POLICY AND PRACTICE REVIEWS published: 27 November 2019 doi: 10.3389/fphar.2019.01279 Reimbursement Status and Recommendations Related to Orphan Drugs in European Countries Ewa Stawowczyk 1, Krzysztof Piotr Malinowski 2, Paweł Kawalec 2*, Rafał Bobiński 1, Jacek Siwiec 2, Dimitra Panteli 3,4,5, Helene Eckhardt 3,4,5, Steven Simoens 6, Antònia Agusti 7,8, Marc Dooms 9 and Andrzej Pilc 2,10 1 Faculty of Health Sciences, University of Bielsko-Biala, Bielsko-Biała, Poland, 2 Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland, 3 Department of Health Care Management, Berlin University of Technology, Berlin, Germany, 4 WHO Collaborating Centre for Health Systems Research and Management, Berlin, Germany, 5 Research Hub of the European Observatory on Health Systems and Policies, Berlin, Germany, 6 Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium, 7 Clinical Pharmacology Service, Catalan Institute of Pharmacology Foundation, Vall d'hebron University Hospital, Barcelona, Spain, 8 Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain, 9 University Hospitals Leuven, Leuven, Belgium, 10 Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland Edited by: Deslypere Jean Paul, Objective: To review the reimbursement recommendations issued by selected European Aesculape CRO Pte Ltd, Belgium health technology assessment agencies for orphan drugs and the reimbursement status Reviewed by: of these drugs; to assess the relationship between the type of recommendation and Sven Tops, HCC Healthcare, Belgium reimbursement status. Domenico Criscuolo, Italian Society of Pharmaceutical Methods: The list of orphan drugs to be included in the analysis was obtained from Medicine, Italy the European Medicines Agency and Orphanet. Seven European states were included *Correspondence: in the analysis: Belgium, England, France, Germany, Poland, Scotland, and Spain. Paweł Kawalec For all identified orphan drugs, relevant data on the reimbursement status and type of pawel.kawalec@uj.edu.pl recommendation were collected for each country. The relationship between the type Specialty section: of recommendation and reimbursement status was evaluated separately for each This article was submitted to considered country, using Cohen’s kappa coefficient for the measurement of agreement; Pharmaceutical Medicine and Outcomes Research, sub-analyses for oncology and metabolic drugs were performed. a section of the journal Results: Most reimbursement recommendations for orphan drugs were positive (71%), Frontiers in Pharmacology while approximately 17% were negative and almost 13% were conditional. The highest Received: 15 May 2019 Accepted: 07 October 2019 percentage of positive reimbursement recommendations was observed in Spain (97%) and Published: 27 November 2019 France (95%) and the highest percentage of negative reimbursement recommendations Citation: was revealed for Poland (49%). On average, 65% of the 163 analyzed orphan drugs Stawowczyk E, Malinowski KP, Kawalec P, Bobiński R, Siwiec J, were reimbursed from public funds. The highest number of reimbursed orphan drugs Panteli D, Eckhardt H, Simoens S, was observed in Germany (n = 148), while the lowest, in Poland (n = 41). Considering all Agusti A, Dooms M and Pilc A analyzed drugs, the highest agreement between recommendations and reimbursement (2019) Reimbursement Status and Recommendations Related to status was observed for Spain (value of 1), and the lowest, for Germany (κ = ‑0.03). Orphan Drugs in European Countries. Front. Pharmacol. 10:1279. Conclusions: On average, more than 60% of identified orphan drugs were reimbursed doi: 10.3389/fphar.2019.01279 from public funds in the included countries, and the majority of reimbursement Frontiers in Pharmacology | www.frontiersin.org 1 November 2019 | Volume 10 | Article 1279 Stawowczyk et al. Reimbursement and Recommendations for ODs in European Countries recommendations were found to be positive. The agreement between reimbursement recommendations and reimbursement status differed between the countries, but overall, it did not show any patterns, as it ranged from ‑0.03 to 1 (κ coefficient). Keywords: health technology assessment, drug policy, rare disease, reimbursement, orphan BACKGROUND Clinical development and market authorization of orphan drugs is not enough. Orphan drugs must also be reimbursed From the point of view of epidemiology, diseases may be divided from public funds to be accessible to patients, particularly as into common, rare, and ultra-rare. First and foremost, there their prices are usually