Impact of Managed Entry Agreements on availability of and timely access to medicines: an ex-post evaluation of agreements implemented for oncology therapies in four countries

The restricting cost containment environment in which healthcare systems are required to operate, introduces challenges on policy decisions about the coverage of highly priced pharmaceuticals. These challenges often arise as the evidence presented by manufacturers is not always sufficient to estimate the real-life budget impact, clinical and cost-effectiveness of these high-cost pharmaceuticals. More importantly, the uncertainties posed by the immature evidence submitted by manufacturers may prevent or delay healthcare payers from reaching conclusions on coverage decisions, thus affecting patient access [1].

Against this background, there is an interest from healthcare payers and manufacturers to collaboratively manage the entry of new pharmaceuticals in the market by linking price and reimbursement levels to real-world performance or utilization of medical products with the aim of sharing the risk surrounding the introduction of new technologies with uncertain evidence on their clinical and/or cost-effectiveness profiles. Prices can be linked to future outcomes and/or volumes and the specific conditions of the negotiations are drawn up into product listing agreements usually summarised as Risk Sharing Agreements (RSAs), Managed Entry Agreements (MEAs) or Patient Access Schemes (PAS) [2‐4]. The main types of these agreements are financial-based and health outcomes-based agreements, or occasionally combination of both types. The former includes agreements at the population level (e.g., simple discounts or price–volume agreements) or at the patient level (e.g., utilisation, time, or cost capping schemes), and the latter includes performance-linked schemes (e.g., conditional treatment continuation, outcome guarantee and coverage with evidence development) [5].

It has been suggested that MEAs can improve access to innovative medicines by addressing decision-making related uncertainties and hence, preventing rejection from reimbursement due to uncertain clinical and cost-effectiveness evidence [6‐8]. Nevertheless, these agreements have not yet gained widespread acceptance primarily because their sustainability is unclear and their effectiveness in meeting their objectives has yet to be evaluated [9]. Key issues around the efficiency of MEAs relate to the often lengthy or stalled MEA negotiations causing access delays, and the risk for a product reimbursed with a MEA being delisted following expiry of the agreement thus, impeding patient access [5]. Another area of concern in the implementation of MEAs relates to the administrative burden they are often associated with [7], especially for agreements that require advanced infrastructure systems to support new data generation [10].

Despite the significant attention placed on the implementation of MEAs, the body of evidence on the performance of MEAs to date is weak, as there is still little information on their real-life impact on patients and healthcare systems [11, 12]. The main body of literature attempting to evaluate MEAs is based on theoretical models that assess the economic impact of MEAs [13‐18]. Additionally, the role of MEAs in achieving a meaningful impact on key policy objectives such as cost containment, improved access and reward of innovation, has been discussed in the literature chiefly in the context of describing their “strengths and weaknesses” [3, 7, 19]. The key challenge in conducting empirical impact assessments for MEAs arises due to the confidentiality and limited information available on the specific negotiating terms and operational details of these agreements (i.e., timeframe, patient eligibility, indicators used to monitor outcomes etc.) [3, 11]. Only a few empirical studies exist on the real-life impact of implemented MEAs on pharmaceutical expenditure [20, 21], list prices [11], faster access to cancer medicines [22] and on the ability of outcomes-based schemes to collect meaningful, long-term outcomes data for patients [23, 24]. Additionally, existing empirical literature primarily reflects case studies within one specific setting/country and hence, comprehensive evidence about the broader effectiveness of MEAs in meeting their anticipated objectives remains scarce [9, 25, 26]. For example, Russo et al., (2010) [22] assessed the impact of MEAs on access delays only from the Italian healthcare system perspective and concluded that the impact of MEAs remains equivocal due to diverse health system priorities, different assessment criteria, different market access/purchasing strategies and market sizes across different countries. Other studies concluded that despite MEAs’ potential to improve access, there is no consensus on which MEA types and implementation strategies are the most effective in optimising reimbursement decision-making [13].

