FormalPara Key Points for Decision Makers

There is a high level of interest in risk-sharing agreements between payers, regulatory agencies, and companies.

Underlying reasons for changes in the level of interest in risk-sharing agreements include (1) push for value-based pricing, (2) economic crisis and further push to contain costs, (3) criticism of RSAs in the real world, and (4) diversification of RSAs to fit the purpose.

Increased reporting on pricing and reimbursement practices has led to an improved understanding of risk-sharing agreements.

1 Introduction

According to “Health at a Glance: Europe 2014” [1], the aging population and longer life expectancies will increase the burden on healthcare systems in the coming years. In addition, decreasing odds of success in clinical trials as well as new but expensive technologies have increased drug prices. The increasing cost of healthcare is a major problem for most countries in the EU as they have maintained near-universal healthcare coverage [1]. New and innovative approaches to pricing and reimbursement are 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 [1,2,3,4].

Consequently, pharmaceutical manufacturers are being pressured to demonstrate real-world value for money beyond that of the three traditional criteria of drug regulators: quality, efficacy, and safety [5, 6]. Many countries are employing health technology assessment (HTA) agencies to evaluate on their behalf the real-world worth of new medicinal products [6]. However, the data available on the cost effectiveness of many new and innovative medicines, particularly in oncology, are severely lacking at the time of product launch [7]. This can create a significant level of uncertainty around a product’s performance in the real world, which in turn can cause delays in reimbursement decisions by HTA agencies, resulting in potential revenue loss by manufacturers [7]. Conversely, payers can potentially risk reimbursing expensive medicines that have questionable benefits, and this can direct resources away from patients.

To address this issue, national healthcare payers, HTA agencies, and the pharmaceutical industry found common ground in the form of formal arrangements. The aim has been to share the financial risks associated with new and innovative medicines when the value of a product is not fully observable at the time of its launch [7, 8]. These agreements have many names and come in various forms, but the one characteristic they all have in common is the potential to enable patient access to new medicines that otherwise would not be available at the time of product launch [9]. The most common names for these formal arrangements include risk-sharing agreements (RSAs), payment by results (PbRs), patient access schemes (PAS), or performance-based risk-sharing agreements (PBRSAs), and the overarching concept is managed entry agreements (MEAs) [7, 8, 10,11,12,13]. In this article, we use the term RSA to describe all of the above as it is the most often used in the literature [14]. Years of debate and lack of consensus appear to have impeded the progress of RSAs; however, today the term is accepted and well known in various sectors of the healthcare system [15].

Over the last 15 years, several articles have reported an increase in [12, 16,17,18,19,20,21] or discussed the implications of RSAs [7, 22]. However, to the best of our knowledge, no article has evaluated the number of articles about RSAs alongside the implications of their use to discuss the overall trends in RSA development. This article addresses this issue through a systematic literature review with an aim to (1) track interest and changes in RSAs in the EU over the last 15 years and (2) analyse the ‘how’ (the processes), the ‘who’ (the stakeholders) and the ‘why’ (the circumstances) that have contributed to these changes.

2 Methods

We conducted a systematic literature search and divided selected articles into two groups: (1) quantitative articles to explore changes in the level of interest and (2) qualitative articles to explore the underlying reasons for the changes.

2.1 Literature Search

One author (TJP) performed an initial literature search to compose a list of searchable keywords. Grey literature from Google, Google Scholar, and the official websites of international organizations such as the World Health Organization (WHO), the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), and the Organization for Economic Cooperation and Development (OECD) were used. The decision to focus on EU member states stemmed from the OECD’s yearly evaluation of EU member states and their healthcare spending rates and because European health authorities have more leverage than authorities in other countries to deny reimbursement based on cost-effectiveness studies [1, 14, 15].

The list of keywords and relevant databases were identified in a three-step process. A number of keywords used to define RSAs were identified through the above-mentioned initial literature review. Next, a list of databases was created that only searched for peer-reviewed articles. Keywords were then entered individually into each database to validate the choice of keyword and database. With all predefined filters set (see the “Appendix” for an example), the number of ‘hits’ was taken into consideration when selecting both the keywords and the databases. The following keywords and terms were retained and used in the search: patient access scheme, pharmaceutical risk sharing, risk sharing, risk sharing scheme, risk sharing agreement, managed entry agreement, payment by result, performance based risk sharing agreement, coverage with evidence development, and price volume agreement.