significantly higher than those of drugs is no uniform criterion for defining rare diseases, applicable for common diseases. Reimbursement decisions are increasingly across countries. based on health technology assessment (HTA), usually entailing The criterion used in the European Union (EU) assumes that economic evaluation. HTA agencies issued reimbursement a rare disease affects not more than 5 out of every 10,000 people, recommendations which may be positive, negative, or conditional which corresponds to a population of approximately 253,000 EU (positive after fulfilling additional conditions). Based on the residents (https://www.ema.europa.eu/en/news/development- HTA agency recommendations, decision makers, responsible for medicines-rare-diseases). In line with the definition of the World drug reimbursement, produce a final decision on reimbursement Health Organization, a rare disease is a disease which affects, which may be positive or negative. Positive reimbursement as a maximum, 65 out of 100,000 people, whereas the Swedish recommendation does not guarantee reimbursement, and National Board of Health and Welfare defines a rare disease as similarly negative reimbursement recommendation does not a disease which affects not more than 10 out of 100,000 people always mean a lack of reimbursement. Economic evaluations in a population. In the United States (US), the Orphan Drug Act of orphan drugs are particularly difficult as available clinical (1983) features a provision that a rare disease affects fewer than data are limited and there are usually no relevant comparators. 200,000 residents in the US (i.e., not more than approx. 7 cases Resource use and costs of treatment are also challenging to per 10,000 patients) (Łanda et al., 2009). In Australia and Japan, calculate because very few clinical centers are specialized in a rare disease is defined as affecting 11 and 40 people out of diagnosing and treating rare diseases—collected values may be 100,000 people, respectively (Denis et al., 2009). Similarly, there non-representative, and for many countries even not available. are no commonly adopted international or European definitions Due to their high prices, orphan drugs usually have a very high for ultra-rare diseases. In England, this concept entails a incremental cost-effectiveness ratio (ICER), which typically disease with a prevalence of 1 case per 50,000 people (Łanda surpasses willingness-to-pay thresholds set in different systems et al., 2009), while in Poland, an ultra-rare disease is a disease and may lead to negative reimbursement recommendations which affects not more than 750 people in the population issued by HTA agencies and an exclusion from reimbursement. (Zarządzenie Nr 17/2007 Prezesa Narodowego Funduszu Some countries set different, higher thresholds for orphan Zdrowia z dnia 10 kwietnia 2007 r. w sprawie zasad wdrażania drugs than for medicines used in common conditions. The terapeutycznych programów zdrowotnych finansowanych przez example of such country is the Netherlands, where no drugs Narodowy Fundusz Zdrowia, 2007). The value mentioned above have been excluded from coverage because of their unfavorable corresponds to the definition of an ultra-rare disease adopted in cost-effectiveness (Carrera and IJzerman, 2016). Governments England, i.e., 1:50,000 people. may decide to reimburse orphan drugs despite a negative An orphan drug is a medicinal product that is developed recommendation, if they constitute the only therapeutic option to treat, diagnose, or prevent a specific rare disease (European for a selected group of patients (Kawalec et al., 2018). Medicines Agency, 2018). In recent decades, more and more To provide an overview of the availability of orphan drug medicines have been approved for rare indications. Additionally, funding in statutory health systems in Europe, this study aimed special programmes have been developed to better diagnose, to review reimbursement recommendations issued by European prevent, and treat those conditions (World Health Organization). HTA agencies for orphan drugs and the reimbursement status However, many rare diseases stay without treatment. Medicines of these drugs. This study will also answer the question if for which the targeted population is small are commercially reimbursement recommendation of considered HTA agency unattractive for the pharmaceutical industry. Many orphan for orphan drug corresponds with reimbursement status. drugs would not be developed and authorized without additional Additionally, the subgroups