Drawing more robust conclusions about the pragmatic impact of MEAs is paramount to understand if these agreements represent a sustainable policy tool for improved coverage across countries. This could also help purchasers to identify the most efficient MEA negotiation practices by understanding which situations call for the use of one type of MEA instead of another, and what trade-offs are involved in choosing different contracts [13]. To that end, structured ex-post evaluations of MEAs are essential to assess the impact of existing schemes on a number of key policy goals such as access to medicines, budget control and encouragement of innovation [4, 8, 27]. In practice, these evaluations can take the form of quantitative models that enable the outcomes of these agreements to be compared with those in situations without them [9, 11].

We are not aware of any other empirical studies that involve direct comparisons of MEAs to understand how these agreements influence the level of and/or speed of access to medicines across countries. Therefore, the objective of this study was to contribute evidence around the impact that completed agreements or resubmissions with an agreement have had on a) the levels of access (i.e., resulting in more “listing” recommendations) and b) the time taken to the final decision outcome. These objectives were selected for impact assessment because first, they reflect a key policy goal targeted by health systems across borders [28] and second, because of relevant data availability that ensures feasibility of the required data analysis.

We conducted an analysis of oncology medicines previously rejected from reimbursement, to understand if any MEAs implemented upon evidence resubmission of the above medicines had an impact on enhancing the availability of and timely access to these medicines. Our results suggest that presence of MEAs has the potential to improve the availability of new oncology therapies, by increasing their likelihood for reimbursement if they have previously been rejected. However, presence specifically of outcomes-based agreements can cause significant time delays in reimbursement decision-making and hence, time to access.

Only a few studies have provided a quantitative evaluation of the impact of MEAs on access to medicines [12, 22, 32‐34]. In Italy, it was shown that the introduction of MEAs contributed substantially to an improvement in patients’ access to cancer medicines [12, 34], whereas in Finland and South Korea it was estimated that about 20% and 60% of patented medicines respectively were granted reimbursement due to the presence of a MEA, and of the 60% reimbursed in the later, 23% were previously rejected [32, 33]. Similarly, in Australia, MEAs have been implemented as part of the government’s plan to enhance access to medicines, estimating that MEA implementation can help achieve coverage for about one-third of new medicine-indication pairs [35].

It has also been suggested that reimbursement with a MEA, regardless of its type, can improve time to patient access [22, 36]. We found that, medicine-indication pairs approved with a MEA exhibited longer average time to final reimbursement decision, although only the presence of an outcomes-based agreement specifically (as opposed to presence of a MEA in general) was associated with a statistically significant increase of about 480 days to final funding decision. Comparable findings have been reported by a study of oncology medicines in the Italian setting, which showed an increase in the national time to market of about 150 days for medicines approved with an outcomes-based agreement compared to those approved with a financial scheme [34]. This finding is not surprising; the complexity of outcomes-based contracts in comparison to more simple financial schemes, their negotiation process can often be burdensome and time consuming for manufacturers and payers. Additionally, the collection of additional evidence and if required, the future monitoring and re-assessment of the product, as well as the need to align interpretations of the collected and required data between the different stakeholders involved in reimbursement decision-making may introduce further delays [10, 37, 38].

Discrepancies in the conclusions of existing literature around the impact of MEAs on time to access may be explained on the grounds that regardless of their type, MEAs can only improve time to market access if negotiation processes are well structured and based on sufficient preparation ahead of time such that the proposed schemes have a clear rationale and truly address the uncertainties raised by the competent authorities assessing the technology in question [39]. Growing concerns have been expressed in the literature that MEAs are increasingly used as “an operational tool” to agree on commercial price negotiations and confidential discounts rather than as a tool for managing the actual risk arising from immature data [40]. Therefore, even simple financial schemes need to be implemented such that they meaningfully address the uncertainties that a new therapy presents with, rather than implemented simply as a tool to achieve lower prices. More importantly, when financial schemes are used solely as a cost containment process on top of other cost containment policies, they can add little benefit in terms of outcomes for patients and increase delays in the long term [41]; for example, they might grant access to interventions which might prove cost-ineffective in the long-run with the consequence that these technologies will be delisted after expiry of the agreement and eventually harm patient access, if there is no comprehensive risk management plan in place, in case of delisting [42].

