FormalPara Key Points for Decision Makers

Managed entry agreements are in operation around the world and they can be an important tool to address uncertainties related to new medicines/health technologies including their potential budget impact.

Managed entry agreements can provide several benefits including reimbursing new medicines where this would have been difficult and managing increasing demand for medicines within available resources benefitting all countries. Decision makers should also consider their limitations and challenges before adopting different schemes including those with outcome-based schemes.

This paper provides a worldwide vision of managed entry agreements including their advantages, disadvantages and key considerations to support decision makers for the future.

1 Introduction

1.1 Rationale Behind Managed Entry Agreements (MEAs)

Providing efficient, safe, equitable and accessible health services to all citizens is the goal of many countries, especially those with universal healthcare systems [1, 2]. Initiatives and activities to achieve this goal across countries have been enhanced by the constant monitoring of their progress to achieve Sustainable Development Goal 3, i.e. ensuring healthy lives and promoting well-being for all at all ages [3, 4]. However, this is becoming more challenging with ageing populations across many countries, the increase in the prevalence of chronic non-communicable diseases, the instigation of single disease model guidelines and policies, along with the continual launch of new higher priced medicines to address areas of unmet need [2, 5,6,7,8,9,10,11,12,13,14,15,16]. There are now concerns that even high-income countries are failing to provide high-quality services as resource pressures grow [17,18,19], leading to delays to their funding and utilisation [20,21,22]. This builds on the limited use of biological medicines to treat patients with immunological diseases among middle-income European countries vs higher income countries in view of their costs and co-payment issues [15, 23, 24]. Similarly, there is greater availability of cancer medicines and those for orphan diseases among higher income European countries vs lower income countries again owing to a number of reasons including issues of costs, affordability and other priority demands [25,26,27]. However, funding and co-payment concerns may be eased by the increasing availability of oral generic cancer medicines and biosimilars along with aggressive discounting by originator manufacturers to secure procurement and utilisation once originators lose their patents [28,29,30,31,32,33]. Currently, for instance, a course of standard treatment for early-stage HER2-positive breast cancer including doxorubicin, cyclophosphamide, docetaxel and trastuzumab would cost approximately 10 years of average annual wages in South Africa; however, costs are expected to fall appreciably with the availability of biosimilar trastuzumab alongside generic doxorubicin, cyclophosphamide and docetaxel [27, 34, 35].

The increasing prevalence of patients with non-communicable diseases, with an associated increase in medicine use, as well as high requested prices for new medicines for patients with cancer and orphan diseases [36,37,38,39,40], has increased the focus on medicines and their expenditures in recent years. We have seen the price per life-year gained for new cancer medicines rising up to four-fold during the past years after adjusting for inflation [39, 41], alongside high requested prices for new medicines for orphan diseases [5, 40]. In view of this, coupled with increasing prevalence rates, expenditure on medicines for cancer now dominate pharmaceutical expenditure in high-income countries [42,43,44]. In Europe, total expenditure on medicines for cancer doubled from €14.6 billion in 2008 to €32 billion in 2018 (in 2018 prices and exchange rates) [45], with the cost of cancer care accounting for up to 30% of total hospital expenditure driven by the increasing cost of medicines [46,47,48]. Overall, worldwide sales of medicines for oncology are estimated to reach US$200 billion by 2022, up from US$133 billion in 2017, despite the increasing availability of biosimilars and low-cost oral generics [44]. There are also concerns with rising expenditure on medicines for orphan diseases with worldwide sales envisaged to be over US$178 billion in 2020 [8, 49, 50]; potentially offset by the increasing use and availability of low-cost generics and biosimilars [50].

The emotive nature of cancer and orphan diseases has enhanced their potential for funding and reimbursement in high-income countries at high prices despite the limited health gain of a number of new medicines [40, 51,52,53,54,55,56,57]. However, as mentioned, this has resulted in their variable and limited funding in lower income countries, similar to the situation seen with immunological diseases [15, 25, 26]. The focus on medicines can also distort funding decisions as seen with considerable funding for immunotherapeutic regimes in a number of middle-income countries; however, on average, only 22% of patients have access to safe, affordable and timely cancer surgery in these countries [58]. There is likely to be a similar challenges with funding new advanced therapy medicinal products, as well as regenerative medicines, given current requested prices, the number of these medicines in development and the degree of uncertainty surrounding them, which is leading to new models being proposed for their funding including performance-based annuity payments [13, 59,60,61,62,63,64,65].