of drugs registered in oncological incentives (Franco, 2013). The EU regulatory framework allows and metabolic indications were analyzed separately. marketing authorization holders for orphan drugs to: 1) obtain scientific advice on clinical trial protocols at a reduced charge, 2) gain access to the European Medicines Agency centralized METHODS licensing procedure, 3) get reduction of registration costs, and 4) benefit from 10 years of market exclusivity after registration The full list of orphan drugs to be included in the analysis was (European Medicines Agency, 2018). obtained from the website of the European Medicines Agency Frontiers in Pharmacology | www.frontiersin.org 2 November 2019 | Volume 10 | Article 1279 Stawowczyk et al. Reimbursement and Recommendations for ODs in European Countries (2018) and Orphanet (2018). All orphan drugs registered till Reimbursement Recommendations for end of July 2018 by the European Medicines Agency (EMA) Orphan Drugs were included. The following European states, for which both We identified 526 reimbursement recommendations, which reimbursement and recommendation data were available, were were issued for the analyzed orphan drugs in all countries. included in the analysis: England, France, Germany, Poland, The highest number of recommendations was identified Scotland, and Spain. Additionally, Belgium was included, but in France (n = 131), Scotland (n = 108), and Spain (n = only the reimbursement status was available for this country. The 103). Considering all states, the majority of reimbursement countries were selected to represent a mixture of health system recommendations for orphan drugs were positive (71%), financing modalities and expected availability of reimbursed while 17% were negative and almost 13% were conditional. orphan drugs. Information on reimbursement status and type The highest percentage of positive reimbursement of recommendation was collected by experts in each included recommendations was observed in Spain (97%) and France country using publicly available information (Supplementary (95%). In England there was a similar percentage of positive Table 1). Schematic figure on methodology was presented in and conditional reimbursement recommendations—42% Supplementary Figure 1. and 47%, respectively. The highest percentage of negative Drugs with multiple rare indications were treated as reimbursement recommendations was observed in Poland one observation (all indications of the drug treated as one). (49%) and Scotland (32%). In France, the HTA agencies issued Reimbursement recommendations were coded as follows: no conditional reimbursement recommendations for orphan negative—reimbursement from the public fund is not drugs (Figure 1). recommended, positive—reimbursement from public fund is About 41% (216 out of 526) of reimbursement recommendations recommended, or conditional—reimbursement is recommended were issued for orphan drugs used for oncologic indications. The but only if additional conditions are met. This coding was not highest percentage of recommendations for oncologic drugs directly applicable for Germany, as new medicines are generally among all recommendations for orphan drugs was observed in automatically reimbursable upon marketing authorization; England (63.6%), Poland (44.1%), and Scotland (40.7%), while this is picked up further in the Discussion section. Only the the lowest, in France (35.1%). Considering all analyzed countries, reimbursement status was assessed, but no information on drug the majority of reimbursement recommendations for oncologic availability in each country was collected. The data on the type of orphan drugs were positive (69%), while 16% were negative reimbursement recommendations and reimbursement status were and 15% were conditional. The highest percentage of positive summarized with counts and percentages. As more than 30% of the reimbursement recommendations for oncologic orphan drugs orphan drugs included in the analysis were registered in oncological was observed in France (96%) and Spain (95%), while the lowest, indications, and about 20% were registered in metabolic indications, in Poland (40%) (Table 1). those subgroups of drugs were also analyzed separately. About 17% (89 out of 526) of reimbursement As reimbursement policy and HTA agency guidelines for recommendations were issued for orphan drugs used for orphan drugs differ among European countries, the relationship metabolic indications. The percentage of recommendations for between the type of recommendation and