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Patient Access to Medicines for Rare Diseases in European Countries

Open AccessPublished:March 15, 2018DOI:https://doi.org/10.1016/j.jval.2018.01.007

      Abstract

      Background

      The number of authorized orphan and non-orphan medicines for rare diseases has increased in Europe. Patient access to these medicines is affected by high costs, weak efficacy/safety evidence, and societal value. European health care systems must determine whether paying for expensive treatments for only a few patients is sustainable.

      Objectives

      This study aimed to evaluate patient access to orphan and non-orphan medicines for rare diseases in 22 European countries during 2005 to 2014.

      Methods

      Medicines for rare diseases from the Orphanet list, authorized during 2005 to 2014, were searched for in the IMS MIDAS Quarterly Sales Data, January 2005 – December 2014 (IQVIA, Danbury, CT). The following three measures were determined for each country: number of available medicines, median time to continuous use, and medicine expenditure. A medicine was considered available if uninterrupted sales within a 1-year period were detected.

      Results

      From 2005 to 2014, 125 medicines were authorized and 112 were found in the search. Of those, between 70 (63%) and 102 (91%) were available in Germany, the United Kingdom, Italy, France, and the Scandinavian countries. These countries were also the fastest to enable continuous use (3–9 mo). Only 27% to 38% of authorized medicines were available in Greece, Ireland, Bulgaria, Romania, and Croatia, which took 1 to 2.6 years to begin continuous use. A country’s expenditure on medicines for rare diseases in 2014 ranged between €0.2 and €31.9/inhabitant.

      Conclusions

      Patient access to medicines for rare diseases varies largely across Europe. Patients in Germany, Scandinavian countries, Switzerland, France, and the United Kingdom can access larger numbers of medicines in shorter time.

      Keywords

      Rare diseases are usually chronic, life threatening, or chronically debilitating and affect up to 5 in 10,000 people [

      European Medicines Agency. Orphan designation. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp&mid=WC0b01ac0580b18a41. Accessed November 5, 2016.

      ,

      Orphanet. Rare disease registries in Europe. Available from: http://www.orpha.net/orphacom/cahiers/docs/GB/Registries.pdf. Accessed March 2, 2016.

      ,
      • Richter T.
      • Nestler-Parr S.
      • Babela R.
      • et al.
      Rare disease terminology and definitions—a systematic global review: report of the ISPOR Rare Disease Special Interest Group.
      ]. They are often poorly diagnosed and treated [

      European Medicines Agency. Orphan designation. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp&mid=WC0b01ac0580b18a41. Accessed November 5, 2016.

      ,

      European Organisation for Rare Diseases (EURORDIS). About rare diseases. Available from: http://www.eurordis.org/about-rare-diseases. Accessed June 14, 2016.

      ]. Although each rare disease affects only a few individuals, together they affect around 6-8% of the total European population [

      European Medicines Agency. Orphan designation. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp&mid=WC0b01ac0580b18a41. Accessed November 5, 2016.

      ,
      • Richter T.
      • Nestler-Parr S.
      • Babela R.
      • et al.
      Rare disease terminology and definitions—a systematic global review: report of the ISPOR Rare Disease Special Interest Group.
      ,

      Orphanet. The portal for rare diseases and orphan drugs. Available from: http://www.orpha.net/consor/cgi-bin/Education_AboutOrphanet.php?lng=EN. Accessed March 2, 2016.

      ]. Several regulatory and financial incentives have enhanced the research and development of new medicines for rare diseases (e.g., the European Medicines Agency [EMA] orphan designation) [

      European Medicines Agency. Orphan designation. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp&mid=WC0b01ac0580b18a41. Accessed November 5, 2016.

      ,

      European Commission. Regulation (EC) No 141/2000 of the European Parliament and of the Council. Available from: http://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2000_141_cons-2009-07/reg_2000_141_cons-2009-07_en.pdf. Accessed August 23, 2016.

      ,

      Innovative Medicines Initiative. Europe’s partnership for health. Available from: https://www.imi.europa.eu/content/home. Accessed August 23, 2016.

      ]. These incentives have increased the number of authorized medicines for rare diseases [

      European Medicines Agency. Orphan designation. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp&mid=WC0b01ac0580b18a41. Accessed November 5, 2016.

      ,
      • Hughes-Wilson W.
      • Palma A.
      • Schuurman A.
      • et al.
      Paying for the orphan drug system: break or bend? Is it time for a new evaluation system for payers in Europe to take account of new rare disease treatments?.
      ,

      Orphanet. List of medicinal products for rare diseases in Europe. Available from: http://www.orpha.net/orphacom/cahiers/docs/GB/list_of_orphan_drugs_in_europe.pdf. Accessed March 2, 2016.

      ]. In addition to the medicines with the orphan status, other medicines for rare indications that are not designated as orphans have been authorized [

      Orphanet. Rare disease registries in Europe. Available from: http://www.orpha.net/orphacom/cahiers/docs/GB/Registries.pdf. Accessed March 2, 2016.

      ,

      Orphanet. List of medicinal products for rare diseases in Europe. Available from: http://www.orpha.net/orphacom/cahiers/docs/GB/list_of_orphan_drugs_in_europe.pdf. Accessed March 2, 2016.

      ]. The international European portal for rare diseases, Orphanet, provides a complete list of both based on the European Commission’s Community Registers on orphan medicines and medicines suggested for orphan designation [

      Orphanet. List of medicinal products for rare diseases in Europe. Available from: http://www.orpha.net/orphacom/cahiers/docs/GB/list_of_orphan_drugs_in_europe.pdf. Accessed March 2, 2016.

