In the European Union, a rare disease is considered to affect fewer than five patients per 10,000 inhabitants, whereas in the United States, it is defined as affecting fewer than 200,000 patients throughout the entire country, which implies one per every 1, 200 inhabitants [1]. Within this group of diseases, ultra-rare diseases are distinguished as those whose prevalence is even lower (one patient per 50,000 inhabitants) [2]. The World Health Organization (WHO) estimates that there are between 5,000 and 7,000 rare diseases, with 250 new ones discovered each year [3] and these affect 7% of the population globally. Despite their low prevalence, rare and ultra-rare diseases together affect approximately 30 million people in the European Union and 3 million in Spain in particular [4]. These diseases often pose a threat to the lives of the affected patients, produce chronic or severe disability and lead to a notable decrease in quality of life.

Orphan drugs are those intended to diagnose, prevent, or treat rare diseases. In 1993, the United States Government and in 2000, the European Union recognised the need to create regulatory mechanisms to encourage the development of orphan drugs [5-7]. Following the implementation of these measures, in the United States, 282 drugs and biological products were approved through 2007, compared to the 10 treatments approved prior to that time [8]. In the European Union, the new regulations elicited a significant increase in the number of drugs marketed, with 60 drugs authorised through 2010 [7].

The increase in the designation of orphan drugs and the associated economic impact are a controversial issue in developed countries, where an economic impact of €265 billion is expected over the next decade, in contrast to the current value of approximately €140 billion [9].

The designation of orphan drugs in the European Union is granted by the European Medicines Agency (EMA), although their funding lies in the health systems of the member countries, which also consider economic criteria [10]. The funding of orphan drugs is a challenge for health care systems because these drugs are often costly and have limited effectiveness [11]. However, in regard to funding orphan drugs, stakeholders generally consider other criteria, such as the severity of the disease, the absence of other therapies for the same disease and the cost to the patient if the medication is not reimbursed by the health care system [12].

There is debate among administrations over these therapies’ effectiveness, cost-effectiveness, prevalence and economic impact, which explains the important differences between countries in financing these medicines [13]. The objective of the present study was to describe the evidence available on orphan drugs marketed in Spain from 2010-2015 in epidemiological, clinical and economic terms. Results from this study could contribute to improve the knowledge related to the approval of orphan drugs in Spain and could be of help for decision-makers when decisions about reimbursement of these drugs have to be made.

A search for orphan drugs approved by the EMA from January 2010 to December 2015 was performed. For each drug, data were collected on the dates of authorisation and commercialisation, the existence of conditional approvals, the therapeutic group and the indication. These data were obtained from the official website of the EMA [14]. The date of authorisation in Spain was obtained from the Summary of Product Characteristics provided by the Spanish Agency of Medicines and Health Products (AEMPS) [15]. The date of commercialisation in Spain was obtained from the Bot PLUS 2.0 database of the Spanish General Council of Official Colleges of Pharmacists (CGCOF) [16]. This information was used to calculate the time from the authorisation of the orphan drug by the European Commission (EC) to the authorisation in Spain and the time from the authorisation in Spain to commercialisation.

For the marketed drugs, data on the prevalence of the diseases for which they are indicated were collected using epidemiological data from the periodic report “Orphanet, rare diseases series” [17] and from the ex-factory price of the medicinal products marketed in December 2015 based on the Bot PLUS 2.0 database [16]. The estimates of the monthly pharmacological cost per patient were calculated from the EFPs of the different medicinal products of the orphan drugs and the dosage included in the Summary of Product Characteristics for each medication. For the calculation of drug costs and in the specific situation that the drug dosages are different depending on the patient’s weight, m2 of body surface area, or platelet count, information of the patient profile included as the base case in the economic evaluations published by the Scottish Medicines Consortium (SMC) was considered. For those drugs that had several medicinal products, the calculation was performed using the medicinal products with a lower cost and if the medicine required loading doses and maintenance doses, the calculation used the monthly cost for the maintenance doses.

The populations affected by rare diseases in Spain in 2015 were estimated using data on the Spanish population as of January 1, 2015, which were collected by the Spanish National Institute of Statistics (INE) [18] and data on the prevalence of these diseases.

Furthermore, the orphan drugs authorised in Spain during the period evaluated were selected for an analysis of the characteristics of the clinical trials that served as the basis for their authorisation. Data were collected on the phase and design of each trial, the comparator used, the number of patients, the duration of the study and the inclusion of instruments to measure the patients’ quality of life. The data were obtained from the evaluation reports published on the official website of the EMA [14].