Typically, the decision to reimburse and fund new higher priced medicines is often hampered by numerous uncertainties that exist regarding their effectiveness, safety and cost effectiveness, as well as their potential budget impact in routine clinical care [2, 66,67,68,69]. This can cause concern especially in patients with cancer where there is a high failure rate with turning promising phase II data into positive findings in later studies, i.e. phase III and beyond [70,71,72,73,74,75]. Having said this, new medicines for patients with hepatitis C have achieved the desired reductions in viral loads and statins have achieved the desired reduction in cardiovascular events post-launch [76,77,78].

However, truly innovative and valued technologies are not necessarily receiving appropriate funding limiting patient access once launched [7, 15, 79, 80]. Potential methods to address this include creating budgetary space through encouraging the use of low-cost generics and biosimilars where pertinent, improving the competitiveness of the off-patent market for orphan drugs as more medicines for orphan diseases lose their patents building on examples in Europe including imatinib, which was initially launched as an orphan disease medicine, developing new models for pricing considerations especially for orphan diseases including multi-criteria decision models, which can also be used for priority setting, as well as developing fair pricing models [32, 56, 81,82,83,84,85,86,87,88,89,90,91,92]. There has also been a growth in managed entry agreements (MEAs) across countries to help with reimbursement and funding of new valued medicines. These agreements are principally aimed at enhancing the affordability and value of new medicines at launch and post-launch given their frequent substantial budget impact and clinical uncertainty in routine clinical care at the time of their launch [9, 18, 67, 69, 93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109]. This is particularly the case for new medicines for oncology and orphan diseases [68, 93, 104, 110,111,112,113,114,115].

1.2 Definition of MEAs

According to Ferrario and Kanavos [94], MEAs typically consist of “a set of instruments used to reduce the impact of uncertainty and high prices when introducing a new medicine”, providing access to new typically higher priced, but considered cost-effective, technologies under pre-established conditions between both parties [67, 94, 97, 116]. Numerous terms have been used to describe such schemes, including risk-sharing arrangements, risk-sharing schemes, MEAs, managed entry schemes, performance-based risk-sharing schemes, performance-based risk-sharing arrangements, outcome-based MEAs, outcome-based contracting and patient access schemes [2, 5, 69, 95,96,97, 104, 117,118,119,120,121,122,123,124]. These agreements or schemes typically use different methodologies to reduce uncertainties related to the technology, especially its value and budget impact, and are typically tailored to a given situation and country [95, 121, 122, 125].

Managed entry agreements are now the generally used term rather than “risk-sharing scheme”. The Health Technology Assessment International society defines MEAs as “an arrangement between a manufacturer and payer or provider that enables coverage or reimbursement of a health technology subject to specific conditions” [69, 122, 126, 127]. According to the taxonomies developed by Adamski et al. [97], Ferrario et al. [93], the World Health Organization, and the International Society for Pharmacoeconomics and Outcomes Research, such agreements can be subdivided into payments that are linked to health outcomes or, alternatively, the financial considerations, where the price is defined considering quantitative measures such as the estimated consumption of the technology in question [68, 94, 97, 104, 121, 128,129,130]. The design of these agreements does differ across countries, suggesting that different cultures, systems and goals may require different programmes and approaches. However, the rationale is often similar. Table 1S of the Electronic Supplementary Material (ESM) provides illustrative details of the different schemes and examples that have existed or are still ongoing across countries. Insurance companies in the USA are also now entering into value-based contracts with hospitals to share the risk [131].