reimbursement status metabolic drugs among all recommendations for orphan drugs was assessed separately for each country. The agreement between was similar between the countries. Considering all analyzed recommendations and reimbursement status for each country countries, the majority of reimbursement recommendations separately as well as between countries (for both recommendations for metabolic orphan drugs were positive (75%), while 20% and reimbursement status) was assessed using Cohen’s kappa coefficient of agreement (κ) for the measurement of agreement. The κ coefficient can range from ‑1 to 1, with values lower than 0 denoting no agreement, 0 representing the amount of agreement by random chance, and 1 denoting perfect agreement. The values between 0.01 and 0.20 denote slight agreement, between 0.21 and 0.40—fair agreement, between 0.41 and 0.60—moderate agreement, between 0.61 and 0.80—substantial agreement, and between 0.81 and 0.99—almost perfect agreement (Cohen, 1960). All κ coefficients were supported with 95% confidence intervals and rounded to two decimal places. RESULTS Overall 163 orphan drugs were identified in EMA and Orphanet databases, including 54 drugs with oncological indication and 33 FIGURE 1 | Percentage of positive, negative, and conditional reimbursement drugs with metabolic indication; the list was valid for July 2018 recommendations for orphan drugs (all) in analyzed countries (Supplementary Table 2). Frontiers in Pharmacology | www.frontiersin.org 3 November 2019 | Volume 10 | Article 1279 Stawowczyk et al. Reimbursement and Recommendations for ODs in European Countries TABLE 1 | Recommendation for oncologic and metabolic drugs. Drugs Recommendation England Scotland France Spain Poland Germany All Oncologic Negative 3 (8.6%) 11 (25.0%) 2 (4.3%) 1 (2.6%) 15 (50.0%) 2 (8.7%) 34 (15.7%) Positive 17 (48.6%) 22 (50.0%) 44 (95.7%) 36 (94.7%) 12 (40.0%) 19 (82.6%) 150 (69.4%) Conditional 15 (42.9%) 11 (25.0%) 0 (0%) 1 (2.6%) 3 (10.0%) 2 (8.7%) 32 (14.8%) Metabolic Negative 2 (25.0%) 9 (56.3%) 1 (4.0%) 0 (0%) 6 (66.7%) 0 (0%) 18 (20.2%) Positive 4 (50.0%) 5 (31.3%) 24 (96.0%) 18 (100%) 3 (33.3%) 13 (100%) 67 (75.3%) Conditional 2 (25.0%) 2 (12.5%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 4 (4.5%) were negative and 4% were conditional. The highest percentage drugs were used for metabolic indications. On average, of positive reimbursement recommendations for metabolic 64% of analyzed metabolic orphan drugs were reimbursed orphan drugs was observed in Spain, Germany (100%; see from public funds, with the highest percentage observed in caveat on the German system in the Discussion section, Germany (97%), England and Scotland (82%), while the lowest below), and France (96%), while the lowest, in Scotland (31%) in Poland (21%) (Table 2). and Poland (33%) (Table 1). Reimbursement Status for Orphan Drugs Agreement in Reimbursement Status The reimbursement status was assessed for 163 orphan drugs. Between Countries On average, 65% of analyzed orphan drugs were reimbursed Agreement in reimbursement status was assessed among all from public funds. The highest number of reimbursed orphan analyzed countries. The highest κ coefficient of agreement for drugs was observed in Germany (n = 148, 90.8%), England all analyzed drugs was 0.91, observed between England and (n = 115, 70.6%), Scotland (n = 113, 69.3%), and France Scotland, and the lowest was 0.07, observed between Poland (n = 112, 68.7%), while the lowest, in Poland (n = 41, 25.2%) and Germany (Table 3; see caveat on the German system in the (Figure 2). Out of the 163 orphan drugs, 54 (33%) were Discussion section). Considering only oncologic orphan drugs, used for oncologic indications. On average, 69% of analyzed the highest agreement (κ = 0.82) was observed between England oncologic orphan drugs were reimbursed from public funds, and Scotland. The lowest agreement (κ = 0.11) was observed with the highest percentage observed in Germany (89%), between England and Spain, Scotland and Poland, as well as France (80%), England and Scotland (72%), while the lowest, Poland and Germany (Table 4). For metabolic drugs, the highest in Poland (31%). More than 20% of the analyzed orphan agreement (κ = 1) was observed between England and Scotland, and the lowest (‑0.07), between Spain and both England and Scotland (Table 5). Agreement in Recommendations Between Countries Agreement in recommendations was also assessed. The highest κ coefficient of agreement for all analyzed drugs was 0.57, observed between England and Scotland, and