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

BACKGROUND: Most 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. METHODS: Six 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. RESULTS: Different 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. DISCUSSION: The 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.

Shining a light in the black box of orphan drug pricing.

BACKGROUND: The 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. METHODS: Annual 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. RESULTS: Repurposed 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. CONCLUSIONS: This 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.

Clinical evidence for orphan medicinal products-a cause for concern?

BACKGROUND: The difficulties associated with organising clinical studies for orphan medicinal products (OMPs) are plentiful. Recent debate on the long-term effectiveness of some OMPs, led us to question whether the initial standards for clinical evidence for OMPs, set by the European Medicines Agency (EMA) at the time of marketing authorization, are too low. Therefore, the aim of this study was to quantitatively evaluate the characteristics and quality of clinical evidence that is presented for OMPs to obtain marketing authorization in Europe, using the new and validated COMPASS tool. METHODS: We quantitatively assessed the characteristics and quality of clinical evidence of the pivotal studies of 64 OMPs as described in the European Public Assessment Report and/or the Scientific Discussion document prepared by the Committee for Human Medicinal Products of the EMA. RESULTS: The 64 OMPs were altogether authorized for 78 orphan indications, for which 117 studies were identified as 'pivotal' or 'main' studies. In approximately two thirds of the studies, the allocation was randomized (64.8%) and a control arm was used (68.5%). Half of the studies applied some type of blinding. Only a minority (26.9%) of the studies included a Quality-of-Life (QoL) related endpoint, of which a third claim an improvement in QoL. Upon analyzing the quality of reporting, we found that some aspects (i.e. the endpoints, the sampling criteria, and the interventions) are well described, whereas other items (i.e. a description of the patients and of potential biases) are not reported for all studies. CONCLUSIONS: In conclusion, the pivotal studies that are the basis for marketing authorization of OMPs are a cause for concern, as they exhibit methodological flaws i.e. the lack of QoL-related endpoints as outcome, lack of blinding in the study design and the use of surrogate endpoints. Additionally, there are shortcomings in the reporting of those studies that complicate the interpretation. A more demanding regulatory process for OMPs is needed to guide evidence-based clinical decision-making.

Ethical, legal and social implications of rare diseases and orphan drugs in Europe: meeting report of a Brocher symposium.

Ethical, legal and social implications of rare diseases and orphan drugs in Europe (Brocher symposium) Geneva, Switzerland 18-19 April 2013 As part of the Scientific Program of the Fondation Brocher, a two-day symposium on orphan drugs and rare diseases was held on the shores of Lac Léman in Geneva. Specific focus was on the ethical, legal and social implications of rare diseases and orphan drugs in Europe. The symposium gathered about 30 international stakeholders and experts, representing different scientific disciplines, the pharmaceutical industry and patient representatives.

Development and validation of COMPASS: clinical evidence of orphan medicinal products - an assessment tool.

BACKGROUND: Rare diseases are defined as life-threatening or chronically debilitating diseases with a prevalence of 50 out of 100,000 individuals or less. Orphan medicinal products (OMPs) are intended for the treatment of rare diseases. The assessment of quality of evidence in small populations is often complex. Many generic tools are unfit. Therefore, the aim of this study was to develop and validate a new tool to assess the quality of OMPs' clinical evidence (COMPASS). METHODS: Firstly, a draft version of the COMPASS tool, developed by the authors and consisting of three parts, was amended based on suggestions obtained in four rounds of expert consultation. Secondly, the tool was put through three rounds of validation. The data source was information provided on the Orphanet website and in European Public Assessment Report (EPAR) document of the European Medicines Agency. RESULTS: The first pilot round revealed a high (92.2%) inter-rater agreement for part one of the tool. After further improvements, the final inter-rater agreement was 86.4% for part two (on methodological quality) and three (on quality of reporting) of the tool. The COMPASS tool does not attempt to score or rank the quality of clinical evidence, but rather to give an outline of various, key elements with respect to quality of clinical evidence of OMP studies. CONCLUSIONS: The COMPASS tool can be applied to assess the quality of evidence of an OMP based on information in the registration dossier, for example by local reimbursement agencies, pharmacists or clinicians. In that way, the tool can contribute to making reimbursement and/or treatment decisions increasingly more founded on the principles of evidence-based decision making.

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.

Orphan drugs for rare diseases: is it time to revisit their special market access status?

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 Euros [interquartile range; IQR 406.57 Euros]) than non-designated drugs (16.55 Euros [IQR 28.05 Euros]) 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.