Table 1 Synopsis of activities surrounding managed entry agreements (MEAs) and funding medicines in key South American countries
Full size table

1.3 Challenges and Benefits from MEAs

There is a general consensus that outcome-based schemes are more challenging than financial-based schemes in view of the necessary infrastructure involved [93, 96, 104, 112, 124, 125, 132]. There are also concerns whether outcome-based schemes actually achieve a shift in resource allocation to more effective medicines and/or patient populations [133]. This can potentially be seen with the use of surrogate markers in outcome-based schemes especially in patients with solid tumours as these may not necessarily translate into improved outcomes [53, 134,135,136,137]. Other concerns regarding outcome-based agreements include a belief that ending reimbursement when conditional schemes for new medicines fail to demonstrate the necessary value can be more difficult in practice than starting such schemes [138]. However, reimbursed prices are not increased when the value of a new medicine is shown to increase as more data become available. However, we believe such situations are rare in practice with phase II and III studies principally including selected patients compared with routine clinical care and there can be concerns with turning positive trends in surrogate markers into similar improvements in outcomes [53, 75, 136]. Principal concerns regarding financial-based agreements include the lack of transparency with respect to discounts and rebates [57, 93]. This is of critical concern among countries that rely on external reference pricing for their deliberations and where patient co-payments are based on list rather than discounted prices [57, 139]. Appropriate redaction of publicly available documents is one way forward in addition to growing calls for increased transparency [117, 140, 141]. There are concerns though with appropriate incentives for pharmaceutical companies if prices continue to fall and there is price fixing at lower costs with increased transparency [142]. However, increasing discussions regarding fair pricing approaches for new medicines will necessarily involve increased transparency [85, 86, 90, 143].

However, there can be considerable benefits with MEAs. These include reimbursing and funding new medicines where this would have been difficult to achieve; demonstrating negotiated outcomes can be achieved in practice, as seen with the statins in the UK and new medicines for hepatitis C in Sweden; only paying for agreed outcomes, as seen with new treatments for hypercholesterolaemia in USA; increasing the use of biomarkers to better target treatments and resources, as seen with medicines for multiple myeloma; and finally, keeping within agreed budgets through discounts and rebates [9, 76, 97, 106, 144, 145]. In Italy, there were concerns with the effectiveness of donepezil and other treatments for patients with Alzheimer’s disease when first launched, resulting initially in a 100% co-payment for these medicines [97]. However, a study undertaken among 500 Alzheimer Evaluation Units (CRONOS study) in Italy demonstrated a similar health gain in patients with mild-to-moderate Alzheimer’s disease in routine care compared with those seen in the clinical trials, which resulted in the Italian National Health Service subsequently fully funding these medicines (‘A’ classification) provided patients were treated in specialist outpatients clinics [97, 146].

These examples of MEAs can be seen as part of a general approach within healthcare systems to monitor the effectiveness, safety and value of new medicines where possible especially where there are concerns initially with their effectiveness, safety and value in routine clinical care [144, 147,148,149,150,151,152,153,154,155,156]. In addition, there is a general movement from a policy model of one-time evaluation regarding the incorporation of a new technology into healthcare systems towards a model of multiple evaluations of new health technologies over time. Such activities are likely to grow with the emergence of electronic health records and information systems across countries [14, 157].

The potential savings in terms of cost avoidance from financial-based MEAs can be appreciable. In the Netherlands, savings from financial-based agreements in 2017 was €150 million and €203 million in 2018 [9], equating to 4.4% of total pharmaceutical sales in 2017 [158]. In Belgium, after adopting MEAs, the total extent of discounts under the various MEAs was €23.7 million in 2013 rising to €273.4 million in 2017, again equating to 4.4% of total pharmaceutical sales [158]. A similar situation was seen in France in 2015 where the following rebates occurred under agreed MEAs [9]:

  • Price–volume agreements: €573 million.

  • Budget caps (medicines for orphan diseases): €139 million.

  • Outcome-based agreements: €98 million.

  • Discounts: €94 million.

  • Cost/patient (based on an agreed treatment scheme and average daily costs): €82 million.

  • Others (not specified): €29 million.

In Colombia, the Colombian Ministry of Health and Social Protection through the Pan American Health Organization (PAHO) was able to make a centralised purchase for new treatments for hepatitis C cutting the price by nearly 80% [159]. By the end of October 2018, the centralised purchase had benefited 1069 patients with a healing rate of 96.2% [159]. In Brazil, the Ministry of Health recently published a performance evaluation guideline to provide continuous assessment of technologies incorporated in the National Health System (Sistema Único de Saúde-SUS) [160]. The first evaluation in the country was made for intramuscular beta interferon 1a, attesting its inferiority compared with other beta interferons already incorporated by the SUS [161].