      ].
      Patient access has several interpretations and is determined by several factors, including time to regulatory approval, market availability, or reimbursement; reasons for delays in these times; outcomes of technology appraisals; and conditions of reimbursement, including prescribing restrictions and copayments [

      Orphanet. List of medicinal products for rare diseases in Europe. Available from: http://www.orpha.net/orphacom/cahiers/docs/GB/list_of_orphan_drugs_in_europe.pdf. Accessed March 2, 2016.

      ,
      • Côté A.
      • Keating B.
      What is wrong with orphan drug policies?.
      ,

      European Public Health Alliance. EPHA Briefing Document on Access to Medicines in times of Austerity. Available from: http://v2.epha.org/IMG/pdf/FINAL_EPHA_Briefing_on_Access_to_Medicines.pdf. Accessed June 26, 2016.

      ,
      • Wilson A.
      • Cohen J.
      Patient access to new cancer drugs in the United States and Australia.
      ,
      • Cohen J.
      • Faden L.
      • Predaris S.
      • et al.
      Patient access to pharmaceuticals: an international comparison.
      ,
      • Blankart C.R.
      • Stargardt T.
      • Schreyögg J.
      Availability of and access to orphan drugs: an international comparison of pharmaceutical treatments for pulmonary arterial hypertension, Fabry disease, hereditary angioedema and chronic myeloid leukaemia.
      ]. This study investigates the following three factors of patient access to medicines for rare diseases: how many medicines are available, median time to continuous use, and medicine expenditure.
      The main concerns in providing patient access to these medicines are high cost and often weaker efficacy and safety evidence [
      • Hughes-Wilson W.
      • Palma A.
      • Schuurman A.
      • et al.
      Paying for the orphan drug system: break or bend? Is it time for a new evaluation system for payers in Europe to take account of new rare disease treatments?.
      ,
      • Côté A.
      • Keating B.
      What is wrong with orphan drug policies?.
      ,
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Kanavos P.
      • Nicod E.
      What is wrong with orphan drug policies? Suggestions for ways forward.
      ]. Nevertheless, they have important societal value because they improve patient quality of life and increase highly limited treatment options of a particular rare disease [
      • Kanavos P.
      • Nicod E.
      What is wrong with orphan drug policies? Suggestions for ways forward.
      ,
      • Drummond M.F.
      • Wilson D.A.
      • Kanavos P.
      • et al.
      Assessing the economic challenges posed by orphan drugs.
      ,
      • Gericke C.A.
      • Riesberg A.
      • Busse R.
      Ethical issues in funding orphan drug research and development.
      ]. Different health technology assessment processes and decision-making policies can lead to important differences in access to these medicines among countries [

      European Public Health Alliance. EPHA Briefing Document on Access to Medicines in times of Austerity. Available from: http://v2.epha.org/IMG/pdf/FINAL_EPHA_Briefing_on_Access_to_Medicines.pdf. Accessed June 26, 2016.

      ,
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,

      European Parliament, Directorat-general for internal policies. Differences in costs of and access to pharmaceutical products in the EU 2011. Executive summary. Available from: http://www.europarl.europa.eu/RegData/etudes/etudes/join/2011/451481/IPOL-ENVI_ET(2011)451481_EN.pdf. Accessed June 12, 2016.

      ,
      • Simoens S.
      Pricing and reimbursement of orphan drugs: the need for more transparency.
      ,
      • Denis A.
      • Mergaert L.
      • Fostier C.
      • et al.
      A comparative study of European rare disease and orphan drug markets.
      ]. Nevertheless, each country faces the same decision—whether paying for an expensive treatment for only a few individuals is sustainable [
      • Hughes-Wilson W.
      • Palma A.
      • Schuurman A.
      • et al.
      Paying for the orphan drug system: break or bend? Is it time for a new evaluation system for payers in Europe to take account of new rare disease treatments?.
      ,
      • Côté A.
      • Keating B.
      What is wrong with orphan drug policies?.
      ,
      • Drummond M.F.
      • Wilson D.A.
      • Kanavos P.
      • et al.
      Assessing the economic challenges posed by orphan drugs.
      ,
      • Simoens S.
      Pricing and reimbursement of orphan drugs: the need for more transparency.
      ,
      • Schey C.
      • Milanova T.
      • Hutchings A.
      Estimating the budget impact of orphan medicines in Europe: 2010 - 2020.
      ,
      • Orofino J.
      • Soto J.
      • Casado M.A.
      • et al.
      Global spending on orphan drugs in France, Germany, the UK, Italy and Spain during 2007.
      ,
      • Kanters T.A.
      • Steenhoek A.
      • Hakkaart L.
      Orphan drugs expenditure in the Netherlands in the period 2006-2012.
      ,
      • Logviss K.
      • Krievins D.
      • Purvina S.
      Impact of orphan drugs on Latvian budget.
      ,

      World Health Organization. Access to new medicines in Europe: technical review of policy initiatives and opportunities for collaboration and research 2015. Available from: http://apps.who.int/medicinedocs/documents/s21793en/s21793en.pdf. Accessed July 26, 2017.

      ]. Therefore, orphan and non-orphan medicines for rare diseases represent a challenge for all health care systems in Europe [
      • Drummond M.F.
      • Wilson D.A.
      • Kanavos P.
      • et al.
      Assessing the economic challenges posed by orphan drugs.
      ,
      • Simoens S.
      Pricing and reimbursement of orphan drugs: the need for more transparency.
      ].
      The aim of this study was to estimate patient access to different medicines for rare diseases from the comprehensive Orphanet list in various European countries in the past decade.

