Access to orphan drugs in western Europe: can more systematic policymaking really help to avoid different decisions about the same drug?

Abstract

When the Scottish government recently launched a £21 million fund to provide patients with rare diseases access to treatment, Alex Neill, the Scottish Health Secretary, stated that ‘it was only right that Scottish patients with rare conditions had access to innovative medicines which were clinically justified, and that they were not disadvantaged due to the very high cost of these treatments’. This statement raises questions about the criteria that play a role in reimbursement decisions on orphan drugs. This editorial examines the criteria that were used in the decisions about the reimbursement of an orphan drug for Pompe disease and explores methods to improve the transparency and consistency of reimbursement decisions for orphan drugs in general.

Keywords:

• access
• multi-criteria decision analysis
• orphan drugs
• Pompe disease
• reimbursement

Orphan drugs/enzyme replacement therapies

Orphan drugs are drugs for rare diseases, and the number of orphan drugs available on the market is increasing [1]. The reimbursement of these drugs is often a dilemma for decision-makers because the treatment costs per patient are generally much higher than for non-orphan drugs.

Examples of orphan drugs are enzyme replacement therapies (ERTs), which are therapies for metabolic diseases. Examples of ERTs are laronidase for mucopolysaccharidosis I, idursulfase for mucopolysaccharidosis II, and agalsidase alfa and beta for Fabry disease. These therapies are associated with high costs, with annual costs ranging from €200,000 to 600,000 per patient [2].

The case of Pompe disease & ERT in the Netherlands

Alglucosidase alfa is an ERT for the treatment of Pompe disease, a rare metabolic disease (1 per 40,000) with two distinct forms (classic-infantile and late-onset). Without treatment, patients with the infantile form will not survive their first year of life. Adult patients can survive until their 60s or 70s, but their average life expectancy is still much shorter than in the general population [3]. Patients with Pompe disease have a health-related quality of life (hrQoL) of 0.72 (based on the Euroqol 5D), which is lower than the Dutch average of 0.87 [4]. In the past, only the symptoms of the disease (particularly muscle weakness and reduced respiratory function) could be treated. However, about 10 years ago, the introduction of alglucosidase alfa gave patients and their families hope that their disease could finally be treated effectively. The Dutch government added alglucosidase alfa to a newly made positive list of orphan drugs which were temporarily reimbursed (i.e., for 4 years), conditional on collecting additional evidence of the real-world effectiveness and cost–effectiveness in the Netherlands. After 4 years, the reimbursement dossier informing the re-assessment was submitted to the Health Care Insurance Board (College voor Zorgverzekeringen [CVZ]), which advised the Ministry of Health. At the time of re-assessment, there was evidence that ERT dramatically improved life expectancy of infantile patients [5] and improved muscle strength and respiratory function in adult patients [6]. There were also indications that ERT may improve survival in adult patients, but little was known about its effect on hrQoL [7]. Ultimately, CVZ found that there was sufficient evidence that ERT increased survival in infants but limited evidence regarding its effectiveness in adults. Partly due to the substantial costs of ERT, the incremental cost–effectiveness ratios (ICERs) of ERT versus no ERT (i.e., symptom management) were high (infants: €900,000 per QALY gained; adults: €15 million per QALY gained); adults: €15 million per QALY gained). When the reimbursement dossier was submitted, there were 113 patients with Pompe disease in the Netherlands, 92 of whom received ERT (2009 data) and the annual budget impact of treating all eligible patients was €41 million.

In the summer of 2012, the preliminary recommendation by CVZ on the reimbursement of ERT leaked to the press, who gave much attention to CVZ’s recommendation to reimburse ERT only for the infantile form of Pompe disease. However, following a storm of criticism, the Health Minister began price negotiations with the manufacturer. This resulted in what was called a ‘substantial’ price reduction of the drug, but the actual size of the discount was kept confidential. In October 2013, the minister announced that ERT was to be reimbursed for all patients, both infants and adults.

The status of ERT for Pompe disease in other countries

In Scotland, a reimbursement dossier was submitted to the Scottish Medicines Consortium (SMC) and was evaluated in 2007 [8]. The SMC concluded that ERT increases survival for infants, but concluded that its effectiveness among adults was not yet established. The cost-effectiveness ratios were £244,000–318,000 per quality adjusted life year (QALY) gained for infantile patients and £819,000 per QALY gained for adults. The SMC concluded that the economic case supporting reimbursement was not sufficiently demonstrated. The annual budget impact of treating all patients was estimated to be £2.8 million. The SMC did not recommend reimbursement for either patient group.