1.4 Objectives of the Paper

In 2019, the Brazilian Minister of Health announced that a new modality of technology acquisition would be adopted through risk-sharing agreements for relevant high-price medicines [162, 163]. However, there was an identified need to learn from the experiences in other countries. As a result, we undertook a combined approach to provide guidance to the authorities in Brazil. This included an integrative review, documenting a range of international experiences with MEAs, along with information on MEAs from other South American countries. In addition, an appraisal of the principal issues and concerns among health authority personnel and their advisers from multiple countries, including middle-income countries, involved in the design and implementation of MEAs.

Consequently, the overall aim of this paper is to provide a basis for critical considerations surrounding the implementation of future performance-based agreements among the authorities in Brazil. Such considerations may also be pertinent for other middle- and higher-middle income countries going forward as they refine existing MEAs as well as appraise new MEAs for their markets.

2 Methods

2.1 Combined Approach

An integrative review approach was adopted to achieve the objective. The first stage involved a review of MEAs across countries. The review question was ‘What are the health technology managed entry agreements that have been applied around the world?’ We were aware that a number of reviews have been conducted and published regarding MEAs [93,94,95, 97, 104, 106, 164,165,166]; however, we wanted to consolidate these and expand them to include Latin America. This review was supplemented with published studies not retrieved in the search, coupled with other sources from the senior-level co-authors regarding ongoing arrangements within key South American markets (second stage), as only limited published information was found. The countries included Argentina, Brazil, Colombia and Uruguay.

The third stage involved senior-level health authority personnel, their advisers and academics from a range of high- and middle-income countries involved with implementing and/or researching MEAs, coupled with senior-level personnel from PAHO and the World Bank, providing guidance on potential advantages and disadvantages, as well as key considerations that the authorities in Brazil should consider as they progress with MEAs. This was based on the literature review, combined with their own experiences and activities. The contextualising of the findings from the multiple approaches was principally from a payer (national or regional health authority or health insurance company) perspective, as this was the main emphasis of the paper.

This three-part approach was adopted because of the limited information regarding the implementation of MEAs and their impact, especially outcome-based schemes, available in the published literature [5, 9, 93, 94]. These combined approaches have been successfully used before when providing guidance and feedback to key stakeholder groups in disease areas and situations of interest [8, 83, 93, 97, 167,168,169,170,171,172].

2.2 Search Design for the Literature Review

Search strategies were designed for PubMed, EMBASE, LILACS and Cochrane Library databases on 5 March, 2019. The literature search used the strategy outlined by the Cochrane guideline, considering the population, intervention/exposure, comparator and, in some cases, the outcomes (clinical results) [PICO] [173]. This review considered: problems, topics of interest and outcomes:

  • Problem: MEAs;

  • Topic of interest: medicines or health technologies;

  • Outcomes: experiences, processes, performances and efficiency of MEAs.

Descriptors and words were extracted from the three main controlled vocabularies according to Cochrane, Medical Subject Headings (MeSH) for the MEDLINE database and others, including the Emtree thesaurus for EMBASE database and Health Sciences Descriptors (DeCS) for Latin America databases. Some synonyms and keywords were also added to the search on all text. The search strategies used in each database are detailed in Table 2S of the ESM.

2.3 Inclusion and Exclusion Criteria for the Literature Review

This review included the following eligibility criteria for potential studies:

  • Inclusion papers in Portuguese, English or Spanish concerning payment for performance and/or risk-sharing agreements and/or MEAs experiences across countries and suppliers for medicines or health technologies, including systematic or integrative reviews, as well as abstracts published in annals.

  • Exclusion dissertations or theses; editorials; news; commentaries; letters to the editor; guidelines; and studies that did not identify the payment for performance/risk-sharing agreements/MEA.

The eligibility of potential studies was assessed by two researchers (MSC and ALP), using the Rayyan® web app. They undertook the initial screening of the studies by reading the titles and abstracts. Disagreements were solved by a third researcher (CZD). Subsequently, the articles selected were analysed by reading the full text. Articles were subsequently included in the review if they met the inclusion criteria. Disagreements were assessed by a third reviewer (MMG). Grey literature was also considered as an important strategy to recover eligible studies in this review as we believed a number of MEAs may be contained in the grey literature and not published. This was conducted via a manual search of the references in the first selected papers, additional search in Google/Google academics, as well as with suggestions from the co-authors and others working in this field. Any conflict was also resolved by another researcher (CZD), who made the final decision.