      Methods

      Patient access was estimated using the following three aspects: the number of medicines for rare diseases in continuous use, time to their first continuous use, and total medicine expenditure. The data analysis was performed in IBM SPSS v23.0 and Microsoft Excel. The data are presented as frequencies of available medicines and the median times to continuous use. Medicine expenditures are presented as the total annual sales (€).

      Scope of Medicines for Rare Diseases

      The study included medicines for rare diseases from the Orphanet list, authorized via centralized procedure at the EMA between 2005 and 2014 [

      European Medicines Agency. Orphan designation. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp&mid=WC0b01ac0580b18a41. Accessed November 5, 2016.

      ,
      • Côté A.
      • Keating B.
      What is wrong with orphan drug policies?.
      ]. The Orphanet list comprises the medicines with a rare disease indication with and without the orphan designation from the EMA. Three medicines containing sitaxentan sodium, rilonacept, and dextromethorphan/quinidine were withdrawn from the European market during the inclusion period (2005–2014) and were thus excluded from the start of the study.

      Selected European Countries

      We included all the largest European countries, along with smaller ones for which the sales data from the IMS MIDAS Quarterly Sales Data, January 2005 – December 2014, were available. The following 22 European countries were analyzed: Austria, Belgium, Bulgaria, Croatia, Czech Republic, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Netherlands, Norway, Poland, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, and the United Kingdom (UK).

      Study Period

      The medicines for rare diseases that were authorized between January 1, 2005, and December 31, 2014, were included. The sales data were obtained for the same period.

      The IMS Health Data

      Quarterly value sales from the IMS MIDAS Quarterly Sales Data, January 2005 – December 2014 (IMS Health Data; IMS Health Incorporated, Danbury, CT) were used [
      IMS PADDS Database viewer. IMS MIDAS Quarterly Sales Data, January 2005 – December 2014. Danbury, CT: IQVIA.
      ]. These data were used for all medicines in the scope and for those European countries where sales data of the full medicines list could be found [
      IMS PADDS Database viewer. IMS MIDAS Quarterly Sales Data, January 2005 – December 2014. Danbury, CT: IQVIA.
      ].
      Each medicine from the Orphanet list was searched using the official product name at the EMA and the name of the active substance. This two-fold approach provided true information for the majority of the medicines. Some products may not have been identified because the IMS Health Data records the medicines under only one international name. In such cases, an internet search was performed to find other brand names of the product.
      Despite the two-fold search, 13 products were not clearly identifiable because their product names were imprecise. Among these medicines were a tobramycin and mannitol inhalation powder; four human immunoglobulins; two filgrastim agents; and six other medicines containing everolimus, afamelanotide, lomitapide, bosentan, and a combination of human coagulation factor VIII and human von Willebrand factor. In cases of lomitapid, tobramycin inhalation powder, and one of the human immunoglobulins, similar product names were detected, but the sales data for these products appeared before the marketing authorization dates of the medicines originally searched. For the remaining 10 medicines, different product names were detected according to the search by active substance; however, these were approved for other indications (e.g., immunoglobulins were only detected according to “human immunoglobulin” showing products that could be used for several indications) or their sales data appeared before the marketing authorization date of the medicines originally searched. Therefore, we excluded these 13 products from the analysis to avoid potential bias (Tables S1 and S2 in the Supplementary Materials found at 10.1016/j.jval.2018.01.007).
      The complete sales data for the medicines detected in the database were accessible for 22 European countries. For each country, the data were given either as hospital and retail panel separately or as hospital and retail combined. For 16 countries, both panels were given separately. In the case of Sweden, the combined data were reported. For Austria, Greece, Hungary, and Ireland, only retail sales data were available. Table S3 in the Supplementary Materials (found at 10.1016/j.jval.2018.01.007) presents the types of IMS Health Data reported for each country.

      Data Analysis

      First, the total number of medicines authorized between 2005 and 2014 was investigated according to the year of authorization. Main indication fields of these medicines were also searched using the Anatomical Therapeutic Chemical classification [

      World Health Organization Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2016. Available from: http://www.whocc.no/atc_ddd_index/. Accessed March 7, 2016.

      ]. Furthermore, we investigated the following three main patient access measures for each of the 22 European countries: the number of medicines available, the median time to first continuous use after marketing authorization, and the medicine expenditure during the study period. All measures were observed for all medicines for rare diseases, together and separately, with and without the orphan status.

      Medicine Availability

      A medicine was considered available if continuous sales were detected in the database. Continuous sales were sales without interruption within a 1-year period, meaning that they were detected in four consecutive quarters (Q) (i.e., Q4-2010, Q1-2011, Q2-2011, Q3-2011). However, a 1-quarter gap (zero sales in one quarter) within the 1-year period was allowed (i.e., Q4-2010, gap, Q2-2011, Q3-2011 or Q4-2010, Q1-2011, gap, Q3-2011 or Q4-2010, Q1-2011, Q2-2011, gap). In all the presented cases, Q4-2010 was noted as the period of first continuous use. This way, one-time-only use or potentially nondistributed medicine supplies could be excluded.
      The time to first continuous use was determined for each country for the available medicines. The time difference was calculated between the date of the first continuous use and the marketing authorization date. If continuous sales were detected before marketing authorization, the marketing authorization date was considered as the time of first continuous use. No negative times were considered because they could represent other means and mechanisms of patient access, such as compassionate use. The times were then compared among the countries as absolute times, and a pooled value was determined for all countries.