The following databases were searched for peer-reviewed literature: PubMed, Scopus, Web of Science, and Embase for all years leading up to January 2016. No publication date filter was used so older articles were not overlooked. The search was limited to English-language articles. Only agreements or schemes relating to pharmaceutical products were included; medical devices and diagnostic tools were excluded because pharmaceuticals require a higher level of evidence for reimbursement. The inclusion criteria specified that the title of the article included or alluded to at least one of the searched words and was about or relevant to the objective. The article had to be related to pharmaceutical products; be conducted or published in and/or about EU member states; and/or involve the sale of pharmaceutical products (i.e. reimbursement). The exclusion criteria included articles about non-EU member states (e.g. USA, Australia, Asia, Israel, and Africa), capitation (monetary allocation to doctors, physicians, nurses, and hospitals), vaccines, medical devices, diagnostic tools, hospital financial schemes, and/or pure financial schemes. Additional exclusion criteria included Medicaid or Medicare (as these pertain to the US health system), administrative work with and without physicians, and/or needles and syringes. Abstract screening was conducted by one author (TJP) using the same filtering criteria as used in the title screening and involved a more in-depth analysis of the article’s contents.

The same author categorized articles as either quantitative or qualitative research using criteria based on Creswell’s [23] description of quantitative and qualitative methods: (1) quantitative methods “involve the process of collecting, analyzing, interpreting, and writing the results of a study,” and (2) qualitative methods “are purposeful sampling, collection of open-ended data, analysis of text or pictures, representation of information in figures and tables, and personal interpretation of the findings.” A simplified explanation of the differences between these two approaches is that quantitative articles collect and analyse data in the form of numbers and qualitative articles collect and analyse data in the form of words [24]. Some articles were described as mixed method reviews as they incorporated both qualitative and quantitative research; these articles were categorized as quantitative research.

2.2 Data Extraction and Qualitative Analysis

For each peer-reviewed article that passed both levels of initial screening, two levels of data extraction were performed by one author (TJP). First, the summary information (i.e. authors, title, abstract, and article classification) was extracted for all articles into an evidence table. Second, key concepts, data (i.e. numerical values), and summaries of findings presented for all articles were extracted, forming the basis of the final evidence table. Information extracted from quantitative articles focused on the number and/or type of RSAs investigated or tracked and the country and specific years in which the RSAs took place. Information extracted from qualitative articles focused on the reasons for a shift towards value-based healthcare systems and the need to implement RSAs. Other key concepts included recommendations on how, when, and where RSAs were implemented, examples of both successful and failed RSA attempts, and other possible debates for or against their use. At this point, a synthesis, keeping close to the original findings of each study, was created and integrated into a whole, forming a draft summary.

The author TJP used a qualitative content analysis to identify recurrent themes and concepts retrieved from the draft summary. This process involved the use of inductive category development where themes and concepts were formed while summarizing and assessing the extracted information. These categories were deduced step by step within a feedback loop wherein the categories were revised, eventually filtering out the main points of analysis [24, 25]. Saturation was reached when the analysis of data showed recurring themes and no new insights. The combination of the report on healthcare expenditure rates from the OECD [1] and the time-related themes identified in the qualitative content analysis allowed for the possibility of a historical interpretation of the political and economic pressures that led to the increased interest in RSAs in the EU.

3 Results

3.1 Trends in the Level of Interest in Risk-Sharing Agreements (RSAs) Over Time

The systematic literature search retrieved 2144 scientific articles; 641 remained after title screening, and 238 remained after abstract review. Of these 238 articles, 100 contained quantitative data and 138 contained qualitative data (Fig. 1).

Fig. 1
figure 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

The number of articles found for each year in the systematic review was used to create Fig. 2, which illustrates how publication rates varied by year. The 100 quantitative articles were published at a steadily increasing rate between 2008 and 2015, and the 138 qualitative articles fluctuated in a succession of waves as of 2009, increasing in 2015. This quantitative analysis helped identify an increasing level of interest in RSAs in the last 15 years (Fig. 2).

