The aim of this study was to review and compare types of reimbursement recommendations for orphan drugs issued by eight European health technology assessment (HTA) agencies and the reimbursement status of these drugs in the corresponding countries. Separate calculations were also performed for three sub-groups: ultra-orphan drugs, oncology orphan drugs and other (non-ultra, non-oncology) orphan drugs.
We reviewed drugs authorized by the European Medicine Agency (EMA) between 1 November 2002 and 30 September 2015. Among these, we identified 101 orphan drugs. Seventy-nine of them were assessed by eight European HTA agencies. The average rates of positive, conditional and negative reimbursement recommendations issued by these agencies were 55.7 %, 15.3 % and 29.0 %, respectively. On average, 21.2 % of EMA-authorized orphan drugs were reimbursed in the eight European countries studied: 49.0 % of those with positive, 53.6 % of those with conditional, and 16.0 % of those with negative reimbursement recommendations. In addition, 5.4 % of orphan drugs that had not been assessed by any of the eight HTA agencies were also reimbursed. The shares of oncology, ultra, and other orphan drugs that were assessed by HTA agencies were similar, with the lowest share observed in ultra-orphan drugs (72 %) and the highest in other orphan drugs (80 %). In terms of reimbursement, 20 % of oncology orphan drugs, 25 % of ultra-orphan drugs and 21 % of other orphan drugs were reimbursed.
Reimbursement of orphan drugs does not always correspond to the type of HTA recommendation. While the highest rate of reimbursement is observed (unsurprisingly) among drugs with positive or conditional recommendation, a high rate of reimbursement (11 %) is also observed among ultra-orphan drugs that had never been assessed by any HTA agency.
While the definition of orphan diseases varies between countries, it is generally accepted that diseases affecting between 1 and 8 persons per 10 000 are regarded as orphan or rare diseases. Within the European Union (EU), orphan conditions are defined by the EMA as life-threatening or chronically debilitating conditions that affect no more than 5 in 10 000 people (which is equivalent to approximately no more than 250 000 in the EU (for each condition)) . Making recommendations on the reimbursement of orphan drugs may be difficult for European Health Technology Assessment (HTA) agencies because of the lack of sufficient clinical and cost data. Prices of orphan drugs are often high, when we compare them with prices of non-orphan drugs, due to small therapy populations. As a result, decisions on the public reimbursement and the number of reimbursed orphan drugs vary between EU member states.
Almost all of the eight European HTA agencies issued in the period of the study (from the beginning of August 2015 till the end of December 2015) three types of recommendations: positive, partially positive (conditional) and negative. The Dutch HTA agency did not issue negative recommendations while the Swedish one did not issue partially positive recommendations. Information on the types of recommendations issued in the eight countries is summarized in Table 1.
The aim of this study was to evaluate the relationship between the reimbursement recommendations of HTA agencies in eight countries in Europe and the reimbursement status of orphan drugs in these countries, i.e. the accessibility of such drugs for patients. In this study we answered the question if the positive recommendation of a HTA agency translates to the positive reimbursement decision in case of orphan drugs.
The study covers the following countries and HTA agencies: Germany - G-BA (Gemeinsamer Bundesausschuss), France – HAS (Haute Autorité de Santé); the Netherlands – ZIN (Zorginstituut Nederland;), Poland – AOTMiT (Agencja Oceny Technologii Medycznych i Taryfikacji;); Sweden – TLV (Dental and Pharmaceutical Benefits Agency), and three of the four countries of the United Kingdom (England – NICE (National Institute for Health and Care Excellence), Scotland – SMC (Scottish Medicines Consortium), and Wales – AWMSG (All Wales Medicines Strategy Group).
The analysis was based on a review of the Orphanet database. During the first stage of this review, we identified all EMA-authorized drugs that were designated as orphan drugs. The review covered drugs authorized between 1 November 2002, which is when the EMA registered the first orphan drug, and 30 September 2015. For all identified orphan drugs, we collected the following information publicly available on chosen agencies` websites in each of the eight countries: (1) was it assessed by the HTA agency? (2) what type of reimbursement recommendation (positive, conditional, or negative; see Table 1) was issued by the HTA agency for this particular drug? and (3) is the drug actually reimbursed? The same data was then collected separately for three sub-groups of orphan drugs: oncology orphan drugs, ultra-orphan drugs, and non-ultra and non-oncology orphan drugs.