      Medicine Expenditure

      Medicine expenditure for each country was calculated directly from the sales at a manufacturer price reported in the IMS Health Data using constant euro exchange rate [
      IMS PADDS Database viewer. IMS MIDAS Quarterly Sales Data, January 2005 – December 2014. Danbury, CT: IQVIA.
      ]. The proportions of medicine expenditure spent on medicines with and without orphan designation were also calculated. Furthermore, the sales data were weighted by population size. The total country population data were obtained from the World Health Organization Global Health Expenditure Database [

      World Health Organization. Global health expenditure database: indicators and data. Available from: http://apps.who.int/nha/database/Select/Indicators/en. Accessed June 18, 2016.

      ]. Finally, a comparison was made among countries’ medicine expenditures in euros per capita, according to the country-specific total pharmaceutical sales reported in the Organisation for Economic Co-operation and Development (OECD) data portal [

      Organisation for Economic Co-operation and Development. OECD.Stat database. Pharmaceutical sales indicator. Available from: https://stats.oecd.org/Index.aspx?DataSetCode=HEALTH_PHMC. Accessed June 20, 2016.

      ]. Total pharmaceutical sales included sales for prescription medicines in pharmacies and hospitals. Some countries reported total pharmaceutical sales as sales in pharmacy only. The data for Bulgaria, Croatia, Greece, Poland, and Romania were not reported in the OECD database, so these countries were not included in this comparison.

      Results

      Number of Medicines Authorized in Europe

      Between 2005 and 2014, 125 medicines for rare diseases were approved. Among them, 71 were granted the orphan designation by the EMA. The other 54 medicines are used for different rare diseases but do not have the orphan designation [

      Orphanet. List of medicinal products for rare diseases in Europe. Available from: http://www.orpha.net/orphacom/cahiers/docs/GB/list_of_orphan_drugs_in_europe.pdf. Accessed March 2, 2016.

      ]. Each year, 7 to 18 new medicines for rare diseases were approved (Fig. 1). According to the Anatomical Therapeutic Chemical classification, 44% of the authorized medicines were new antineoplastic and immunomodulating medicines intended to treat rare cancers, inborn immune deficiencies, and other immune diseases (Fig. 1).
      Fig. 1
      Fig. 1The number of medicines for rare diseases authorized each year between 2005 and 2014 according to the first level of Anatomical Therapeutic Chemical classification.
      Among 125 authorized medicines for rare diseases, 13 medicines were excluded because they could not be properly identified. Finally, 112 medicines were used in the further analysis.

      Medicine Availability

      Number of available medicines

      Of the 112 medicines included, the largest number of medicines for rare diseases were in continuous use in Germany and the UK, where 102 (91%) and 95 (85%) medicines were used, respectively (Fig. 2).
      Fig. 2
      Fig. 2Availability of orphan and non-orphan medicines in each country. The total number of available medicines in each country is presented in parentheses. *Only retail sales data were available.
      The countries continuously using between 60% and 70% of the included medicines for rare diseases were Sweden, Italy, Norway, and France. In Finland, Spain, Austria (retail data only), Slovakia, and Belgium, between 50% and 60% of these medicines are used. Among the countries, orphan medicines represent between 47% and 63% of the medicines for rare diseases in continuous use. The smallest European markets for rare diseases, according to the number of available medicines, were Greece (retail data only), Ireland (retail data only), Bulgaria, Romania, and Croatia.
      Eleven medicines were available in all 22 countries included in the study. Excluding Austria, Greece, Hungary, and Ireland, which report only retail data, four additional medicines were revealed. Table 1 presents the list of medicines that were in continuous use in all the countries, according to their active substance and indication for which these were authorized.
      Table 1The list of medicines for rare diseases that were in continuous use in all the European countries included in the study (medicines are listed according to the year of authorization and Anatomical Therapeutic Chemical classification code)
      Active substanceATC codeYear of marketing authorizationIndicationOrphan designation
      SildenafilG04BE032005Pulmonary hypertensionYes
      Bevacizumab
      The use of the medicine in Austria, Greece, Hungary, and Ireland for which only retail data are reported could not be determined, but the medicines were in continuous use in all the remaining countries.
      L01XC072005Nonsmall-cell lung carcinoma; renal cell carcinoma; colorectal, ovarian, and breast neoplasmsNo
      ErlotinibL01XE032005Nonsmall-cell lung carcinoma, pancreatic neoplasmsNo
      Somatropin
      The use of the medicine in Austria, Greece, Hungary, and Ireland for which only retail data are reported could not be determined, but the medicines were in continuous use in all the remaining countries.
      H01AC012006Prader-Willi syndrome, pituitary dwarfism, Turner syndromeNo
      SunitinibL01XE042006Neuroendocrine tumours, Gastrointestinal stromal tumours, Renal cell carcinomaNo
      DasatinibL01XE062006Chronic myelogenous leukemia (BCR-ABL positive), precursor cell lymphoblastic leukemia-lymphomaYes
      DeferasiroxV03AC032006Beta-thalassemia, iron overloadYes
      Trabectedin
      The use of the medicine in Austria, Greece, Hungary, and Ireland for which only retail data are reported could not be determined, but the medicines were in continuous use in all the remaining countries.
      L01CX012007Ovarian neoplasms, sarcomaYes
      NilotinibL01XE082007Chronic myelogenous leukemia (BCR-ABL positive)Yes
      AmbrisentanC02KX022008Pulmonary hypertensionYes
      Azacitidine
      The use of the medicine in Austria, Greece, Hungary, and Ireland for which only retail data are reported could not be determined, but the medicines were in continuous use in all the remaining countries.
      L01BC072008Myelodysplastic syndromesYes
      EverolimusL01XE102009Renal cell carcinoma, pancreatic neoplasms, breast neoplasmsNo
      TocilizumabL04AC072009(Juvenile) rheumatoid arthritisNo
      EltrombopagB02BX052010Idiopathic thrombocytopenic purpuraNo
      PazopanibL01XE112010Renal cell carcinomaNo
      ATC, Anatomical Therapeutic Chemical classification; BCR-ABL, breakpoint cluster region/Abelson protooncogene fusion gene.
      low asterisk The use of the medicine in Austria, Greece, Hungary, and Ireland for which only retail data are reported could not be determined, but the medicines were in continuous use in all the remaining countries.