Fig. 2
figure 2

Trends in risk-sharing agreement peer-reviewed articles are shown divided into the number of total (blue diamond), qualitative (orange square), and quantitative (grey triangle) articles. Critical events for price negotiation in Europe are labelled in grey boxes and corresponding years are marked by orange arrows. The four overall themes and their corresponding timeframes are shown under the x axis in blue boxes. AIFA Italian Medicines Agency, AMNOG Pharmaceuticals Market Reorganization Act, DE Germany, EMA European Medicines Agency, NHS National Health Service, NICE National Institute for Care and Excellence, HTA health technology assessment, IT Italy, PAS patient access scheme, PBRSA performance-based risk sharing, PPRS Pharmaceutical Price Regulation Scheme, RSA risk-sharing agreement, UK United Kingdom, VBP value-based pricing

3.2 Trends in Underlying Reasons for Change in Level of Interest Over Time

From the evidence table for all articles (see the Electronic Supplementary Material for the complete table; examples shown in Table 1), four overall time-related themes emerged from the qualitative analysis: (1) push for value-based pricing (VBP), (2) economic crisis and further push to contain costs, (3) criticism of RSAs in the real world, and (4) diversification of RSAs to fit the purpose.

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

3.2.1 Push for Value-Based Pricing

Our results suggest increasing demands from national healthcare payers in the early 2000s to have pharmaceuticals priced according to the benefits they offered as a means to help allocate limited resources more efficiently as healthcare costs increased [26]. This approach, known as VBP, should balance the price of a new drug with the true value to patients [26]. As early as 2001, the idea of outcomes-based guarantees was beginning to be considered a viable alternative pricing and reimbursement strategy, and not merely a theory [26]. The initial idea of outcomes-based guarantees was a scheme whereby if a drug failed to meet predefined expectations, then the pharmaceutical company would have to refund the costs of the drug to the health authorities [26]. In theory, it was assumed this would encourage pharmaceutical companies to promote proper utilization by physicians, thereby ensuring that health authorities did not waste resources on treatments that did not meet expectations in the real world [26]. We found no peer-reviewed articles that provided empirical evidence on RSAs between 2000 and 2003, possibly because the discourses at the time were theoretical and therefore lacking quantitative data.

At the same time, awareness of outcomes-based schemes was growing as the UK National Institute for Health and Care Excellence (NICE) approved beta interferon for multiple sclerosis (MS) where the base cost for the therapy ranged from £42,000 to £90,000 per quality-adjusted life-year (QALY) gained [27, 28]. This approval introduced one of the first novel RSAs in healthcare. However, Sudlow and Counsell [29] raised doubt in their article “Problems with UK government’s risk-sharing schemes for assessing drugs for multiple sclerosis” as beta interferon was approved without evidence of cost effectiveness. This explains the spike in the number of qualitative articles around 2003 and 2004 (Fig. 2).

The number of published articles dropped from 2005 to 2006 (Fig. 2) as data on the UK beta interferon RSA for MS were still lacking. The impact of the Italian Medicines Agency (AIFA) in 2004 as the national authority responsible for drug regulation in Italy is discussed further in the following sections. In 2007 (Fig. 2) the number of qualitative articles spiked as results of the UK’s RSA were anticipated. At that time, many articles were questioning whether such schemes were actually necessary [30,31,32].

3.2.2 Economic Crisis and Further Push to Contain Costs

At the end of 2007 and the beginning of 2008, RSAs and HTAs were beginning to emerge in the UK. At this point, the push for value-based healthcare and pricing had substantial backing as healthcare resources were significantly limited and budgets were cut. HTA agencies throughout Europe were tasked with measuring the cost effectiveness of new medicinal products before national healthcare payers would reimburse the product [6]. Pharmaceutical companies were now required to not only prove quality, efficacy, and safety but also to provide significant data on the cost effectiveness and budget impact of their new products, more commonly known as the ‘fourth hurdle’ [6]. The change of power from regulators to payers became even more important in 2008.

One result of the economic crisis was that many countries quickly introduced a wide variety of cost-containment strategies to help curb pharmaceutical spending [1]. These cost-containment strategies were more reactive than proactive responses to the crisis and aimed to reduce the initial cost of new pharmaceuticals [1]. Cost containment was attempted by introducing international reference pricing (IRP), price cuts, compulsory rebates, the promotion of generics, increased co-payments, a more centralized public procurement system, and, lastly, a reduction in coverage by excluding certain pharmaceuticals from reimbursement [1]. In essence, the economic crisis of 2008 helped catalyse the implementation of VBP. One example of this was the new Pharmaceutical Price Regulation Scheme (PPRS) that was passed in the UK, which formally introduced PAS as part of its legal framework in 2009 and was an important shift in the UK’s pricing and reimbursement framework [33]. The UK pushed its NHS to consider the social value of medical treatments in an attempt to solve the problem of inequity and to promote innovation and a focus on underrepresented patient groups [34]. Similarly, Germany approved the Pharmaceuticals Market Reorganization Act (AMNOG) in 2011 whereby an early benefit assessment became mandatory to obtain reimbursement. This can be viewed as a formal move to VBP [35]. The policy shifts in the pricing and reimbursement practices of these two countries helped signal the end of the era of free pricing in some of Europe’s largest markets [36].