Following the National Institute for Health and Care Excellence (NICE) definitions, we have used the following disease prevalence rates for including a drug in our analysis: prevalence of less than 5 per 10 000 for orphan drugs and less than 1 per 50 000 for ultra-orphan drugs . Information on the prevalence of diseases (i.e. classification as an orphan disease) was taken from the Orphanet database and information on the indications for all selected orphan drugs was taken from the EMA’s website (http://www.ema.europa.eu/ema).
We have identified 101 EMA-authorized orphan drugs in the period studied. The eight HTA agencies evaluated between 19.8 % and 74.3 % of all identified orphan drugs. The HAS (France) assessed the highest number of orphan drugs (75), while the NICE (England) assessed only 20 (Fig. 1). Among the 101 orphan drugs identified, 22 (22 %) have not been assessed by any of eight HTA agencies.
The average rates of positive, conditional, and negative recommendations issued by the HTA agencies were 55.7 %, 29.0 %, and 15.3 %, respectively. The highest rate of positive recommendations was found in Germany (100 %), and the lowest in the Netherlands (13.2 %). However, the Dutch ZIN agency issued 73.7 % of conditional recommendations, which is the highest rate of conditional recommendations among the eight HTA agencies (Table 2).
Overall, it appears that the higher the number of assessed drugs, the lower the probability of positive and conditional HTA recommendations (Fig. 2).
The analysis does not warrant any statements about causal relationship between the existence of special HTA criteria and the share of positive and/or conditional HTA recommendations or the number of reimbursed orphan drugs. However, out of the three countries that have special HTA criteria for orphan drugs (France, Germany and Scotland), two (France and Germany) have very high rates of positive and conditional HTA recommendations for such drugs (Figs. 2 and 3).
Countries that have special criteria for orphan drugs in the reimbursement process seem to have higher shares of orphan drugs (as a share of all assessed orphan drugs) that are actually reimbursed – as a share of all assessed orphan drugs (Germany, Netherlands, Sweden; Fig. 4). The existence of special criteria for orphan drugs in the reimbursement process seems to play a lesser role for non-assessed orphan drugs (Fig. 5). The existence of special criteria for orphan drugs in the HTA and reimbursement processes may therefore have some impact on the access to such drugs for patients.
If all positive HTA recommendations translated into actual reimbursement, the Netherlands and Poland would have the lowest number of reimbursed orphan drugs (5 and 7, respectively) and France the highest (64), followed by Sweden (41) and Scotland (31). However, in most countries, the number of reimbursed orphan drugs was much lower than the number of positive HTA recommendations (e.g. 20 vs. 64 for France). In England, Poland and in the Netherlands the number of reimbursed orphan drugs was higher than the number of positive recommendations (Table 2).
On average, 21.2 % of the total of 101 orphan drugs studied (i.e. EMA-approved orphan drugs) were reimbursed in the European countries. The highest rate of reimbursed orphan drugs was observed in Sweden (40.6 %) and the Netherlands (29.7 %). The lowest rate was reported in Scotland (10.9 %). In terms of the share of reimbursed orphan drugs in the total number of assessed orphan drugs, the highest values were observed in Sweden (95 %), Germany (80 %) and the Netherlands (79 %) and the lowest in Scotland (18 %), Wales (19 %) and France (27 %) (Table 2).
The highest rate of reimbursement was observed for drugs that obtained a positive or conditional recommendation from a HTA agency (49.0 % and 53.6 %, respectively (for all countries), compared to 16.0 % for negative recommendations). Poland and the Netherlands were the countries where the highest shares of drugs with a negative recommendation (31.3 % and 40.0 % of drugs, respectively) were reimbursed from public funds. On average, 5.4 % of orphan drugs that have never been assessed by any HTA agency were reimbursed (Table 2).
Ultra-orphan, oncology, non-ultra and non-oncology orphan drugs
Among the 101 identified orphan drugs, 18 (17.8 %) were classified as ultra-orphan, 34 (33.7 %) were registered with oncologic indications and 50 (49.5 %) were non-ultra and non-oncology orphan drugs. The eight HTA agencies evaluated between 5.6 % (England, Germany) and 72.2 % (Wales, France) of all identified ultra-orphan drugs, between 32.4 % (Germany, Netherlands) and 76.5 % (France) of all identified oncology orphan drugs and between 14.0 % (England) and 74.0 % (France) of all non-ultra and non-oncology orphan drugs. Among the ultra-orphan, the oncology and the non-ultra and non-oncology orphan drugs, 5 (28 %), 7 (21 %) and 10 (20 %), respectively, have never been assessed by any of the eight HTA agencies.