      Time to first continuous use

      Germany had the shortest median time to first continuous use, which was 3 months after marketing authorization for both orphan and non-orphan medicines. The UK, Sweden, Norway, and Switzerland had median times of 6 months. In Austria, Finland, France, and Greece, half the medicines for rare diseases were available within 1 year after marketing authorization. Other countries were slower in enabling first continuous use, taking from 1 to 2.6 years for introducing half of the medicines available on their markets (Fig. 3).
      Fig. 3
      Fig. 3Median plot with times to first continuous use of medicines for rare diseases for each European country. The countries are listed according to the increasing median times for orphan and non-orphan medicines, respectively. Upper and lower bars represent the values of third and first quartiles, respectively. Time differences are given as point estimates of quarterly data. The median times for all medicines for rare diseases available in each country are given in parentheses. M, median; Mpooled, pooled median value; m – months.
      In smaller European markets (e.g., Bulgarian, Croatian, Czech, Romanian, Slovenian), longer median times to first continuous use were observed. The times of particular available medicines in these countries were very different and took up to 5 or more years. The pooled median time value for all the countries was 1 year. Also, separate pooled median times for orphan and non-orphan medicines were both equal (1 year). The average (standard deviation) for all countries of mean times between marketing authorization and first continuous use of the available medicines for rare diseases was estimated at 1.6 (0.6) years. The average (standard deviation) of orphan and non-orphan medicines were similar, 1.6 (0.7) and 1.5 (0.6) years, respectively.
      For the 11 medicines available in all countries, the pooled median time to first continuous use was 0.5 year. The individual country median times of these 11 medicines were either the same as or shorter than the times of all available medicines with the exception of Bulgaria, Croatia, and Romania, where median times were longer.

      Medicine Expenditure

      The expenses for medicines for rare diseases increased each year when new medicines were approved across all countries, except for Greece, where the expenditure decreased after 2011. The largest pharmaceutical expenditures per inhabitant for medicines for rare diseases were observed in Germany, Switzerland, France, and Belgium throughout the study period. In 2014, the expenditure for the medicines available amounted to €31.9/inhabitant in Germany and €27.0/inhabitant in Switzerland. Greece had the lowest expenditure for medicines for rare diseases in 2014, which was €0.2/inhabitant for medicines in retail sales only (Fig. 4).
      Fig. 4
      Fig. 4Total expenditure for orphan and non-orphan medicines for rare diseases in 2014, presented in euros per inhabitant for each country. *Only retail sales data were available.
      The total expenditures for medicines for rare diseases were allocated differently for orphan and non-orphan medicines among the countries. The proportion of resources spent on orphan medicines in 2014 represented between 33% (Czech Republic and Poland) and 63% (Ireland) of the total expenditure on medicines for rare diseases.
      Fig. 5 presents the country comparison in total expenditure for medicines for rare diseases, according to the total pharmaceutical sales reported by the OECD. The countries that seemingly allocated more money for medicines for rare diseases are Germany and Slovenia (approximately 8% of the total retail pharmaceutical sales). Norway and Czech Republic allocated fewer resources for these medicines (approximately 3% of the total pharmaceutical expenditure in hospitals and pharmacies) compared with other European countries. Also, the expenses for medicines for rare diseases in Austria, Ireland, and Hungary were lower than in other countries, but only retail sales data are presented for these countries.
      Fig. 5
      Fig. 5Total annual country expenditure on medicines for rare diseases in 2014 (in euros per inhabitant) according to the total pharmaceutical sales in 2014 reported by the Organisation for Economic Co-operation and Development. Total pharmaceutical sales data were not reported in the Organisation for Economic Co-operation and Development database for Bulgaria, Croatia, Greece, Poland, and Romania, which therefore are not presented. *Only retail sales data were available. Black diamonds, retail and hospital consumption included in the total pharmaceutical sales; grey diamonds, only retail consumption included in the total pharmaceutical sales.