All these pressures on the healthcare budget forced payers to discuss how to properly balance costly medications with the population’s needs while simultaneously making coverage decisions while uncertain of the outcomes [37]. Furthermore, the evaluation of cost effectiveness with incremental cost-effectiveness ratios (ICERs) and/or QALYs of all new drug applicants was a costly and time-consuming task. As a remedy, national payers introduced HTA agencies to act as an intermediary and make recommendations on their behalf [30, 38].

HTA agencies became more important as authors such as McCabe et al. [4], Lucas et al. [39], and Chawla et al. [40] discussed how manufacturers increased their production of drugs that surpassed the acceptable cost-effectiveness measurements (e.g. cost per QALY or ICER) even though the main reasoning behind rejection by NICE was a drug with an ICER >£30,000 per QALY. Chawla et al. [40] reported that HTA agencies usually have two options to reach an agreement about a drug’s price and reimbursement status: (1) to reduce the initial cost of the treatment (financial discount) to meet the cost-effectiveness ratio and (2) to enter into a PBRSA (outcomes-based) to overcome any uncertainty the payer may have regarding the product’s real-world performance. Although Chawla et al. [40] suggested that RSAs do not guarantee a positive recommendation by HTA agencies, other authors agreed that the increase in the use of RSAs, especially for new oncology therapies, appeared to indicate that reimbursement was still very possible as long as both parties share the financial risks while the company has time to demonstrate the value of their drug [41,42,43,44,45].

3.2.3 Criticism of the Use of RSAs in the Real World

The shift to VBP came with its own set of problems. According to McCabe et al. [4], payers were at risk of jeopardizing their own healthcare system if medicines deemed cost effective during product launch were in fact not as cost effective in the real world. The authors raised this concern because of a lack of standardization for cost-effectiveness thresholds between and within different healthcare systems [4]. The inappropriate use of predefined thresholds such as ICERs or QALYs resulted in appraisals that were not always transparent or robust [4, 30, 38, 46]. Cohen et al. [47] questioned the use of ICERs and/or QALYs as reimbursement parameters because cost effectiveness only evaluates overall gains in health. Conversely, a budget-impact analysis with coverage with evidence development (CED) takes into account the healthcare budget as a whole; therefore, Cohen et al. [48] suggested this was more important than a cost-effectiveness analysis in reimbursement decision making.

As shown in Fig. 2, the sudden spike in qualitative articles published in 2009 and 2010 was the result of attempts by numerous authors to characterize and define RSAs. For example, McCabe et al. [11] proposed a framework for defining and evaluating risk-sharing schemes. In addition, Carlson et al. [18] attempted to categorize and examine PBRSAs by performing a review using public search databases. Their search yielded 14 performance-linked reimbursement schemes, ten conditional treatment continuation schemes, and 34 CED schemes; 36 of the 53 PBRSAs took place in the EU [18].

Confidence in the viability of PBRSAs was waning as there were still not enough concrete examples of successful schemes to fundamentally alter reimbursement policies [15, 46]. In 2010, Towse and Garrison [22] and Towse [49] acknowledged the lack of empirical evidence for successful RSAs and tried to define RSAs based on previous definitions. In 2011, the number of qualitative articles published dropped substantially. For this period, the most that could be said is that enthusiasm for the use of RSAs in many countries continued [12], as the number of quantitative articles being published grew steadily.

3.2.4 Diversification of RSAs to Fit the Purpose

As of 2013, there were 148 identified PBRSAs, with a majority implemented between 2007 and 2011 [18]. As shown in Fig. 3 [18], the rate at which new RSAs were being implemented levelled out. Although the number of drugs with RSAs attached to them plateaued in 2012–2013, the majority of the new schemes were financial based, demonstrating a shift away from PBRSAs to minimize administrative burden [16,17,18].