the lowest was –0.15, observed between Scotland and Germany (Table 6). Considering only oncologic orphan drugs, the highest agreement (κ = 0.72) was observed between England and Scotland, and the lowest (κ = ‑0.13), between Scotland and Germany (Table 7). The highest agreement for metabolic drugs was between England and Scotland as well as Scotland and Poland (κ = 0.55). Small number of drugs precluded us from FIGURE 2 | Percentage of reimbursed orphan drugs (all) in analyzed the calculation of the agreement between other combinations countries. of countries (Table 8). TABLE 2 | Reimbursement status for oncologic and metabolic drugs. Drugs Reimbursement England Scotland France Spain Poland Germany All status Oncologic Not Reimbursed 15 (27.8%) 15 (27.8%) 11 (20.4%) 17 (31.5%) 37 (68.5%) 6 (11.1%) (31.2%) Reimbursed 39 (72.2%) 39 (72.2%) 43 (79.6%) 37 (68.5%) 17 (31.5%) 48 (88.9%) (68.8%) Metabolic Not Reimbursed 6 (18.2%) 6 (18.2%) 12 (36.4%) 14 (42.4%) 26 (78.8%) 1 (3.0%) (32.8%) Reimbursed 27 (81.8%) 27 (81.8%) 21 (63.6%) 19 (57.6%) 7 (21.2%) 32 (97.0%) (67.2%) Frontiers in Pharmacology | www.frontiersin.org 4 November 2019 | Volume 10 | Article 1279 Stawowczyk et al. Reimbursement and Recommendations for ODs in European Countries TABLE 3 | Agreement in reimbursement status between countries for all analyzed drugs. Scotland France Spain Poland Germany England 0.91 (0.84–0.98) 0.38 (0.22–0.53) 0.17 (0.02–0.33) 0.18 (0.10–0.27) 0.17 (0.03–0.31) Scotland 0.33 (0.17–0.48) 0.21 (0.05–0.36) 0.18 (0.09–0.27) 0.16 (0.02–0.30) France 0.52 (0.39–0.66) 0.22 (0.13–0.31) 0.29 (0.15–0.44) Spain 0.33 (0.23–0.42) 0.23 (0.11–0.36) Poland 0.07 (0.03–0.10) TABLE 4 | Agreement in reimbursement status between countries for oncologic drugs. Scotland France Spain Poland Germany England 0.82 (0.64–0.99) 0.40 (0.12–0.67) 0.11 (‑0.16 to 0.39) 0.17 (0.00–0.35) 0.26 (‑0.01 to 0.54) Scotland 0.30 (0.01–0.58) 0.20 (‑0.07 to 0.48) 0.11 (‑0.07 to 0.29) 0.26 (‑0.01 to 0.54) France 0.43 (0.17–0.69) 0.21 (0.08–0.34) 0.52 (0.22–0.82) Spain 0.35 (0.18–0.52) 0.32 (0.07–0.58) Poland 0.11 (0.02–0.20) TABLE 5 | Agreement in reimbursement status between countries for metabolic drugs. Scotland France Spain Poland Germany England 1.00 (1.00–1.00) ‑0.03 (‑0.33 to 0.28) ‑0.07 (‑0.35 to 0.21) 0.02 (‑0.12 to 0.17) ‑0.05 (‑0.15 to 0.04) Scotland ‑0.03 (‑0.33 to 0.28) ‑0.07 (‑0.35 to 0.21) 0.02 (‑0.12 to 0.17) ‑0.05 (‑0.15 to 0.04) France 0.62 (0.35–0.89) 0.27 (0.07–0.46) 0.10 (‑0.09 to 0.30) Spain 0.33 (0.11–0.56) 0.08 (‑0.07 to 0.23) Poland 0.02 (‑0.02 to 0.05) TABLE 6 | Agreement in recommendations between countries for all analyzed drugs. Scotland France Spain Poland Germany England 0.57 (0.24–0.89) ‑0.06 (‑0.11 to ‑0.00) ‑0.04 (‑0.10 to 0.02) 0.11 (‑0.04 to 0.27) ‑0.08 (‑0.16 to ‑0.00) Scotland ‑0.06 (‑0.12 to 0.00) ‑0.02 (‑0.07 to 0.02) 0.30 (0.09–0.50) ‑0.15 (‑0.26 to ‑0.04) France ‑0.03 (‑0.05 to ‑0.00) 0.06 (‑0.02 to 0.15) ‑0.08 (‑0.14 to ‑0.02) Spain 0.08 (‑0.03 to 0.19) ‑0.08 (‑0.16 to ‑0.00) Poland 0.08 (‑0.12 to 0.28) TABLE 7 | Agreement in recommendations between countries for oncologic drugs. Scotland France Spain Poland Germany England 0.72 (0.35–1.00) ‑0.07 (‑0.13 to ‑0.00) ‑0.06 (‑0.14 to 0.03) 0.12 (‑0.04 to 0.29) ‑0.07 (‑0.16 to 0.03) Scotland ‑0.09 (‑0.20 to 0.02) ‑0.05 (‑0.15 to 0.04) 0.19 (‑0.01 to 0.39) ‑0.13 (‑0.26 to 0.00) France ‑0.04 (‑0.09 to 0.02) 0.07 (‑0.06 to 0.19) ‑0.07 (‑0.16 to 0.03) Spain 0.06 (‑0.06 to 0.19) ‑0.09 (‑0.21 to 0.04) Poland ‑0.05 (‑0.33 to 0.23) TABLE 8 | Agreement in recommendations between countries for metabolic drugs. Scotland France Spain Poland Germany England 0.55 (‑0.16 to 1.00) NA NA NA NA Scotland NA NA 0.55 (‑0.16 to 1.00) NA France NA NA NA Spain NA NA Poland NA NA not available; impossible to assess due to small number of cases. Frontiers in Pharmacology | www.frontiersin.org 5 November 2019 | Volume 10 | Article 1279 Stawowczyk et al. Reimbursement and Recommendations for ODs in European Countries Agreement Between Recommendations and Reimbursement Status Within Countries Considering all analyzed drugs, the highest κ coefficient of agreement between recommendations and reimbursement status was observed for Spain (κ = 1) and the lowest, for Germany (κ = ‑0.03; please refer to comment in Discussion) (Figure 3). For the subgroup of oncologic drugs, the corresponding κ values were 1 for Spain and 0 for Germany (Figure 4). For metabolic drugs, the corresponding κ values were 0.31 for Poland and ‑0.3 for England (Figure 5). DISCUSSION This study analyzed the type of