Morel, T., Arickx, F., Befrits, G., Siviero, P., van der Meijden, C., Xoxi, E., et al. (2013). Compatibility of cost and outcome uncertainty with the need for access to orphan medicines: a comparative study of entry agreements managed in seven European countries. Orphanet J. Rare Dis. 8:198. doi: 10.1186/1750-1172-8-198 It is difficult to assess the extent to which performance-based MEAs have been successful so far. Few countries have formally evaluated their experience. Confidentiality of agreements remains a barrier to independent evaluation, and there is little public evidence. However, available information from expert interviews and previous studies suggests that coverage of evidence-based development agreements (ITNs) has so far had a poor record in reducing uncertainty about drug efficacy.
Pay-as-you-go (PbR) agreements are still used quite frequently, but they don`t always generate evidence of product performance because the data used to trigger payments isn`t always aggregated and analyzed. The administrative burden of collecting and analysing data on the effectiveness of medicines can also make their execution costly. Across Europe, uncertainty and high prices for health technologies have led stakeholders to adopt multilateral environmental agreements. Two main types of MEAs were heavily applied, Financial Data Based Agreements (ABAs) and Performance-Based Agreements, including individual performance-based agreements and Evidence Development Coverage (ITNs). Service-based agreements have not been considered as much so far, but are increasingly being used. Many European countries are turning to EDCs to remove uncertainty and facilitate market access while negotiating product prices and reimbursement rates. Despite the interest in JEPs, European countries have turned to ABFs due to the complexity and burdens associated with BAPs. Market access agreements between pharmaceutical companies and payers have attempted in recent years to track this innovation through “managed entry agreements,” where treatment is approved at a certain price for a specific patient population and/or type of cancer.
Simply put, a Managed Entry Agreement (MEA) is an agreement between pharmaceuticals and payers for a therapy for a specific use case, population, or need with specific price determinations. During the interviews, manufacturers stated that the EMA had systematically asked them to collect additional data through RCTs, safety studies or patient registries under conditional marketing authorisations. However, these studies did not necessarily provide the specific data that national HTA agencies and payers are looking for. Closer coordination of ex-post evidence requirements between HTA bodies and the regulator could mean that better evidence development could lead to flexible pricing arrangements. If there was an opportunity to do so, many companies would be interested in exploring such opportunities as they could enable value-based pricing. In addition, payers indicated that once a product was made available to patients, removal from the list when evidence no longer supported coverage was not possible due to a lack of mechanisms that would facilitate delisting and weak societal support for the removal of reimbursement decisions based on economic evidence. These findings have implications for healthcare stakeholders, as while outcome-based controlled market entry agreements for Adaptive Pathways products are needed to facilitate market access, the lack of infrastructure in many countries that would easily allow data collection needs to be addressed and feasible models and mechanisms identified. Discussions during the ADAPT-SMART3 workshop revealed that apart from health-related technical, systemic and policy factors, a lack of trust between payers and manufacturers could be one of the main barriers to wider use of outcome-based agreements.
Payers and HTA agencies indicated that they consistently see very high prices for new products without much differentiation based on value added, while manufacturers indicated that payers seemed more concerned about budgetary impact and are not willing to consider more complex agreements4. We believe that an adaptive pathway could be a well-suited environment to address some of these trust issues for the following reasons: (i) Adaptive Pathways products should have a reasonable expectation of significant added value5, meaning that questionable product value would be less problematic, (ii) early dialogue takes place years before products enter the market, which could facilitate the development of viable payment models, where there is broad stakeholder consensus on the need for such products, and (iii) Adaptive Pathways products would be closely monitored once they are on the market and ways to facilitate oversight for regulatory and HTA purposes could be explored, for example in the framework of the EMA Registries6 initiative. Ferrario, A., and Kanavos, P. (2015). Dealing with uncertainty and high prices of new medicines: a comparative analysis of the application of controlled entry agreements in Belgium, England, the Netherlands and Sweden. Ploughshare. Sci. Med. 124, 39–47.
doi: 10.1016/j.socscimed.2014.11.003 Note: This taxonomy is based solely on the structuring of agreements. All types of agreements can exist not only between companies and health insurance companies, but also between companies and other types of institutions that make up a health system, including government agencies or national authorities responsible for coverage or pricing decisions and/or health technology assessment (HTA), regional health authorities, health care providers, etc. Especially for products used in the inpatient hospital sector, MOEs may exist between companies and hospitals. Source: Authors of the study based on Carlson (2010), Ferrario and Kanavos (2013) and Gerkens et al. (2017). Keywords: Registry, Managed Entry Agreement, Orphan Drug, Treatment of Rare Diseases, Regulatory Approval, Innovation Recognition, Results-Based Managed Entry Agreements The convergence of all these forces makes 2021 the year managed entry agreements are truly scaled. We have more and more pipelines of innovative therapies that require complex agreements, in addition to the growing demand for healthcare delayed during the Covid-19 era, coupled with better data sources and improved technological solutions. Companies are expected to conduct a joint scientific advisory process involving regulators and HTA agencies as part of the adaptation pathways, which has already occurred for some of the pilot products.
This process should lead to an integrated evidence-building plan where regulatory applications would be complemented by HTA applications. Those requests would be translated into relevant instruments at national level, such as managed entry agreements, in accordance with national procedures and guidelines, as charging and reimbursement are the responsibility of the Member States. Real-world evidence gathered after initial approval would be used to supplement – not replace – initial regulatory requirements and could allow for a better understanding of optimal product use (p.B understanding patient subgroups and stakeholders) to maximize effect and minimize risk. This article begins with a brief overview of the existing taxonomy of Managed Entry Agreements (MEAs) and provides a history of its implementation. The novelty of the article lies in several highlights, including the introduction of service-based agreements and a proposed structure for their taxonomy, solid literature questioning the ability of MEAs to achieve their goal of eliminating uncertainties, and the development of MEAs that have been reintroduced as hidden differential prices. Flowchart to include studies describing managed entry-level agreements. Managed Entry Agreements (MEAs) are agreements between companies and healthcare payers that cover new drugs while managing uncertainty about their financial impact or performance. Financial agreements are used in at least two-thirds of OECD countries and EU Member States. Many of these countries also use performance-based agreements that perform hedging, payments to companies, or discounts paid by companies based on product performance, but these MEAs are less common.
With the support of the European Commission, the OECD reviewed countries` experience with performance-based multilateral environmental agreements to identify best practices and possible ways to improve the use of these agreements in the future. As innovative and highly expensive therapies hit the market, service-based agreements and the creation of appropriate conditions will be crucial to establishing sustainable healthcare, making this invaluable for manufacturers seeking faster access to the market. Some felt that Adaptive Pathways products would rely more on observational studies that would replace phase III studies. In practice, however, conditional marketing authorisation is usually granted with the legal obligation to conduct confirmatory clinical trials, rather than relying solely on observational studies. Banzi et al. (2015) reviewed the 24 conditional marketing authorizations between 2006 and 2014 and documented the study designs that formed the basis for approval, as well as the specific obligations required by regulators (Banzi et al., 2015). Conditional marketing authorisations are generally granted on the basis of: (a) a single-arm Phase II study; (b) a single-arm phase II study plus a phase III RCT (ongoing or completed); (c) interim data from a Phase III RCT; or (d) Double-blind phase III RCTs. In addition, for 22 of the 24 products, the type of study at which the manufacturer was required by law to convert conditional marketing authorisation into full marketing authorisation was an RCT; Typically, a phase III RCT, final analysis of a phase III RCT, or long-term follow-up of a phase III RCT was requested (Banzi et al., 2015). .