Fig. 3
figure 3

Figure obtained from Carlson et al. [18]

Number of performance-based arrangements by year. Hybrid arrangements included the following: PLR|CTC: 2; PLR|FU: 1; PLR|CTC|FU: 12; CED|PLR: 2; CED|PLR|FU: 1. CED coverage with evidence development, CTC conditional treatment continuation, FU financial/utilization, PLR performance-linked reimbursement

According to Spoors et al. [17] and Pritchett et al. [50], it was clear that difficulties with the implementation and evaluation of PBRSAs, mostly in the UK, had shifted the focus to the more simplified financial-based RSAs. As an example of this, Briceno and Seoane-Vazquez [51] reviewed 207 NICE drug appraisals between September 2001 and September 2014 and determined that more than 45% of the appraisals published after 2010 included a confidential discount from the company to the NHS. This study highlighted that most high-cost drugs achieved a positive evaluation from NICE only if a simple discount was offered through a PAS [51, 52]. Although the UK primarily preferred discounts, PBRSAs were also successful. Sumra and Walters [53] reported on one such case in their article “A long term analysis of the clinical and cost effectiveness of glatiramer acetate from the UK multiple sclerosis risk sharing scheme.” This study involved the creation of a model for the clinical and cost effectiveness of glatiramer acetate (GA) using 6 years’ worth of data from the UK Multiple Sclerosis Risk-Sharing Scheme and a 20-year time horizon [53]. Based on their model, the authors concluded that the long-term efficacy and cost effectiveness of GA was greater than estimated during the planning of the RSA [53]. Giovannoni et al. [54] conducted a follow-up review and reported that this positive review allowed for the price to increase following the agreed upon amount at the start of the RSA 6 years prior. In light of successful PBRSAs such as this, Antonanzas et al. [55] determined that financial-based RSAs were preferred by payers when non-responding patients bore a small impact on the overall health budget but—when the cost was high—a PBRSA was preferred only if there was a low monitoring burden.

In Italy, RSAs became a standard procedure to access the Italian Market, and a recent study by Tettamanti et al. [56], the AIFA, and local resources assessed 82 therapies from 2006 to 2015. More than half of the therapies (59%) had a PBRSA, 33% were financial-based, and 1% used both schemes [56]. According to the data, PBRSAs slowly replaced financial-based RSAs over the years and constituted 78% of the total schemes [56]. The authors concluded that one reason for the change to PBRSAs was that the AIFA relied heavily on their extensive online patient-monitoring registries [50]. The AIFA monitoring registries allow for the continuous evaluation of pharmaceuticals in clinical practice and may in fact allow for quicker access to medicines and promotion of innovation at affordable prices [57]. Fasci et al. [58] presented an example of this in their article “Conditional Agreements for Innovative Therapies in Italy: The Case of Pirfenidone” when an RSA was put in place for pirfenidone in the treatment of idiopathic pulmonary fibrosis to gain reimbursement in 2013. By the time of price renegotiation, new data from phase III clinical trials and clinical practice were used to support the cost–benefit profile of pirfenidone [58]. According to this article, the evidence allowed the AIFA to overcome their previous uncertainties about the benefits of the drug and to remove the RSA while still covering the reimbursement costs [58].

Eastern Europe has also seen an increase in the number of published articles pertaining to their experiences with RSAs. Similar to the UK’s position on the adequate use of RSAs, a systematic literature review and expert analysis by Kolasa et al. [59] determined that PBRSAs were better suited for real-world application when dealing with uncertainties surrounding cost effectiveness, and financial-based RSAs were deemed more appropriate for budgeting and cost containment. Since cost-effectiveness and budget-impact analyses have become a requirement in most healthcare systems for setting the reimbursement of highly innovative drugs, Zizalova et al. [60] in the Czech Republic recently evaluated whether or not these costs matched those in the real world. They concluded that estimated costs were exceeded by 31–332% in five cases [60]. In six other cases, real costs did not achieve the estimations, running from 12 to 91% under the estimated costs. This study concluded that cost estimations for highly innovative drugs, although required in budget-impact analysis, did not contribute to a reasonable decision and had no real practical impact [60]. In Hungary, an analysis on the cost of treatment with new antiviral therapies for hepatitis C virus (HCV) by Kocsis et al. [61] was submitted to the HTA agency, which found that the introduction of these new drugs placed a financial strain on payers. As such, RSAs appear to be a promising solution for balancing payer uncertainty with the market access for new medicines in Eastern Europe [61, 62].

