Eline Picavet

Cost-Effectiveness Assessment of Orphan Drugs

In September 2012, the Dutch Healthcare Insurance Board issued advice not to reimburse orphan drugs that target lysosomal storage disorders: agalsidase alfa and agalsidase beta for Fabry disease and alglucosidase alfa for Pompe disease [1, 2].With respect to the former, the Healthcare Insurance Board concluded that enzyme replacement therapy offered an added therapeutic value compared with symptomatic treatment of Fabry disease [1]. However, enzyme replacement therapy was not cost effective at an incremental cost of euro3.3 million per quality-adjusted life-year gained. The unfavourable cost effectiveness originated from the limited additional therapeutic value (as a result of the slow progression of the disease) and high costs: enzyme replacement therapy costs euro200,000 per patient per year, resulting in a total budget impact of euro11 million per year for the Netherlands. The Healthcare Insurance Board argued that continued reimbursement of enzyme replacement therapy for Fabry disease would imply that limited resources are not available to reimburse other, more cost effective health technologies.With respect to the latter, the Healthcare Insurance Board recommended to restrict reimbursement of alglucosidase alfa for Pompe disease to patients who suffer from the classic form of the disease and to patients who show symptoms of the (non-)classic disease during their infancy [2]. Alglucosidase alfa was found to generate an added therapeutic value over best supportive care, was cost effective at an incremental cost of euro0.3-0.9 million per quality-adjusted life-year gained in the classic form of Pompe disease, but was not cost effective at an incremental cost of euro15 million per quality-adjusted life-year gained in the non-classic form of Pompe disease. The annual cost of treating a patient with alglucosidase alfa amounted to euro0.4-0.7 million.1 A Scientific ConundrumThese two examples highlight some of the scientific challenges involved in assessing the cost effectiveness of orphan drugs.Uncertainty tends to surround the safety and effectiveness of orphan drugs at the time of market launch. This clinical uncertainty may result from difficulties involved in recruiting a sufficient number of patients across countries, the lack of randomized controlled trials, and the use of surrogate efficacy measures [3]. As a result, there is an urgent need for the development of methodological guidelines about the assessment of the (cost) effectiveness of orphan drugs for (ultra-)rare diseases. In England and Wales, the National Institute for Health and Clinical Excellence (NICE) will be responsible for assessing orphan drugs from April 2013 onwards and has committed itself to developing methods to guide such an assessment [4].Dutch physicians who are involved in treating patients with these lysosomal storage disorders have argued that the Healthcare Insurance Board is not able to issue an informed advice due to the lack of long-term data on safety and effectiveness [5]. For instance, on the occasion of the public hearing of the Dutch Healthcare Insurance Board on 21 September 2012, Professor Hollak stressed that the main challenge with enzyme replacement therapy is that effectiveness is different across patient subgroups [6]. While a clear benefit was shown in some patients, in others, such as those with end-renal or cardiac disease, a lesser benefit was observed. No conclusions can nonetheless be drawn as the overall amount of data remains too small, resulting from the low number of Dutch patients. To address this issue, the idea has been proposed to launch a compulsory Europeanwide registry following marketing authorization of an orphan drug [5]. The establishment of such registries for rare diseases is supported by the European Medicines Agency and by many member states, although registries are not without methodological limitations [3].The ethical principle underlying economic evaluation is that scarce resources are allocated to the most cost-effective health technologies with a view to maximizing population health. …

Orphan Drugs for Rare Diseases

Orphan drugs are intended for diseases with a very low prevalence, and many countries have implemented legislation to support market access of orphan drugs. We argue that it is time to revisit the special market access status of orphan drugs. Indeed, evidence suggests that there is no societal preference for treating rare diseases. Although society appears to assign a greater value to severity of disease, this criterion is equally relevant to many common diseases. Furthermore, the criterion of equity in access to treatment, which underpins orphan drug legislation, puts more value on health improvement in rare diseases than in common diseases and implies that population health is not maximized. Finally, incentives for the development, pricing and reimbursement of orphan drugs have created market failures, including monopolistic prices and the artificial creation of rare diseases. We argue that, instead of awarding special market access status to orphan drugs, there is scope to optimize research and development (R&D) of orphan drugs and to control prices of orphan drugs by means of, for example, patent auctions, advance purchase commitments, pay-as-you-go schemes and dose-modification studies. Governments should consider carefully the right incentive strategy for R&D of orphan drugs in rare diseases.

Drugs for rare diseases: influence of orphan designation status on price.

The literature indicates that the expenditure on orphan drugs will be increasing over the coming years. The market for orphan drugs has inherent market characteristics that sometimes result in high prices. The aim of this study was to analyse whether awarding orphan designation status has an influence on the price setting of drugs for rare disease indications. To this effect, prices of designated orphan drugs were compared with other non-designated drugs for rare disease indications. We identified 28 designated orphan drugs and 16 comparable non-designated drugs for rare disease indications for which we collected official hospital prices (per defined daily dose) in Belgium in 2010. Orphan-designated drugs had a higher median price (€138.56 [interquartile range; IQR €406.57]) than non-designated drugs (€16.55 [IQR €28.05]) for rare disease indications (p < 0.01). In conclusion, our results suggest that awarding orphan designation status in itself is associated with higher prices for drugs for rare disease indications. In order to gain full insight into orphan drug pricing mechanisms, future research should focus on collecting information about the different factors influencing orphan drug pricing.