reimbursement recommendations issued for orphan drugs in selected European countries, together with the reimbursement status. Most Western European countries FIGURE 5 | Agreement Between Recommendations and Reimbursement were included in the analysis, but only one from Central Eastern Status—metabolic drugs. Europe (CEE; Poland). The reason for that was because data on reimbursement status and reimbursement recommendations were not available in other CEE countries; Poland was the only CEE state Belgium. Overall, in 2016, the Drug Reimbursement Committee with relevant data on drug reimbursement widely available online. issued 27% of positive and 27% of negative recommendations. No detailed information on the reimbursement The Committee was not able to issue any recommendations in recommendations for individual orphan drugs was available in the case of 9% of the assessed orphan drugs, and it advised to negotiate the managed entry agreement in 37% of cases. Taking those recommendations into account, the Minister issued positive decisions on the reimbursement of 73% of orphan drugs, and negative in 27%. In Germany, new medicines are reimbursable upon entering in the market; manufacturers can set their price freely for the first year of circulation. Early benefit assessment of new active substances by the Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) was introduced by the Pharmaceutical Market Restructuring Act (Arzneimittelmarktneuordnungsgesetz, AMNOG), which came into force on 1st January 2011. Drugs with new active substances undergo a benefit assessment based on an evidence dossier submitted by the manufacturer. The G-BA classifies the magnitude of the new drug’s added benefit compared to current FIGURE 3 | Agreement Between Recommendations and Reimbursement best practice. This classification is the basis for the negotiation of Status—all drugs. the drug’s reimbursement price between the German Association of Statutory Health Insurance Funds and the manufacturer, which applies after the first year of circulation. In most cases, the reimbursement status remains unaffected. To allow for the special characteristics of orphan drugs, the AMNOG considers an added medical benefit of an orphan pharmaceutical as proven by means of the marketing authorization, unless its turnover at the expense of statutory health insurance exceeds €50 million in 12 months. If that mark is surpassed, a dossier has to be filed and a full benefit assessment takes place, followed by price negotiation. In England, the assessment of orphan drugs for rare conditions is part of the Highly Specialised Technologies (HST) program. Following a consultation process in 2017, it was recommended that NHS England automatically fund drugs for ultra-rare conditions if the ICER of the drug is below £100,000 per QALY, a threshold which is substantially higher than the one usually applied for drugs (https://www.nice.org. FIGURE 4 | Agreement Between Recommendations and Reimbursement uk/about/what-we-do/our-programmes/nice-guidance/nice- Status—oncologic drugs. technology-appraisal-guidance/consultation-on-changes-to- Frontiers in Pharmacology | www.frontiersin.org 6 November 2019 | Volume 10 | Article 1279 Stawowczyk et al. Reimbursement and Recommendations for ODs in European Countries technology-appraisals-and-highly-specialised-technologies). countries, being the highest in Greece and the lowest in Romania. Technologies under the HST program are generally subject to The survey revealed some differences in the legal requirements a budget impact provision: if their budget impact exceeds £20 for the pricing and reimbursement of biotechnological orphan million in any of the first 3 years, negotiations between NHS medicinal products among the countries included in the England and the manufacturer may be initiated. The SMC in study. All EU countries have developed and implemented Scotland may consider at a Patient and Clinician Engagement pharmacoeconomic guidelines with or without some specific (PACE) meeting further aspects of the new active substance for reimbursement requirements for orphan medicinal products. treatment of a rare disease, which were not part of the submitted Cost-effectiveness analysis, cost-utility analysis, Markov models, manufacturer dossier (https://www.scottishmedicines.org.uk/ meta-analysis, and discount rates for costs and outcomes were how-we-decide). required only in Bulgaria, Poland, and Hungary. The access to Given the common framework of the NHS in England orphan medicinal products was similar among the