In Wales, ERT is reimbursed for infants but not for adults due to limited evidence on clinical effectiveness [9]. Treatment is reimbursed for juvenile patients with the late-onset form.

In England, various ERTs, including ERT for Pompe disease, have been funded through a specific policy agreement since 2008 [10]. Patients are treated according to a clinical protocol with clear start and stop criteria, and only receive treatment in designated treatment centers.

In France, the Transparency Committee concluded in 2006 that ERT had a substantial benefit in the treatment of the infantile form of the disease, leading to a positive reimbursement decision [11]. For late-onset patients, the committee concluded that the benefit was insufficient in the absence of a formal demonstration of efficacy. The committee re-assessed the therapy in 2010 on the basis of new evidence, concluding that there was a minor benefit from ERT. Consequently, the committee recommended an annual assessment of the effects of ERT in late-onset patients. A re-assessment in 2012 yielded the same recommendations. The committee wants to be informed about the reason of discontinuation when a patient’s treatment is stopped.

In Italy, ERT was placed on the national formulary in 2006 for infantile and late-onset patients with Pompe disease [12].

ERT is reimbursed in Belgium for both infantile and late-onset patients [13].

Multi-criteria decision analysis

The example of ERT in Pompe disease illustrates the great variability in reimbursement decisions of orphan drugs between European countries. This is not an isolated case; similar differences between countries have been observed for other orphan drugs [14]. One could argue that all countries with a centralized reimbursement system make decisions in two steps: first by gathering the necessary information (the assessment phase) and then making a decision (the appraisal phase). The observed differences in reimbursement decisions might result from differences between countries in both phases.

In the assessment phase, the evidence on efficacy is unlikely to differ between countries. For Pompe disease, the various countries, indeed, based their conclusions on the same efficacy studies (e.g., AGLU 1602 for infantile patients [15]; AGLU 2804 for late-onset patients [16]). However, data on incidence and prevalence of the disease, severity distribution, treatment patterns, drug prices, absolute and relative treatment costs, budget impact and/or cost–effectiveness may vary considerably. Country-specific cost–effectiveness studies are, therefore, required to reflect these differences.

In the appraisal phase, the available evidence is weighted and additional criteria and societal preferences come into play. The criteria used in the reimbursement decisions and their corresponding weights differ internationally, contributing to differences in judgments between countries. In the case of Pompe disease, equity considerations such as the right of equal access to innovative drugs for patients with rare diseases may play a role. Perhaps, decision-makers are willing to accept higher cost–effectiveness ratios to compensate for the fact that the society has neglected rare diseases and failed to develop treatments for them. The life-threatening nature of infantile Pompe disease, which leads to babies dying during their first year of life, is a crucial factor in decision-making. There is, indeed, evidence from stated preference studies that concepts such as ‘fair innings’ [17] and ‘the rule of rescue’ [18] are considered relatively important when people are asked to choose between different treatments [19].

Currently, we do not know how much the differences in reimbursement decisions between countries result from differences in the assessment and appraisal phase. This is because transparency in decision-making is lacking; we neither know which criteria are used in reimbursement decisions nor know how these are weighted and traded off against each other. If transparency is truly desired, an alternative framework for decision-making is needed. Multi-criteria decision analysis (MCDA) provides an explicit and systematic way of using various criteria to inform decision-making [20]. MCDA may support the justification and communication of reimbursement decisions to the public, as these reimbursement decisions result from a transparent and reproducible process. However, the pathway to MCDA requires a sufficient understanding of the criteria and their relative weights. Furthermore, we have to realize that the proper use of MCDA will not necessarily lead to identical reimbursement decisions across countries. For one thing, different criteria might be used in different countries. But even if the same criteria were to be used, differences might still persist, because criteria weights may be country-dependent, partly reflecting differences in how strongly policymakers and the general public feel about the equity considerations mentioned above. As the one-Incremental cost-effectiveness ratio-fits-all paradigm slowly fades and a new MCDA one slowly emerges, more research is needed for a better understanding of its consequences in various fields, including reimbursement decisions about orphan drugs.

Financial & competing interests disclosure.

This study was financially supported by the Netherlands Organization for Health Research and Development (ZonMw; grant no. 152002045). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.