The highest rate of reimbursed drugs with positive HTA recommendations is observed among ultra-orphan drugs (53 %), while among other groups this rate ranges from 46 % (oncology orphan drugs) to 49 % (non-ultra, non-oncology orphan drugs). About 5 % of drugs which have never been assessed by an HTA agency is reimbursed from public funds. This rate is much higher for ultra-orphan drugs - 11 % (Table 3).
In terms of access to ultra, oncology, non-ultra and non-oncology orphan drugs, the highest rate of reimbursement is observed in ultra-orphan drugs (25 %). In other groups, i.e. oncology orphan drugs and non-ultra, non-oncology orphan drugs this rate is around 20–21 %. Poland has the highest rate of reimbursement for ultra-orphan drugs (50 %) while Germany has the lowest (6 %). In Sweden, 47 % of oncology-orphan drugs are reimbursed from public funds and only 6 % of such drugs are reimbursed in England, Wales and Scotland. The highest rate of reimbursement for non-ultra, non-oncology orphan drugs is observed in Sweden (36 %) and the lowest in Scotland (10 %).
The average rates of positive, conditional and negative recommendations issued by all HTA agencies for ultra-orphan drugs were 56.1 %, 15.8 % and 28.1 %, respectively. The highest rate of positive recommendations for ultra-orphan drugs was seen in England, Sweden and Germany (100 %) and the lowest in the Netherlands (0 %); however, the Dutch ZIN issued 80 % of conditional recommendations for ultra-orphan drugs. The average rates of positive, conditional and negative recommendations for oncology orphan drugs were, respectively, 60.2 %, 12.8 % and 27.1 %. The highest rate of positive recommendations for oncology orphan drugs was observed in Sweden and Germany (100 %) and the lowest in the Netherlands (18.18 %). In case of non-ultra and non-oncology orphan drugs the average rates of positive, conditional and negative recommendations were, respectively, 53.3 %, 16.7 % and 30.0 % (Fig. 6). The highest rate of positive recommendations for above group of drugs was observed in Germany (100 %) and the lowest in the Netherlands (13.64 %).
On average, 25 % of EMA-authorized ultra-orphan drugs, 19.9 % of oncology orphan drugs, 20.8 % of non-ultra and non-oncology orphan drugs were reimbursed in the eight countries. The shares of reimbursed ultra-orphan drugs and non-ultra, non-oncology orphan drugs in the total number of such drugs with positive, conditional and negative reimbursement recommendations (and in the total number of not assessed ultra-orphan drugs) were on average higher than the respective shares for oncology orphan drugs (Fig. 7).
In many European countries HTA is used to assess the value of new technologies, including orphan drugs. This is usually more difficult for orphan compared to non-orphan drugs because reliable clinical and economic evidence required for this purpose is often unavailable for the former due to small numbers of patients. This is despite incentives for pharmaceutical companies to develop such products and the use of less stringent criteria for trials of drugs with designated orphan indications .
Based on our research it appears that the higher the number of assessed drugs, the lower the number of positive and conditional HTA recommendations. Some of countries (France, Scotland) apply special criteria to orphan drugs in the HTA process or while deciding on the reimbursement (Netherlands, Sweden) or both (Germany) (Table 4). There seems to be a positive correlation between the existence of such special HTA criteria and the shares of orphan drugs with positive or negative HTA recommendations and between the existence of special criteria in the reimbursement process and the shares of orphan drugs that are actually reimbursed. As it was not an objective of our analysis, we suggest further studies on this topic in a future.
In terms of HTA rejection rates (probability of negative HTA recommendations), Mardiguian et al.  found that NICE in England had the highest rejection rate (40 %) while SMC in Scotland had one of the lowest rejection rates (30 %) among the five countries considered (Australia, Canada, England, Scotland and Wales). In our analysis we found that England had a lower rejection rate than Scotland (35 % compared to 47.5 %). This is likely explained by the fact that our sample size (101 drugs) was much higher than that of Mardiguian and colleagues (29 drugs) but comparisons of countries with different healthcare systems (England vs. Australia or Canada) should be performed with caution. Mycka et al.  compared orphan drugs assessment in Germany with HTA agencies in five other countries. However, also in this case it is difficult to compare their results with the results of our analysis given the differences in the sample sizes (19 vs. 101) and healthcare systems. To our best knowledge no other evaluations referring to the types of HTA agencies’ recommendations or the relationship between the type of HTA recommendations and the reimbursement status of drugs were performed and published elsewhere
While more than 78 % of approved orphan drugs have been assessed by the European HTA agencies, only a fifth of them (21 %) is reimbursed from public funds. While this also applies to oncology orphan drugs (79 % have been assessed and 20 % have been reimbursed) and non-ultra, non-oncology orphan drugs (80 % and 21 %, respectively), the share of ultra-orphan drugs that are reimbursed is higher (25 %) (72 % of identified ultra-orphan drugs have been assessed by the HTA agencies). This may be because the likelihood of being able to use an alternative treatment for ultra-orphan diseases is much lower than for non-ultra-orphan diseases. Countries that have special criteria for orphan drugs in the reimbursement processes appear to have higher shares of assessed drugs that are reimbursed from public funds; however, this relationship has not been tested in anyway.