2.4 Analysis of the Results from the Literature Review

The data extracted from the publications were analysed by country through a descriptive analysis approach. The variables considered were: year, type of agreement, type of technology/medicine, clinical condition, and the payers and providers involved. Relevant additional publications known to the co-authors that were not covered in the literature search were also included to add depth and robustness to the paper.

3 Results

3.1 Literature Review

A systematic literature review conducted among the four databases retrieved 2299 articles. Seventy-four articles remained after removing duplicates and reading the titles and abstracts. After a full reading of the papers and the inclusion of manual and grey literature, 25 studies remained, addressing 446 agreements (Fig. 1 of the ESM).

Of these, 432 agreements included medicines and only 14 included other technologies or procedures. Most of the arrangements were financial, including discounts and volume (43%), followed by performance-based schemes (36%). More than half of the agreements involved antineoplastic medicines. Among the pharmaceutical companies involved in such arrangements, Novartis, Roche and Pfizer were the most cited. Table 3S of the ESM presents the main characteristics of the MEAs identified in the studies.

The agreement categories: “outcomes”, “impact results” and “other aspects” were typically not fully addressed in the included studies, which meant we could not deeply analyse the results and performance of the agreements. Most countries kept key information, such as discounts or rebates, confidential or have not published such data in journals or conferences [103, 106, 132]. This is a concern, particularly regarding publicly funded healthcare systems as this information cannot be used to guide pricing considerations in other countries as identified in a number of publications and reviews [5, 93, 174, 175]. Having said this, care is needed to still incentivise companies to invest in new medicines whilst maintaining the sustainability of healthcare systems [142]. Such deliberations will continue with growing calls for fair pricing for new medicines among key stakeholder groups [85, 90, 143, 176], with the World Health Organization arguing that improving price transparency should be encouraged on the grounds of good governance with no conclusive evidence on its downside [27]. Figure 2S of the ESM depicts which countries are already practicing MEAs, according to the literature.

3.2 Summary of Studies Broken Down by Continent and Country

Table 4S of the ESM provides the details of the MEAs among selected countries found from the literature review and supplemental data, building on the information presented in Table 3S of the ESM. Overall, we see financial-based MEAs as the principal type of MEA in a number of European countries. Until the end of 2015, in Poland, for example, the most common types of MEAs for new medicines included discounts (43.6%) and other schemes (34.5%), which typically involved free supplies and payback arrangements (21.8%). There were no outcome schemes in operation at this time [177].

By the end of 2018, there were over 100 MEAs established in the National Health Service Scotland that are part of the patient access schemes [119]. The vast majority were simple discount schemes (discount at the point of invoice). Less than 10% of the MEAs involved more complex financial schemes and only one was an outcome-based scheme. There are likely to be similar arrangements in England and Wales. However, the situation may change in the UK with criteria for ring-fencing monies to fund new cancer medicines where there are concerns with their cost effectiveness now changed with the requirement that new applications be part of an agreed managed access scheme that includes the collection of health service utilisation data to inform subsequent funding decisions alongside ongoing debates on this subject [178, 179].

In Canada, MEAs are principally financial-based schemes involving the pan-Canadian Pharmaceutical Alliance for publicly funded drug programmes and patients [116]. Currently, outcome-based schemes are seen as challenging because of the lack of integrated real-world data sources in Canada [116]. As new medicines increasingly target niche populations, it may require data from more than one country to combine their real-world data to gain enough patients to assess meaningful findings [125, 180]. Table 5S of the ESM summarises the types of MEAs found in a number of different countries with a range of geographies, gross domestic product and financing of healthcare systems.

3.3 MEAs in Key South American Countries

The literature review retrieved scant information regarding agreements in South American countries. In this approach, when consulting other sources (suggested by co-authors from these countries) regarding ongoing arrangements within key South American markets, some activities, including planned agreements, and the funding of medicines were summarised (Table 1).