As many healthcare systems faced budget constraints and pressures by the year 2015, difficulties in making choices about what treatments to fund remained. According to Focsa [63], there is a willingness to pay a fair price for new drugs and the benefits they potentially can offer, but many current healthcare systems do not have the necessary infrastructure and evaluation processes. Patient monitoring has the potential to pave the way for accurate RSAs that directly link patient benefits with the cost of the treatment [63]. Dranitsaris et al. [64] concluded that VBP and RSAs could allow for earlier access to new treatments, improved transparency in pricing, the inclusion of multiple stakeholders, the recognition of highly innovative therapies, and a more predictable return on investments for manufacturers.

4 Discussion

To address the uncertainty surrounding RSAs, our study identified four time-related themes that explain the underlying reasons for the fluctuating levels of interest in RSAs over the past 15 years.

The growing interest in the use of RSAs among pharmaceutical companies and healthcare institutions in the EU over the past 15 years has emphasized the knowledge gap in the literature between what is publicly known and what is actually practiced, partially due to a lack of transparency from both parties [7, 22]. As a result, empirical evidence and validated success stories have been lacking in past years, and this has led to substantial debates about the sustainability of alternative pricing and reimbursement processes [7, 22]. However, details of and results from RSAs that were originally not publically available are now beginning to emerge [52, 65], enabling this study.

This study shows that, in the early 2000s, predominantly qualitative articles were being published because evidence for the number of RSAs implemented was essentially non-existent as no RSA scheme had been introduced at the time. Our study identified that initially, in 2000, only a few authors and healthcare institutions were discussing the use of RSAs in the EU, although a lack of articles published in this time span could have been the result of delays in the publication process. Nonetheless, it was evident that the increased need for alternative pricing and reimbursement strategies for market access has led to a significant increase in interest in RSAs. However, with this increased level of interest, our study has identified valid arguments and questions surrounding their use by both advocates and opponents of RSAs.

Our study shows that, after the economic crisis in 2007–2008, both the discussion and the implementation of RSAs increased significantly. As a result, the number of RSAs increased as more evidence was collected and presented as quantitative articles. In addition, fluctuations were seen in the number of qualitative articles published as the viability, budget impact, and sustainability of RSAs was discussed and debated. In the following years, a substantial number of both qualitative and quantitative peer-reviewed articles were published, providing invaluable data and information about how many RSAs were being put in place and the results of some older schemes. These articles also reaffirmed the issues being dealt with by national healthcare payers as pharmaceutical expenditure continued to increase significantly across many OECD countries [66]. Several articles have concluded there is no ‘one size fits all’ or perfect method of risk sharing, and it should only be used when the standard conditions of access are hindered by uncertainty about cost effectiveness [2, 5, 46]. Additional studies have shown that special considerations must be made as to the appropriateness of an RSA, its objectives, and whether or not staff and IT systems are available to support the administrative burden [2, 5, 46].

We identified several countries that have largely influenced policies surrounding RSA use. These include the UK, Italy, France, Germany, and—more recently—Eastern Europe. We would like to note that the UK has played a very important role as it was one of the first countries to implement an RSA and has maintained very detailed records. In addition, RSAs have been implemented in many countries in the EU in accordance with each countries’ own evaluation, governance, reporting, and evidence-collection practices [50]. As such, many countries have had different results and outcomes when implementing RSAs, and manufacturers must consider each country and their implementation processes as key indicators when deciding on the use of RSAs [50]. However, differences in HTA assessment criteria have led to a noticeable difference in drug benefit evaluations, recommendations, and overall access to several EU markets for each drug [67].

Although RSAs continue to emerge in many EU countries, Neumann et al. [14], Carlson et al. [15, 68], and Towse and Garrison [15] have discussed and identified some of the most notable barriers to their implementation as being (1) transaction and administrative costs; (2) limitations to online tracking systems; (3) identifying and agreeing on scheme details such as clinical endpoints, and price negotiations, etc.; (4) IRP; and (5) the lack of trust between payers, manufacturers, and healthcare providers.

