 2010;10:153. doi:10. 1186/1472-6963-10-153. Author’s contributions All authors (TJP, JMT, and THL) con- 3. Duerden M, Gogna N, Godman B, Eden K, Mallinson M, Sulli- tributed to the design of the study, review of the study search pro- van N. Current National Initiatives and Policies to Control Drug tocol, analysis and interpretation of the results, and writing and Costs in Europe: UK Perspective. J Ambul Care Manag. review of the manuscript. TJP prepared the search protocol, per- 2004;27(2):132–8. formed the database searches and all screening, analysed the data, and 4. McCabe CJ, Bergmann L, Bosanquet N, Ellis M, Enzmann H, prepared the draft of the manuscript. von Euler M, et al. Market and patient access to new oncology products in Europe: a current, multidisciplinary perspective. Ann Compliance with Ethical Standards Oncol. 2009;20(3):403–12. doi:10.1093/annonc/mdn603. 5. Cano-Chancel A, Long M, Sparrowhawk K. Risk sharing: what’s Data availability statement All data generated or analysed during at risk and what’s being shared. Value Health. 2010;13(3):A95. this study are included in this published article and its supplementary 6. Taylor RS, Drummond MF, Salkeld G, Sullivan SD. 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Introduction of formal risk sharing agreements (RSA): a promising solution for sustainable and

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