3.4 Key Considerations for MEAs from a Payer’s Perspective

There are a number of considerations that need to be carefully considered when starting MEAs, especially among middle-income countries. These can be divided into their potential advantages (Box 1) and disadvantages (Box 2), as well as key areas to consider during initial negotiations with pharmaceutical companies and their implementation (Box 3). These have been identified from the literature (Table 1 as well as Tables 1S, 3S and 4S of the ESM), supplemented by the considerable experiences of the co-authors. There is a concern though that middle-income countries will pay more for their medicines than higher income countries. This is because higher income countries potentially have greater economic power when discussing and debating confidential discounts and rebates in MEAs for new medicines [139, 185,186,187,188,189], potentially unbalancing the international market. However, we have seen purchasing consortia forming to address this as seen with PAHO and treatments for hepatitis C in South America [159]. A number of cross-border Pan-European Groups have now formed including BeNeLuxA, Nordic and Valletta groups undertaking joint activities including Horizon Scanning and health technology assessment activities [190,191,192,193], and these are likely to continue. However, joint reimbursement negotiations are at an earlier stage given differences between the reimbursement and legal systems in each country [194].

7 Discussion

Based on the literature review, 97% of MEAs identified involved medicines, typically medicines for oncology, with financial-based schemes the most prevalent. This is perhaps not surprising in view of the complexities typically involved in outcome-based schemes as well as the necessary infrastructure to undertake such schemes (Boxes 2 and 3). Moreover, in reality, financial-based schemes have been perceived as easier to undertake as seen by different recommendations by the National Institute for Health and Care Excellence in England and Wales for the different approaches [201]. In addition, financial-based agreements are generally seen as a more effective method whereby health services can monitor and influence their outlay on expensive medicines. However, this is not universal considering the developments in outcome-based contracting for medicines and diseases areas among managed care organisations in the USA (Table 1S of the ESM). In addition, the UK is now linking the collection of clinical data with funding for new oncology medicines within the cancer drug fund [178].

In our literature review, we found MEAs in most continents. In North America, the USA is notable for the large number of agreements particularly involving several payers (Tables 1S, 4S and 5S of the ESM). As mentioned, this high number of payers is related to the model of their health system with a considerable number of patients covered by different health insurance providers with 67.2% of patients currently covered by private insurance schemes in the USA and 37.7% by government coverage [202]. In South America, Marin et al. referred to Colombia as a pioneer in MEAs [203]. However, a greater understanding of the healthcare system in Colombia with its current challenges would appear to contradict this (Table 1). Whilst no studies were found in the literature review reporting Uruguayan experiences with MEAs, a number of these are now in operation (Table 1) [204]. In Oceania, both New Zealand and Australia have MEAs, and in Asia there are MEAs in existence in China, the Philippines, Singapore, Indonesia, Korea and Taiwan [69, 101, 164].

There are a number of reasons why MEAs have now become widespread across countries. These include, as previously mentioned, progress in science involving more complex treatments. Reasons also include the launch of advanced therapies with typically high associated prices and an associated budget impact, uncertainty, and costs of new treatments as seen with new medicines for cancer and orphan diseases, and the increasing prevalence of chronic non-communicable diseases with ageing populations with implications for appreciably increased use and costs of medicines [8, 39, 40, 61, 93, 205]. As a result, we are likely to see the number of MEAs grow alongside other potential measures for funding new medicines [8]. However, there are concerns that there is limited information to date regarding the results of MEAs to guide future activities [5, 9, 93, 99, 108]. This is complicated by the decision of many countries to preferentially adopt confidential discounts for new and existing medicines as part of any MEA especially within public healthcare systems. This has resulted in increasing calls for transparency; however, this has to be balanced against appropriate incentives for pharmaceutical companies to develop new medicines to address areas of unmet need as well as price fixing considerations [57, 93, 140, 142]. Moreover, the traditional methods of health technology assessment used to support decisions may not be enough by themselves in this context. As a result, more robust and innovative models including multicriteria decision analyses may be required to aid decision making, although there have been concerns with multicriteria decision analyses, which are being addressed [8, 91, 115, 206,207,208,209].

However, despite the many potential benefits of MEAs (Box 1), there are considerable concerns that need to be considered in countries such as Brazil as they seek to implement additional MEAs (Box 2). These include concerns with the extensive adoption of confidential price contracts. This means that no one country can really determine if they are getting optimal discounts compared with their neighbouring countries (Box 2). In addition, high-income countries with appreciable greater populations may use their economic power to negotiate aggressive confidential discounts, which may well not be available to smaller countries to the detriment of their citizens, especially if there are patient co-payments in the country. However, the number of outcome-based schemes may well grow to address uncertainty with a number of new medicines, especially in patients with cancer, being launched and approved by regulatory authorities on the basis of small clinical trials, with pressure on health authorities to fund them as more evidence is generated [75, 210].