Shining a light in the black box of orphan drug pricing

BackgroundThe pricing mechanism of orphan drugs appears arbitrary and has been referred to as a “black box”. Therefore, the aim of this study is to investigate how drug- and disease-specific variables relate to orphan drug prices. Additionally, we aim to explore if certain country-specific pricing and reimbursement policies affect the price level of orphan drugs.MethodsAnnual treatment costs per indication per patient were calculated for 59 orphan drugs with a publicly available price in Belgium, the Netherlands, Czech Republic, France, Italy and the United Kingdom. A multiple linear regression model was built with 14 drug- and disease-specific variables. A Mann-Whitney U test was used to explore whether there is a correlation between annual treatment costs of orphan drugs across countries with different pricing and reimbursement policies.ResultsRepurposed orphan drugs, orally administered orphan drugs or orphan drugs for which an alternative treatment is available are associated with lower annual treatment costs. Orphan drugs with multiple orphan indications, for chronic treatments or for which an improvement in overall survival or quality-of-life has been demonstrated, are associated with higher annual treatment costs. No association was found between annual treatments cost of orphan drugs across countries and the different pricing and reimbursement systems.ConclusionsThis study has shown that prices of orphan drugs are influenced by factors such as the availability of an alternative drug treatment, repurposing, etc. Current debate about the affordability of orphan drugs highlights the need for more transparency in orphan drug price setting.

Market uptake of orphan drugs - a European analysis

What is known and Objective:  Variations in market uptake of an orphan drug have important implications with respect to access to care and inequality of treatment. Therefore, the aim of this study was to quantify both the sales and volume uptake of orphan drugs in Europe and to assess whether a country’s gross domestic product (GDP) and/or health technology assessment (HTA) influences the orphan drugs’ market uptake.

Orphan Drugs for Rare Diseases: Grounds for Special Status

Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I‐III Regulatory, Quality, Manufacturing Postmarketing Phase IV

Reimbursement of orphan drugs in Belgium: what (else) matters?

BackgroundMost orphan drugs do not meet traditional standards of cost-effectiveness. Yet, most orphan drugs are reimbursed, which implies that other factors are taken into account at the time of reimbursement. To increase accountability of decision-makers, there is a need for more transparency in the factors that play a role in reimbursement decisions of orphan drugs. Therefore, the aim of this study is to use a combination of qualitative research methods to examine which official and non-official factors influence reimbursement decisions for orphan drugs in Belgium.MethodsSix semi-structured interviews with past or present members of the Drug Reimbursement Committee (DRC) were performed with a view to obtaining an overview of the potential factors influencing reimbursement. Additionally, these presence of these factors was assessed in the reimbursement dossiers of all orphan drugs (n = 64) for which an application for reimbursement was submitted to the National Institute for Health and Disability Insurance in Belgium between January 2002 and July 2013.ResultsDifferent official (i.e. therapeutic value, budget impact, price and impact in clinical practice) and non-official factors (i.e. pricing and reimbursement in other countries, interference by patient organisations and experts, arguments related to quality of branded drug versus compounding, media attention, innovative character, economic importance, ethical arguments and the political climate) may have influenced past reimbursement decisions for orphan drugs in Belgium.DiscussionThe identification of factors influencing orphan drug reimbursement is a crucial step in the development of a transparent and consistent framework which will guide future decision-making for reimbursement of orphan drugs.

Evaluating and improving orphan drug regulations in Europe: A Delphi policy study

To encourage the development of orphan drugs, the European Union has implemented specific policies in 2000. However, the political, social, scientific and economic context has changed since the implementation of these policies. For that reason, the aim of this article is to evaluate orphan drug policies in Europe. Firstly, key issues on the orphan drug policy were identified based on desk research. Secondly, a Delphi policy study with 47 European orphan drug experts from different backgrounds was carried out to explore these issues. In the round one of the Delphi, responses were received from 18 experts (38.3%) and from ten (55.5%) in the round two. Experts agree that the orphan drug policies in Europe have not outlived their usefulness. Additionally, the importance of reducing country-dependent inequalities in patient access to orphan drugs has been emphasized. Still, there is room for further refinement of the orphan drug policies. Within that context, we formulated several policy recommendations (e.g. enforcing the policy that is in place to reduce the period of market exclusivity for profitable orphan drugs, stating the level of clinical evidence needed to authorize orphan drugs, etc.) with the overall goal to optimize patient access to orphan drugs.

Regulatory watch: The orphan drug pipeline in Europe

The European framework for orphan medicinal products offers a range of incentives to encourage the development of medicinal products for the treatment of rare diseases. To qualify for these incentives, sponsors must obtain — at any stage of development — orphan designation status from the European Medicines Agency (EMA) by fulfilling a set of criteria (see Supplementary information S1 (box)). Once designation is granted, sponsors are required to submit annual reports to the EMA summarizing progress in development. However, little is known about the current state of development of the orphan designations (ODs) that have not yet obtained marketing authorization. With this in mind, we analysed the orphan drug pipeline in Europe by reviewing the active ODs granted between 2002 and 2012 for which an annual report was available in 2013 or 2014. For each OD, data related to the latest completed study, target therapeutic area and sponsor type were collected. We also applied standard success rates for each development phase to our dataset to estimate the number of ODs that may receive marketing authorization (see Supplementary information S1 (box) for details of the dataset and analysis). Between 2002 and 2012, our sample of ODs (n = 605) was spread across a portfolio of 21 therapeutic areas (FIG. 1a), suggesting that translation of rare disease research into product development and healthcare innovation is happening across an increasing number of diseases — notably R E G U L ATO RY WAT C H

Are some orphan drugs for rare diseases too expensive? A study of purchase versus compounding costs

Hospital purchase prices substantially exceed compounding production costs in Belgium for selected orphan drugs that had low costs of research and development and market access procedures. As a result, healthcare payers seem to be paying too much for these orphan drugs and there are arguments for price reductions. Pharmacies can consider compounding, rather than purchasing, these orphan drugs.