      Discussion

      This study provides an insight to patient access to medicines for rare diseases in 22 European countries. Previous published studies assessed patient access and budget impact of orphan-designated medicines only, whereas the scope of this study is broader [
      • Blankart C.R.
      • Stargardt T.
      • Schreyögg J.
      Availability of and access to orphan drugs: an international comparison of pharmaceutical treatments for pulmonary arterial hypertension, Fabry disease, hereditary angioedema and chronic myeloid leukaemia.
      ,
      • Schey C.
      • Milanova T.
      • Hutchings A.
      Estimating the budget impact of orphan medicines in Europe: 2010 - 2020.
      ,
      • Orofino J.
      • Soto J.
      • Casado M.A.
      • et al.
      Global spending on orphan drugs in France, Germany, the UK, Italy and Spain during 2007.
      ,
      • Logviss K.
      • Krievins D.
      • Purvina S.
      Impact of orphan drugs on Latvian budget.
      ,
      • Trama A.
      • Pierannunzio D.
      • Loizzo A.
      • et al.
      Availability of medicines for rare diseases in EU Countries.
      ,
      • Bignami F.
      ]. Herein, all medicines authorized in Europe to treat rare diseases are included, irrespective of the orphan medicine status [

      European Medicines Agency. Orphan designation. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp&mid=WC0b01ac0580b18a41. Accessed November 5, 2016.

      ]. Some countries (e.g., Bulgaria, Croatia, Romania, and Slovenia) representing smaller European pharmaceutical markets that have not been studied before are also included.
      Our results confirm that the number of medicines for rare diseases has increased since after 2010 and that the number of medicines in use and the resources spent vary widely among European countries [
      • Trama A.
      • Pierannunzio D.
      • Loizzo A.
      • et al.
      Availability of medicines for rare diseases in EU Countries.
      ,
      • Bignami F.
      ]. Despite these differences, some medicines are available in all countries and are mostly indicated for treating rare cancers and immune diseases. Similarly, the European Organisation for Rare Diseases (EURORDIS) study in 2010 showed that oncology medicines for rare diseases were the most widely available in nine European countries analyzed [
      • Le Cam Y.
      ]. Furthermore, our mean time to first continuous use seems to be comparable with the findings from the 2007 EURORDIS study that included 17 European countries [
      • Bignami F.
      ]. The study reports the mean European time to first use of orphan medicines as 341 days (0.93 y) after marketing authorization [
      • Bignami F.
      ]. In our study, the average time to first continuous use assessed for orphan medicines was 1.6 years, which seems longer, but it represents uninterrupted use and includes the times of slower European markets. We demonstrated that times to first use for orphan and non-orphan medicines did not differ in the biggest markets, whereas some smaller markets needed more time to introduce orphan medicines compared with non-orphan medicines, which could be due to higher prices [
      • Richter A.
      Assessing the impact of global price interdependencies.
      ,
      • Picavet E.
      • Dooms M.
      • Cassiman D.
      • et al.
      Drugs for rare diseases: influence of orphan designation status on price.
      ]. Our overall results show that in Europe, half of the medicines for rare diseases introduced (orphan or not) are in use within 1 year after marketing authorization. The most successful countries in providing numerous medicines to the market in the quickest time are Germany, Norway, Finland, Sweden, and France, as observed previously [
      • Trama A.
      • Pierannunzio D.
      • Loizzo A.
      • et al.
      Availability of medicines for rare diseases in EU Countries.
      ,
      • Bignami F.
      ,

      International Society for Pharmacoeconomics and Outcomes Research. Global healthcare systems roadmap. Available from: http://www.ispor.org/htaroadmaps/. Accessed September 15, 2016.

      ]. These countries also have specific mechanisms to improve patient access to these medicines and to grant full or substantial reimbursement from public resources [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Trama A.
      • Pierannunzio D.
      • Loizzo A.
      • et al.
      Availability of medicines for rare diseases in EU Countries.
      ,
      • Bignami F.
      ,

      International Society for Pharmacoeconomics and Outcomes Research. Global healthcare systems roadmap. Available from: http://www.ispor.org/htaroadmaps/. Accessed September 15, 2016.

      ]. Italy and Spain have introduced several medicines for rare diseases, but it takes them longer than 1 year until the medicines are first used. In addition, Italy enables full reimbursement of orphan medicines, whereas Spain covers medicines with therapeutic advantage [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Denis A.
      • Mergaert L.
      • Fostier C.
      • et al.
      A comparative study of European rare disease and orphan drug markets.
      ].
      Austria and The Netherlands also provide many medicines in a short time and substantially cover orphan drugs [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Denis A.
      • Mergaert L.
      • Fostier C.
      • et al.
      A comparative study of European rare disease and orphan drug markets.
      ,
      • Young K.E.
      • Soussi I.
      • Hemels M.
      • et al.
      A comparative study of orphan drug prices in Europe.
      ]. Similarly, Ireland is fast in enabling first use, but reimbursement depends on community and national schemes that may not cover the medicine [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ]. Also, the number of medicines reported is quite low and does not represent total product availability.
      Smaller markets, such as the Bulgarian, Croatian, Czech, Greek, Hungarian, Polish, Romanian, Slovenian, and Slovakian markets, offer between one-third and one-half of the medicines analyzed, which is a significant number of medicines for rare diseases. However, the time to first use is much longer and more variable in these markets than in the larger European markets. Possible reasons for the fewer number of medicines are weaker sales reporting to the IMS Health Data and decisions of pharmaceutical companies when to launch the product [
      • Richter A.
      Assessing the impact of global price interdependencies.
      ]. Smaller markets usually refer to larger ones with higher prices in external reference pricing, so fewer medicines and longer delays can be expected [
      • Richter A.
      Assessing the impact of global price interdependencies.
      ,
      • Young K.E.
      • Soussi I.
      • Hemels M.
      • et al.
      A comparative study of orphan drug prices in Europe.
      ]. Nevertheless, some of these, such as Bulgaria, Croatia, Czech Republic, Hungary, Romania, Poland, Slovakia, and Slovenia, have a special reimbursement regimen that covers the total costs for most orphan medicines [
      • Blankart C.R.
      • Stargardt T.
      • Schreyögg J.
      Availability of and access to orphan drugs: an international comparison of pharmaceutical treatments for pulmonary arterial hypertension, Fabry disease, hereditary angioedema and chronic myeloid leukaemia.
      ,
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Trama A.
      • Pierannunzio D.
      • Loizzo A.
      • et al.
      Availability of medicines for rare diseases in EU Countries.
      ,

      2012 Report on the state of the art of rare disease activities in Europe of the European Union Committee of Experts on Rare Diseases 2012 – state of the art of rare disease activities in Slovenia. Available from: http://www.eucerd.eu/?post_type=document&p=1529. Accessed July 26, 2017.