analyzed CEE and Scotland, it is not surprising that recommendations and countries, while the countries with the best access were Hungary decisions on reimbursement status and between these countries and Greece. achieve the highest agreement. Inversely, the particularity of Gammie et al. (2015) analyzed regulations and policies the German reimbursement system, wherein (orphan) drugs used by countries to allow patient access to orphan drugs in are automatically reimbursed unless explicitly excluded, 2015 by performing a systematic review of evidence published probably accounts for the lack of agreement regarding the between 1998 and 2014. They summarized the legislation of 35 recommendations decisions between Germany and the other countries from around the world, including 21 EU countries, countries. Generally, differences in both reimbursement and revealed that different types of special regulations for recommendations and status may be due to different agency- orphan drugs (national orphan drug policies, orphan drug specific evidentiary, risk and value preferences, or stakeholder designation, marketing authorization, marketing exclusivity, input (Nicod, 2017). and tax credits) were present in most countries. A variation Although some research projects were conducted, there is not in the share of orphan drugs accessible for the patient was a similar study evaluating the current situation in various EU also observed. countries. A study published by Zelei et al. (2016), who reviewed A comparative analysis on the access to orphan drugs scientific evidence on the HTA for orphan drugs decision- between the Balkan countries—five EU member states (Bulgaria, making with a special focus on public payers in CEE countries, Croatia, Greece, Romania, and Slovenia) and two EU candidate was identified. The authors revealed that CEE countries are more countries (Serbia and Montenegro)—was performed by Pejcic budget-restricted than Western European countries and could be et al. (2018). The review revealed significant inequalities more affected by the lack of clinical evidence for orphan drugs, among these states as well as an inadequate access to orphan which generally gain marketing authorization earlier than non- drugs approved for the EU market; some improvement on the orphan drugs. access for reimbursement and a better availability of orphan Szegedi et al. (2018) revealed that the highest expenditure on drugs for patients are needed. orphan drugs from 2013 to 2014 was observed in Belgium (€245– Our study revealed that the great majority of the 280 million), and the lowest, in Bulgaria (€8.3–12.2 million). The reimbursement recommendations were positive or conditional number of accessible orphan products, also observed in this study, and about 65% of the considered orphan drugs were reimbursed suggests an equity gap between Eastern and Western Europe. The from public funds. The agreement between the type of spending on orphan drugs as a proportion of the gross domestic reimbursement recommendations and reimbursement status product (GDP) as well as of public pharmaceutical and healthcare could be influenced by the bias between countries (differences expenditures was lower in poorer countries, which indicates a in the decision-making process as well as legislation) and by the substantial inequity in terms of patient access to orphan drugs, distributions of the reimbursement status. Hence, the presented favoring higher-income countries. coefficients should be treated as a descriptive statistic rather than Picavet et al. (2012) analyzed access to orphan drugs in an inference. In addition, the analysis could not be performed almost all EU countries (except for Cyprus, Malta, and Portugal) when no variation in the analyzed variable existed, like in the case based on data from IMS Health (2011). They showed that of recommendations for metabolic drugs in Germany, while for employing an HTA process has an important role in improving 33 metabolic drugs the recommendations were presented for 13 patients’ access to reimbursed orphan drugs, particularly drugs and all of them were positive. For this reason the agreement in low-GDP countries. However, nowadays more low-GDP could not be calculated, as there were no reimbursed drugs with countries use a formal HTA process than in 2011; HTA negative recommendations or negative recommendations and process has been shown to play an important role in improving lack of reimbursement. patient access to reimbursed orphan drugs, particularly in Our study has some