Typically, a number of requirements are needed before MEAs can become a realistic option in middle-income countries. These include (i) a flexible legislative framework, (ii) an adequate infrastructure for data collection within the country to facilitate data entry and enhance the evaluation of all agreed schemes, (iii) potential for integration between the different current databases within a country to aid analysis, (iv) strengthening of current healthcare structures where pertinent to facilitate pertinent data entry and analysis as well as monitoring any agreement especially for outcome-based schemes, and (v) good alignment of the objectives between health authorities, clinicians and pharmaceutical companies including pertinent incentives for all key stakeholder groups. The outcome-based schemes, in particular, can be costly and necessitate in advance agreements regarding the funding for data entry, collection, analysis, medicines during data collection and supervision. Moreover, for allocation decisions, publicly funded healthcare systems need to consider reassessment of currently funded interventions and their value whenever new technologies enter the market [211].

Which type of MEA to choose when entering into negotiations with pharmaceutical and other companies, as well as the key factors to consider when developing these agreements, are part of a number of key issues that health authorities need to consider going forward (Box 3). This is particularly important in priority disease areas such as cancer and rare diseases as new medicines are typically needed in these areas but have commanded high prices despite often limited health gain [40, 55, 108, 212]. These agreements can be performed to improve scientific knowledge regarding new innovative technologies alongside providing early access to patients. However, this has to be balanced against issues of affordability and sustainability of the whole health system. New approaches or funding new medicines are, however, outside of the scope of this paper and may be followed up in future research projects [8]. Alternative access schemes for pharmaceuticals have also recently been collated and discussed by Löblová and colleagues [213], and such discussions will continue.

We are aware of the limitations of this paper regarding the formatting of data and the presentation of the results from the published articles owing to a lack of information regarding the nature of MEAs. This includes defining the parameters used in such agreements as well as the evaluation of the outcomes of any MEA. In addition, not all MEAs as well as not all countries with MEAs are included in this review due to publications not meeting the inclusion criteria. We are also aware that some agreements found in the literature are likely to have expired by now. However, they have been included as examples going forward especially in countries where there are limited outcome-based schemes to date. Despite these limitations, we believe our findings and their implications are robust providing direction to those planning MEAs.

8 Conclusions

We are likely to see a growth in MEAs in the future with the continual launch of new premium-priced medicines including new advanced therapy medicinal products. Alongside this, ageing societies demanding new complex treatments to address unmet needs further increase demands on available resources especially among high- and upper middle-income countries. Managed entry agreements are a potential way forward to address funding pressures alongside other financing approaches. However, MEAs can be complex to administer and require critical appraisal among all key stakeholders before initiation alongside issues of affordability and sustainability for the healthcare system as a whole. However, this has to be balanced against such agreements improving the knowledge base for new innovative technologies as well as providing early access to patients for potentially innovative therapies.

The financial-based agreements are easier to perform, enabling healthcare systems to reduce their outlay for new expensive medicines especially where there are considerable uncertainties surrounding the value of a new medicine in routine clinical care. Nevertheless, as mentioned, the extensive adoption of confidential price contracts across many countries generates market failures. Such discounts mean that no country can really determine if they are getting the best discounts jeopardising the overall goal of reducing the cost of new medicines. However, this has to be balanced against ensuring necessary incentives for companies to develop new technologies to address areas of unmet need. The specificities and peculiarities of each country should also be taken into account when seeking to initiate MEAs alongside adequate infrastructures. These include whether there are robust information systems in place for data collection rather than instigating single registries for each new medicine.

Managed entry agreements can potentially be important tools to improve the scientific capacity and knowledge within countries alongside providing access to new innovative and high-cost medicines whilst seeking to minimise the opportunity costs of the decisions. Incorporating international knowledge and practice can be a crucial strategy to guide countries such as Brazil as they design MEAs for new innovative medicines. We will be researching this further as Brazil starts to introduce MEAs.