      ,
      • Kamusheva M.
      • Stoimenova A.
      • Doneva M.
      • et al.
      A cross-country comparison of reimbursed orphan medicines in Bulgaria, Greece and Romania.
      ]. In contrast, in Greece, medicines are reimbursed if they are cost-effective and patients must provide a copay when the reference price is exceeded [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Kamusheva M.
      • Stoimenova A.
      • Doneva M.
      • et al.
      A cross-country comparison of reimbursed orphan medicines in Bulgaria, Greece and Romania.
      ].
      The largest expenditures on medicines for rare diseases were observed in the countries with greatest numbers and fastest use, such as Germany, Switzerland, France, and Belgium. The most numerous products also were available in these markets [
      • Bignami F.
      ]. All these countries have substantial reimbursement; Germany has full coverage, Belgium has a Special Solidarity Fund for rare diseases, France offers at least partial reimbursement, and Switzerland reimburses with a 10% copayment limited with an annual threshold [
      • Blankart C.R.
      • Stargardt T.
      • Schreyögg J.
      Availability of and access to orphan drugs: an international comparison of pharmaceutical treatments for pulmonary arterial hypertension, Fabry disease, hereditary angioedema and chronic myeloid leukaemia.
      ,
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Denis A.
      • Mergaert L.
      • Fostier C.
      • et al.
      A comparative study of European rare disease and orphan drug markets.
      ]. The prices of medicines for rare diseases in these countries were as much as or more expensive than those in other countries [
      • Blankart C.R.
      • Stargardt T.
      • Schreyögg J.
      Availability of and access to orphan drugs: an international comparison of pharmaceutical treatments for pulmonary arterial hypertension, Fabry disease, hereditary angioedema and chronic myeloid leukaemia.
      ]. When accounting for the total pharmaceutical sales, the proportion spent on medicines for rare diseases per inhabitant seemed to be the greatest in some of the same countries: Germany, France, and Switzerland [
      • Orofino J.
      • Soto J.
      • Casado M.A.
      • et al.
      Global spending on orphan drugs in France, Germany, the UK, Italy and Spain during 2007.
      ]. However, some of the smallest markets, such as Slovenia, also seem to have high proportional costs compared to the total medicines’ expenditure, which could be because here the OECD data do not include hospital consumption, as they do for other countries, and therefore expenditure for rare diseases seems to account for a greater proportion of the total sales. Norway and Czech Republic differ from other countries in the study in that they spend less on medicines for rare diseases; yet, lower medicine prices in both countries need to be considered [
      • Young K.E.
      • Soussi I.
      • Hemels M.
      • et al.
      A comparative study of orphan drug prices in Europe.
      ].
      The leading country in all the aspects studied was Germany, as confirmed in the 2007 EURORDIS study, where many medicines were available (91%) at the fastest time (median time of 3 mo) and the most resources per inhabitant were spent on medicines for rare diseases (€31.9/inhabitant) [
      • Bignami F.
      ]. On the other hand, Germany’s prices were among the highest in Europe, probably due to the free pricing system and the fact that it is widely used as a reference country by other countries [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Orofino J.
      • Soto J.
      • Casado M.A.
      • et al.
      Global spending on orphan drugs in France, Germany, the UK, Italy and Spain during 2007.
      ,
      • Richter A.
      Assessing the impact of global price interdependencies.
      ,

      International Society for Pharmacoeconomics and Outcomes Research. Global healthcare systems roadmap. Available from: http://www.ispor.org/htaroadmaps/. Accessed September 15, 2016.

      ]. Nevertheless, Germany seems to be a good example of fast patient access to the majority of medicines for rare diseases [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Orofino J.
      • Soto J.
      • Casado M.A.
      • et al.
      Global spending on orphan drugs in France, Germany, the UK, Italy and Spain during 2007.
      ,
      • Ades F.
      • Zardavas D.
      • Senterre C.
      • et al.
      Hurdles and delays in access to anti-cancer drugs in Europe.
      ].
      The Scandinavian countries (Finland, Norway, and Sweden) and the UK also were among the most successful in terms of availability [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Trama A.
      • Pierannunzio D.
      • Loizzo A.
      • et al.
      Availability of medicines for rare diseases in EU Countries.
      ,
      • Bignami F.
      ]. Even though their total pharmaceutical sales per inhabitant were as much as or even greater than those in Germany, their expenditures for medicines for rare diseases per inhabitant were much less than those in Germany. Nevertheless, the prices of medicines in the Scandinavian countries are much lower [
      • Denis A.
      • Mergaert L.
      • Fostier C.
      • et al.
      A comparative study of European rare disease and orphan drug markets.
      ,
      • Young K.E.
      • Soussi I.
      • Hemels M.
      • et al.
      A comparative study of orphan drug prices in Europe.
      ]. In addition, in Sweden and Norway, orphan medicines are mostly fully reimbursed, whereas this varies in Finland from 65% to 100% [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Denis A.
      • Mergaert L.
      • Fostier C.
      • et al.
      A comparative study of European rare disease and orphan drug markets.
      ,

      International Society for Pharmacoeconomics and Outcomes Research. Global healthcare systems roadmap. Available from: http://www.ispor.org/htaroadmaps/. Accessed September 15, 2016.