limitations. First of all, we were not low-GDP countries. able to collect relevant data from some European countries, Kamusheva et al. (2018) compared the access of patients with as they were not published online and they were also rare diseases to biotechnological drugs between several CEE unavailable for the collaborating experts and as a result those countries in 2018, reporting that all these countries implemented countries were excluded from the analysis. Moreover, our data special legislation for orphan drugs. The share of accessible depicts the orphan designations identified until July 2018. orphan drugs as well as total expenditures varied across Due to variations in both orphan drugs designations and Frontiers in Pharmacology | www.frontiersin.org 7 November 2019 | Volume 10 | Article 1279 Stawowczyk et al. Reimbursement and Recommendations for ODs in European Countries reimbursement systems in the analyzed countries, the results types of recommendations, and the number of reimbursed orphan of our study provide a snapshot of the situation and would need drugs. The agreement between reimbursement recommendations to be updated in future works. An ongoing monitoring of the and reimbursement status also differed between countries, but reimbursement status of orphan drugs in analyzed countries no patterns could be discerned. This study confirms the existence and current trends in reimbursement decision-making for of equity gaps in orphan drug coverage, reflecting variability in orphan drugs would be especially important, but requires both willingness and ability to pay. a structural foundation beyond the abilities of this work. Also, although reimbursement status and recommendations were examined for 163 identified orphan drugs, it should be DATA AVAILABILITY STATEMENT noted that not all of these orphan drugs are actually on the The raw data supporting the conclusions of this manuscript will market in the selected countries. Cohen’s kappa coefficient be made available by the authors, without undue reservation, to of agreement could be calculated only for those countries any qualified researcher. that issued both positive and negative recommendations. In addition, the value of this coefficient could be affected by the prevalence of levels of the analyzed variables. Only in the cases AUTHOR CONTRIBUTIONS where both recommendation and reimbursement status were available, coefficients were analyzed, which results in different ES, PK, RB, and AP contributed to the conception and/or design sets of drugs used to calculate kappa coefficients in different of the study. ES, PK, DP, HE, SS, AA, and MD contributed to data countries. The kappa coefficient was close to 0 for Germany; acquisition. ES, KPM, and PK contributed to data analysis and/ this is due to the fact that there were only five negative results or interpretation. ES, KPM, PK, and JS drafted the manuscript. of the evaluation of additional benefit and all five drugs were All authors revised the manuscript critically for important finally reimbursed, giving 100% disagreement. intellectual content. Despite those limitations, our study contributes significantly to the field of reimbursement of orphan drugs in European countries. Providing comprehensive and up-to-date information FUNDING on access to reimbursed orphan drug and reimbursement This study was conducted within the statutory project: policies, which may facilitate orphan drug management in “Reimbursement and clinical aspects of orphan drug policy these countries. in Poland and Europe” (project number: K/ZDS/007863). We would like to thank Francis Arickx for help in data acquisition CONCLUSIONS for Belgium. About 65% of identified orphan drugs were reimbursed SUPPLEMENTARY MATERIAL from public funds, and the majority of the reimbursement recommendations were found to be positive. 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The use, World Health Organization. www.who.int. distribution or reproduction in other forums is permitted, provided the original Zarządzenie Nr 17/2007 Prezesa Narodowego Funduszu Zdrowia z dnia 10 author(s) and the copyright owner(s) are credited and that the original publication kwietnia (2007) r. w sprawie zasad wdrażania terapeutycznych programów in this journal is cited, in accordance with accepted academic practice. No use, zdrowotnych finansowanych przez Narodowy Fundusz Zdrowia. distribution or reproduction is permitted which does not comply with these terms. Frontiers in Pharmacology | www.frontiersin.org 9 November 2019 | Volume 10 | Article 1279