This project carries out an analysis of market access of orphan drugs for rare diseases. In the European Union (EU), orphan drugs are intended for the diagnosis, prevention or treatment of rare diseases. These rare diseases are life-threatening or chronically seriously debilitating conditions affecting no more than five in 10,000 persons in the EU. Worldwide, policies are available to stimulate the development and marketing of orphan drugs. Such policies serve to compensate industry for the risks and lower potential return on investment due to the low number of patients. Part 1 of this project, the general introduction, provides the definitions and background related to orphan drugs and rare diseases and presents an overview of the different steps of market access of orphan drugs in the EU. The contents of this project reflect these steps, i.e. orphan designation and marketing authorization are discussed in part 2, pricing is discussed in part 3, reimbursement in part 4 and uptake in part 5. The general introduction also provides an overview of the arguments for and against attributing special status to orphan drugs. Studies on the registration of orphan drugs are reported in part 2. An evaluation of the orphan drug policies in the EU by orphan drug experts is provided in chapter 2.1. Experts perceive the orphan drug policies in the EU as useful. Within the context of continuing to optimize patient access to orphan drugs, several policy recommendations were formulated such as defining the concept of sufficiently profitable in the context of reducing the period of market exclusivity for highly profitable orphan drugs, determining the level of clinical evidence needed to authorize orphan drugs, etc. Chapter 2.2 describes the development and validation of a new tool, COMPASS, to assess the quality of orphan drugs clinical evidence presented for orphan drugs at the time of marketing authorization. The tool was drawn up based on elements derived from existing checklists supplemented with items specifically related to rare diseases and orphan drugs as recommended by six experts. The COMPASS tool can for example be used by local reimbursement agencies for the review of clinical evidence in orphan drug registration dossiers or by clinicians and pharmacists upon considering a (new) orphan drug treatment.The COMPASS tool was used in chapter 2.3 to quantitatively evaluate the characteristics and quality of pivotal studies presented for orphan drugs authorised in the EU before July 1st, 2012. These studies were found to exhibit methodological flaws such as lack of blinding in the study design, lack of QoL-related endpoints as outcome, use of surrogate endpoints, etc. Additionally, there were important shortcomings in the reporting of those studies, which further complicates the interpretation of the clinical evidence. This study shows that a more demanding regulatory process for orphan drugs is needed.Studies on the pricing of orphan drugs are reported in part 3. The influence of orphan designation status on prices of drugs for rare indications is demonstrated in chapter 3.1. The analysis showed that the median price per defined daily dose was higher for drugs with an orphan designation (138.56) than for drugs without an orphan designation used for rare indications (16.55). Chapter 3.2 provides several examples of repurposed drugs for rare indications for which the effectiveness evidence was published prior to the application for orphan designation status. Upon comparing Belgian hospital prices per defined daily dose of selected drugs for common diseases with the price of repurposed drugs for the rare disease indication, differences of up to 200 fold were reported. This pricing practice adds to the budget impact of treating rare diseases. An overview of the international scientific literature on the drivers of pricing of ultra-orphan drugs in described in chapter 3.3. Ultra-rare diseases constitute an informal subcategory, within rare diseases, to describe very rare diseases (i.e. occurring in less than one per 50,000 individuals). The pricing process of ultra-orphan drugs is a complex and non-transparent issue. Evidence in the literature seems to indicate that ultra-orphan drugs are priced based on rarity of the indication and the number of available alternatives.Chapter 3.4 shows how various drug- and disease-specific variables relate to annual treatment costs per patient and per orphan drug indication in six EU Member States. Additionally, it was investigated if certain country-specific pricing and reimbursement policies affect the price level of orphan drugs. 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. Current debate about the affordability of high-priced orphan drugs highlights the need for more transparency in orphan drug price setting.The topic of reimbursement of orphan drugs is discussed in part 4. Because of their high price and difficulties in demonstrating effectiveness, orphan drugs are often perceived as not able to provide value for money. In chapter 4.1 an overview of the evidence on the value for money of orphan drugs is given. Results show that orphan drugs can provide value for money. Considering a threshold of £30,000 per quality-adjusted life years (QALY) (i.e. threshold for reimbursement applied in England and Wales) ten out of a total of nineteen orphan drugs for which data was available, offer value for money.Factors other than cost-effectiveness are also taken into account at the time of reimbursement In chapter 4.2 qualitative research methods were applied to establish that various official (i.e. therapeutic value, budget impact, price and impact in clinical practice) and non-official (i.e. pricing and reimbursement in other countries, interference by patient organisations and experts, arguments related to quality of pharmaceutical compounding, media attention, innovative character, economic importance, ethical arguments and the political climate) factors might influence reimbursement decisions for orphan drugs in Belgium. The identification of these factors is crucial in the development of a transparent and consistent framework which will guide future decision-making for reimbursement of orphan drugs.A study on the uptake of orphan drugs is reported in part 5. Chapter 5.1 shows that the uptake of orphan drugs varies across EU Member States. The highest volumes of orphan drugs in the first year occurred in Member States with a high gross domestic product (GDP) and implicitly, a higher budget for health care, independently of the existence of a formal health technology assessment (HTA) organisation. In contrast, in countries with a low GDP, orphan drugs were less available in countries with a formal HTA-organisation. There, budgetary restrictions can cause the exclusion of less cost-effective orphan drugs. These variations have important implications with respect to access to orphan drugs. Recommendations for a sustainable orphan drug market are proposed in the general discussion in part 6. These recommendations relate to one (or more) of the steps of market access. Several recommendations to improve quality of clinical evidence (for instance by setting trial standards imposing the use of at least one hard endpoint) are formulated. Furthermore, to capture what is valued by patients, patient(s) (organizations) should be able to provide input in an early stage on what endpoints should be considered when developing a new drug for a rare disease. Development of new orphan drugs can be improved by adopting a public-private partnership approach for orphan drug development. Patient registries are an important tool to gather knowledge about the natural course of a rare disease and/or the long-term effectiveness of an orphan drug. Long-term data is required for marketing authorization and to guide reimbursement decisions. Recommendations relating to pricing of orphan drugs include measures to increase transparency in orphan drug pricing, a proposal to prescribe repurposed orphan drugs by international non-proprietary name and a call to revise orphan drug status of sufficiently profitable orphan drugs. Timely access to new orphan drugs can be achieved by implementing managed entry agreements to deal with the uncertainty about cost-effectiveness and by optimizing reimbursement procedures for orphan drugs across EU Member States. Finally, there is a need to define priorities in funding and reimbursement of orphan drugs. Upcoming challenges for the orphan drug pharmaceutical industry are also discussed. For instance, adaptive licensing is expected to reduce the overall cost of development and to have a positive effect on timely access to new drugs. Future research could focus on pricing and budget impact orphan drugs, an issue of continued importance in the aftermath of the financial and economic crisis.