      ,
      • Young K.E.
      • Soussi I.
      • Hemels M.
      • et al.
      A comparative study of orphan drug prices in Europe.
      ,

      Report on the state of the art of rare disease activities in Europe of the European Union Committee of experts on rare diseases 2012 - state of the art of rare disease activities in Norway. Available from: http://www.eucerd.eu/?post_type=document&p=1510. Accessed July 26, 2017.

      ].
      Similarly, the UK enables many medicines in short time but has even lower medicine expenditure than do the Scandinavian countries, which could be due to fixed pricing within the Pharmaceutical Price Regulation Scheme [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Orofino J.
      • Soto J.
      • Casado M.A.
      • et al.
      Global spending on orphan drugs in France, Germany, the UK, Italy and Spain during 2007.
      ,

      International Society for Pharmacoeconomics and Outcomes Research. Global healthcare systems roadmap. Available from: http://www.ispor.org/htaroadmaps/. Accessed September 15, 2016.

      ]. However, in the UK, reimbursement is approved only if cost-effectiveness criteria are met or if the National Cancer Drug Fund covers the treatment [
      • Gammie T.
      • Lu C.Y.
      • Babar Z.U.-D.
      Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries.
      ,
      • Denis A.
      • Mergaert L.
      • Fostier C.
      • et al.
      A comparative study of European rare disease and orphan drug markets.
      ,

      International Society for Pharmacoeconomics and Outcomes Research. Global healthcare systems roadmap. Available from: http://www.ispor.org/htaroadmaps/. Accessed September 15, 2016.

      ].
      Nevertheless, the comparison of patient access among the countries based on the IMS Health Data might not reflect the actual situation across Europe. The IMS Health Data are limited in terms of quality and type of data reported by different countries and therefore provide only patient access estimation.
      In addition, expenditure for medicines for rare diseases could in some cases overestimate the true cost because some medicines are also used for other indications. On the other hand, taking the 13 products that were unidentifiable in the IMS Health Data according to their product names or active substance into account could have resulted in greater overall medicines expenses, especially due to medicines with human immunoglobulins, for which four of five medicines that were approved in the study period had to be excluded for that reason. Still, the database is useful in showing a minimal available collection of medicines for rare diseases in use, and it serves for calculation of time to their access. Continuous use implies that the medicine is probably effectively in use and distributed to patients. Nevertheless, the time when continuous use begins does not necessarily mean that the medicine is reimbursed at that point because the national decision-making bodies can take several months to decide on reimbursement, even for top-selling medicines [
      • Cohen J.
      • Faden L.
      • Predaris S.
      • et al.
      Patient access to pharmaceuticals: an international comparison.
      ,
      • Ades F.
      • Zardavas D.
      • Senterre C.
      • et al.
      Hurdles and delays in access to anti-cancer drugs in Europe.
      ]. Finally, the number of patients requiring the treatment might vary from country to country depending on disease prevalence and potential prescribing restrictions. The 2010 EURORDIS study assessed the approximate proportion of patients with actual access to the orphan medicines at 63% to 73% of all the orphan medicines launched [
      • Le Cam Y.
      ]. In this study, total country populations were used to compare different countries because the true region-specific prevalence and incidence of rare diseases were largely unknown [

      Orphanet. Rare disease registries in Europe. Available from: http://www.orpha.net/orphacom/cahiers/docs/GB/Registries.pdf. Accessed March 2, 2016.

      ,
      • Kanavos P.
      • Nicod E.
      What is wrong with orphan drug policies? Suggestions for ways forward.
      ,
      Orphanet
      ]. The results of our study should be interpreted in the context of real-life patient needs. That said, the best indicator of accessibility to a medicine would be to measure the proportion of patients who are actually receiving medicines that are reimbursed [
      • Côté A.
      • Keating B.
      What is wrong with orphan drug policies?.
      ,
      • De Varax A.
      • Letellier M.
      • Börtlein G.
      • et al.
      ].

      Conclusions

      Important differences in the availability and expenditure for medicines for rare diseases exist among European countries. Patients in Germany, the Scandinavian countries, Switzerland, France, and the UK can access larger numbers of medicines in shorter time than in other European countries. The three countries with the largest expenditures on medicines for rare diseases were Germany, Switzerland, and France.

      Acknowledgments

      The statements, findings, conclusions, views, and opinions contained and expressed in this article are based in part on data obtained under license from the following IQVIA information service: IMS MIDAS Quarterly Sales Data, January 2005 – December 2014, IQVIA. All Rights Reserved.
      The statements, findings, conclusions, views, and opinions contained and expressed herein are not necessarily those of IQVIA or any of its affiliated or subsidiary entities.
      The authors thank FarmInform B.V. for their permission to use the Dutch IMS Health data.
      The authors thank Astra Zeneca UK Limited, Slovenia, for enabling access to the IMS Health Data, namely the IMS MIDAS Quarterly Sales Data, January 2005 – December 2014.

      Supplementary Materials

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