It should be noticed that reimbursement recommendations and reimbursement status of drugs are not the same aspects. Due to financial limitations on reimbursement and increasing costs of pharmacotherapy an aggregating difference between positive recommendations and positive reimbursement decisions (what means a real access to pharmacotherapy) is observed in various countries.
Moreover, in majority of European countries no reimbursement is possible for orphan drugs without previous HTA assessment, which is a tool providing decision makers useful information on clinical efficacy, costs and cost-effectiveness of drugs and let allocate public coverage on pharmacotherapy which should be reimbursed in the lack of sufficient financial resources; we speculate that in coming years in all EU member states such assessment for orphan drugs should be obligatory. On the other hand in some countries (e.g. Poland) some changes of too strict reimbursement requirements for orphan drugs are about to be implemented; currently in Poland tjust the same reimbursement procedures as for drugs used in non-rare diseases have been applied for orphans but probably in coming months a new law will be launched in Poland with a submission of a justification of the proposed price of orphan drug instead of submitting a full economic analysis. This means that the cost-effectiveness analyses for orphan drugs will no longer be obligatory but clinical analysis as well as budget impact analysis should still be submitted during application for reimbursement of orphan drugs in Poland. The similar approach to the orphan drugs’ assessment is observed in France – HAS does not examine the economic evidence in a reimbursement process . In Germany there is a lower accepted significance level for p-values in case of assessment of orphan drugs’ clinical outcomes (when sample size is small) and there is an acceptance of evidence from surrogate endpoints. The economic analysis is not required if the budget impact is less than 50 million euro per annum . Lower levels of evidence are accepted for clinical trials for orphan drugs in Scotland and higher cost per QALY than threshold value for non-orphan drugs is accepted in economic analysis. The flexibility in willingness-to-pay threshold value in case of orphan drugs is also acceptable in Sweden .
The reimbursement status does not always correspond to the type of the recommendation issued by an HTA agency for an orphan drug. The highest rate of reimbursement is observed among drugs with positive or conditional recommendation, but high rate of reimbursement is also observed among ultra-orphan drugs that had never been assessed by any HTA agency.
Agencja oceny Technologii Medycznych i Taryfikacji (Polish HTA Agency)
All Wales Medicines Strategy Group
European Medicines Agency
The General Joint Committee of Germany (Gemeinsamer Bundesausschuss)
French National Authority for Health (Haute Autorité de Santé)
Health Technology Assessment
National Institute for Health and Care Excellence
Scottish Medicines Consortium
Dental and Pharmaceutical Benefits Agency (Tandvårds- och läkemedelsförmånsverket)
National Health Care Institute (Zorginstituut Nederland)
Winstone J, Chadda S, Ralston S, et al. Review and comparison of clinical evidence submitted to support European Medicines Agency market authorization of orphan-designated. Orphanet J Rare Dis. 2015;10:139.
The dataset(s) supporting the conclusions of this article is (are) included within the article (and its additional file(s).
PK: conception and design of the study, collection of data, data extraction, analysis and interpretation of data, drafting the article, final approval, AS: analysis and interpretation of data, revision and rearrangement of the manuscript and final approval, AP: final approval.
The authors declare that they have no competing interests
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Not applicable manuscript does not report on or involve the use of any animal or human data or tissue.
Authors and Affiliations
Drug Management Department, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, ul. Grzegórzecka 20, 31-531, Kraków, Poland
European Observatory on Health Systems and Policies, London, United Kingdom
Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland
London School of Economics, Health and Social Care, London, United Kingdom
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Kawalec, P., Sagan, A. & Pilc, A. The correlation between HTA recommendations and reimbursement status of orphan drugs in Europe.
Orphanet J Rare Dis11, 122 (2016). https://doi.org/10.1186/s13023-016-0501-4