Crinson [69] researched a combination of these barriers in one of the first case studies on the results of an RSA conducted in 2004 and proposed that the NHS was unsuccessful in its attempt to control the cost of beta interferon. Suggested reasons for this were the clinical needs of the patients, the prescribing activities of the doctors, and even the pharmaceutical company’s reluctance to lower its profit margin [69]. By March 2003, fewer patients than planned had entered the RSA scheme and not the thousands needed before November 2004 [70]. Many of the initial problems were delays in setting up the proper infrastructure for the RSA, securing promised funding, and a lack of specialist doctors and nurses to run the clinics [70]. However, these delays were to be expected with such a new and innovative scheme and needed to be overcome in the ensuing years [70].

Although RSAs play an important role in the collection of real-world data, improved patient tracking and monitoring technology may be required for the efficient use of risk sharing in a performance-based model. However, the limitations of digital tracking systems are becoming less of an issue in some countries, as well as for manufacturers, as they are increasing their monitoring registries and implementing new and improved tracking systems to keep pace with modern healthcare needs [71].

RSAs are now used as a means to circumnavigate cost-effectiveness barriers and IRP, when in fact HTA agencies should be viewed as business partners instead of as barriers or hurdles to overcome. Alternative pricing and reimbursement strategies such as RSAs may be the way forward as traditional pricing and reimbursement methods are no longer viable. All EU member states except for the UK and Sweden apply a form of IRP because VBP is more complicated [72]. However, IRP offers payers a means of pricing a pharmaceutical that is not in line with optimal welfare-maximizing pricing [72]. Both manufacturers and payers are now engaged in RSAs as they are trying to find payment models where the real price will differ from the list price. [72]. An RSA or confidential discount to payers can lower the cost of a product without changing the global list price, meaning that a negative impact on a company’s revenue could be avoided [68]. As an example, the PBRSA for bortezomib in the UK allows the list price to be unchanged, while the NHS can be refunded for non-responding patients [68]. This refund allows the net price per unit of drug to be less than the price listed [68]. Ultimately, it is predicted that IRP will cease to exist as the demand for VBP is increasing where payers and HTA agencies are requiring more evidence to make reimbursement decisions [68, 72].

Our review found that RSAs are continuing to emerge as many countries are engaged in new pricing and reimbursement strategies, although barriers to RSAs have been extensively documented [71]. RSAs for high-priced specialty drugs have a place in the future as more personalized medicines and better technology for identifying patient responses are being developed. RSAs have evolved and transformed immensely since their original conception and implementation in the early 2000s. It is assumed they will be primarily financial-based schemes in the coming years in the EU, but a transition back to performance-based schemes could occur in the near future. Technology for patient tracking and monitoring is improving and may match the needs of both the national healthcare payers and the pharmaceutical industry. Conversely, RSAs may no longer be viable as pharmaceutical companies become better at creating and gathering data on the value of their product. In doing so, they will build strong cases, lowering the chances of rejection by HTA agencies. A clear understanding of factors influencing the adoption, implementation, and sustainability of and learning around RSAs are necessary for further implementation strategies, while ongoing evaluation of RSAs is essential and needs to be reported in peer-reviewed articles.

Despite obtaining valuable data about the current use and perception of RSAs, there were limitations to this research. The systematic review may not have found all relevant sources pertaining to RSAs because, before a standardized definition and taxonomy were established, RSAs had various names that are no longer used, and many countries used their own terminology in their own language. Non-English articles were excluded because of language limitations among the people conducting the research. In addition, article publication dates are not always related to the exact year the content was written about because of publication time requirements. This may also be responsible for the lack of published articles in the years 2000–2003. Another reason for the lack of information lies in the fact that the overall process of pricing and reimbursement is classified and not transparent in many countries, and therefore it is difficult to obtain detailed reports and procedures to not only replicate but also to learn from. The number of peer-reviewed articles being published each year may not completely reflect the level of interest in RSAs because this can be considered single channel reporting and does not reflect all channels of literature. The level of interest in RSAs may vary between manufacturers and payers as they are not directly represented by peer-reviewed articles. In spite of these limitations, we feel that the depth and breadth of this study (based on valuable data) makes a considerable contribution to our knowledge of the field.

5 Conclusion

Information gathered in this systematic review indicates that the current level of interest in RSAs in the EU is high 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 of qualitative articles reporting and discussing the underlying reasons for these changes in interest has generally fluctuated over the last 15 years. Despite these fluctuations, the overall level of interest in RSAs remains high and continues to grow.