The findings arising from this study suggest that presence of a MEA per se may not always guarantee a favourable funding decision and/or faster access to oncology medicines. There are additional HTA decision-making variables which determine the final reimbursement decision and the time taken to final decision. More precisely, this study highlights that successful and timely access to oncology therapies is also subject to submission of clinical evidence which presents with minimal uncertainties and is primarily based on clinically relevant instead of surrogate endpoints. Literature has also underscored the importance that HTA decision-makers place on submitting evidence with clinically meaningful outcomes relating to mortality, morbidity, and quality of life [43]. Even though the use of surrogate measures in cancer medicines’ trials is not associated with an HTA decision to reject a medicine [44], a gap between the surrogate endpoint and the final clinical endpoint creates additional uncertainty for decision-makers. Consequently, in this case, decision-makers often need to engage in additional validation processes to extrapolate findings beyond the submitted evidence to estimate the expected true benefits for patients and health systems, and this translates in further delays on the time required to reach a final reimbursement decision [45, 46].

Additionally, it was demonstrated that uncertainties around the study design had a statistically significant contribution in the model explaining time to final reimbursement decision. This was not surprising given that the trial design is often taken into consideration by some HTA agencies, such as SMC where for example, an active-controlled trial is preferred over a placebo one [47]. In the generalised linear model, the “study design uncertainties” variable was negatively associated with time, potentially demonstrating that this specific type of clinical uncertainty might lead to a confident, outright rejection and thus, shorten time to decision-making. This is in alignment with the results presented elsewhere [30], demonstrating that the presence of clinically relevant uncertainties is not typically associated with the flexibility to enter into negotiations for restricted reimbursement.

Finally, it was demonstrated that time to final funding decision can also be influenced by the HTA agency involved in the decision-making process. In our study, the Australian and Scottish HTA agencies exhibited significantly shorter timelines to final funding decision compared to the Swedish and English agencies. Comparable findings have been reported elsewhere. For example, a study assessing the delays introduced by HTA processes across countries in their coverage decisions for oncology medicines, showed that in England median time from EMA regulatory approval date to NICE decision was 783 days, as opposed to an average of 231 days required for SMC decisions [48]. Similarly, more recent figures estimated the mean length of time from EMA authorization to HTA funding decision for oncology and all products at 436 and 335 days respectively for NICE, compared to for example 389 and 262 days respectively for TLV [49]. Overall, it has been reported that NICE exhibits relatively higher timelines to final funding decision compared to other European HTA agencies [49]. On the contrary, as demonstrated in this study, Australia has been reported to have the fastest median timelines from TGA approval to HTA recommendation at national level (127 days) compared to other jurisdictions, including England (386 days), Scotland (293 days) and Sweden (217 days) [50].

Relevant literature suggests that these differences in time to decision-making are shaped by agency specific characteristics and procedures. Specifically for oncology medicines, evidence demonstrates that divergent HTA methodologies across countries underline differences in the time required for new products to enter the market when considering the average time between date of regulatory approval and date of funding decision [51]. For example, since 2011, the TGA/PBAC parallel process has been introduced in Australia and this played an important role in streamlining the regulatory and reimbursement processes, leading to a significantly shortened time gap between marketing authorisation and first funding decision [50, 52]. On the contrary, in England, delays may often occur due to NICE specific modalities such as switching to the Cancer Drugs Fund during the review process [53]. Additionally, in England, time delays due to NICE procedures related specifically to MEA implementation processes have been reported. For example, the PAS Liaison Unit (PASLU) process may delay submissions to NICE, whereby specifically for Single Technology Appraisals the existence of a PAS can result in an average time delay of up to four months compared to Multiple Technology Appraisals with a PAS [53, 54]. In other markets, there is greater flexibly in the negotiation of these agreements with the result that this can eventually accelerate the decision-making process [55], such as in Italy where presence of an agreement typically leads to shorter time to patient access [12, 22]. The above further highlights that time delays associated with the presence of MEAs can be attributed to agency specific procedures for the implementation and negotiation of MEAs [56].

This is the first study to date to conduct a post-implementation evaluation of MEAs across countries, to quantify their impact on two key healthcare system policy goals, namely availability of and timely access to medicines. Since the on-going literature debate on the weaknesses of MEAs is primarily generated by the poor and inconclusive evidence as to whether these agreements have managed to meet their objectives, this study addresses important literature gaps on structured, impact assessment studies of MEAs. More importantly, the conclusions arising from this study can facilitate future policy relevant research around the sustainability of MEAs as an effective funding modality that can be applied for greater and faster access to medicines. Another strength of this study is the holistic approach taken in studying the HTA factors that determine coverage decision outcomes and timelines, whereby we accounted for the role of MEAs as well as the interconnected impact of both uncertainties, SVJs and clinical evidence characteristics, as opposed to existing literature that studies the impact of evidentiary uncertainties or MEAs individually.

Our study is not without limitations. First, accuracy of the models performed would have benefited from a larger sample size; although this study provides a good basis for future analyses, it is recommended that replication of similar analyses in the future could increase the sample size, possibly by including assessments of medicines for other therapeutic areas.

Third, accounting for the reversibility of negative to positive funding decisions as a proxy to availability of medicines is an assumption made for the purposes of simplicity in running the binary logit model. This assumption is a potential limitation of the analysis, since a positive reimbursement decision does not always translate in equal availability of the respective medicine; beyond a favourable funding decision other, macro-economic, country specific and healthcare system specific factors determine the actual availability of and patient access to medicines [55]. Similarly, accounting for the time to final funding decision as a proxy to timely access to medicines was an assumption made for simplicity in running the generalised linear model. This is also a potential limitation of our study, given that (as described above) a positive reimbursement decision does not always reflect ready access to the respective medicine, regardless of how promptly the funding decisions might have been reached. Finally, in the above context, it is also important to recognise that binding HTA outcomes (e.g., Sweden) typically correspond to funding decisions, whereas non-binding HTA outcomes (e.g., England, Scotland, Australia) correspond to recommendations, which are not always translated into funding decisions. However, given that the (non-binding) HTA recommendations in England, Scotland and Australia have been found to largely shape the final funding decisions in these countries [57], we treated the HTA outcomes across all study countries as “funding decisions”; based on that, the terms “recommendation”, “decision” and “decision outcome” all refer to “funding decisions” and have been used interchangeably throughout the text.

Finally, none of the MEAs included in this analysis were implemented across multiple indications of a specific molecule and/or were part of a MYMI agreement. As such, we acknowledge that in our impact assessment study we do not account for and/or explicitly discuss the potential benefits in patient access arising from the novel approach of applying MEAs across multiple indications and years. This approach arises as an increasingly promising strategy to achieve faster and broader patient access by reducing the administrative burden associated with conducting the same upfront evaluation process for each indication of the same product, while aligning price to the value that the product offers for each indication without the need for indication-based pricing [58]. Nevertheless, the introduction of MYMI agreements is also subject to country specific legal arrangements which can contribute to unnecessary delays in the negotiation process. Therefore, understanding the extent to which MYMI agreements can enhance the positive impact of traditional MEA mechanisms on greater and more timely access to medicines, especially in oncology, arises as a priority topic for future impact assessment studies on MEAs.

Despite the application of MEAs being heterogenous across countries and often associated with high administrative burden and potential time delays, MEAs can still contribute to enhanced accessibility at the level of individual countries by allowing patient access to medicines that would not be reimbursed otherwise. However, presence of a MEA itself does not necessarily grant a timely and favourable funding decision as other factors such as the quality of clinical evidence submitted, and the type of endpoint used therein are also paramount in shaping the final funding decision and the respective timelines to decision-making. Of course, even though MEAs offer a higher likelihood for positive reimbursement, the question remains on whether the technologies approved with a MEA add true value in outcomes for patients and healthcare systems, whether they truly address the decision-making uncertainties characterising a technology and whether outcomes-based schemes measure meaningful clinical markers from the payers’ and patients’ perspective. Overall, it arises that only if applied strategically, MEAs can become a mainstay in the future of medicine availability, in reducing the financial burden for healthcare systems and in allowing faster access to new, innovative medicines.