Due to the absence of an organisation that systematically conducts national economic assessments in Spain, international data were used. Information was specifically collected from the National Institute for Health and Care Excellence (NICE) and from the SMC. The type of economic evaluation performed, the value of the incremental costeffectiveness ratio (ICER), the existence of specific agreements to guarantee access to the drug and the final recommendation decision by the agency were identified. The ICER values from these reports were recorded as £/QALY (quality-adjusted life years) for the base case corresponding to the year in which the respective report was published.

From January 2010 to December 2015, the EC authorised 56 orphan drugs with 61 orphan indications. Hereafter, the term “orphan drug” will be used to refer to both orphan drugs and orphan indications. Of these drugs, 44 (72.1%) were authorised for commercialisation in Spain and 19 (31.2%) were finally marketed. The mean time from EC approval to authorisation in Spain was 181 days (median: 81 days, range: 14 to 916 days) and the mean time from EC approval to commercialisation in Spain was 527 days (median: 493 days, range: 124 to 1,032 days) (Table 1).

Table 1: Orphan drugs approved by CE, and authorized and commercialized in Spain.

Of all the orphan drugs authorised in Europe during this period, 34 (56%) had some type of approval restriction due to the establishment of special authorisation requirements. Conditional approvals based on monitoring of the efficacy and safety of the drug and provision of this information at annual intervals were the most requested, totalling 11 (32.4%) approvals. Authorisation under exceptional circumstances wherein annual monitoring was also requested occurred in five of the approvals (14.6%). For the remaining 18 (53%) approvals, other types of studies were requested, or more specific restrictions were imposed (Table 1).

Figure 1 shows the therapeutic areas of the orphan drugs that were designated by the EMA, those that were authorised in Spain and those that were finally marketed during the 2010-2015 period. The most common therapeutic group was antineoplastic drugs, accounting for 37.7%, 50% and 57.9% of the European designations, Spanish authorisations and commercialisations, respectively. The next most common groups in terms of European designations and Spanish authorisations were gastrointestinal and metabolic drugs (13.1% and 9.1%, respectively), although these numbered well below the antineoplastics.

Figure 1: Distribution of the orphan drugs from 2010-2015 by therapeutic area. A) EU authorization; B) Spanish authorization and C) Spanish commercialization. “N” is the number of orphan drugs and “(%)” is the percentage of the therapeutic area.

An average of 1.3 clinical trials were performed per orphan drug to obtain approval authorisation (Table 1 Supplementary Information). Figure 2 shows the temporal evolution of the approvals and commercialisations that occurred during the study period. Increasing trends were observed across time with regard to the number of drugs that obtained the orphan designation, those that were authorised in Spain and those that were finally marketed.

Figure 2: Annual number of orphan drugs from 2010-2015. Authorized by the EC and authorized and commercialized in Spain.

Table 2 shows the characteristics of the clinical trials performed with orphan drugs authorised in Spain during the 2010-2015 period, classified by therapeutic area and totalled. Of the clinical trials, 57.7% were conducted as phase III trials, with the majority being randomised (79.1%), double blind (54.2%) and/or open label (43.7%).

Table 2: Characteristics of the clinical trials of orphan drugs authorized in Spain from 2010-2015.

Most trials used a placebo as a comparator (49.9%), followed by those without an active comparator (27%) and then by those with an active comparator (20.8%).

The clinical trials most commonly had a sample size of 50 to 249 patients (41.6%), with a size of 250 to 500 patients being second most common (27%). In 12.5% of the studies, there were fewer than 50 patients. The mean sample size of the trials was 260 patients.

Studies with a duration of up to 6 months accounted for 31.2% of the studies sampled. However, the duration of clinical trials depended on the type of disease. For example, in the case of antineoplastics, the majority of the trials were extended through the progression of the disease or until unacceptable toxicity (57.8%), without defining a specific period.

The quality of life of the patients was measured in 62.4% of the trials. The result of this evaluation was inconclusive in 31.3%, neutral in 16.6% and favourable in only 14.5%.

Table 3 shows the prevalence for the rare diseases, the estimated population affected by these diseases in Spain in 2015 and the medicinal products and ex-factory price of each drug as well as the estimated monthly pharmacological cost per patient for the drugs marketed in Spain during the period evaluated. The estimated number of patients in Spain with a rare disease for which an orphan drug was marketed was 121,591. Among them, 19,051 patients had postpolycythaemia vera myelofibrosis and 38 patients had post-essential thrombocythaemia myelofibrosis, which had the highest and lowest prevalence, respectively. Moreover, the monthly pharmacological cost per patient ranged from €34,433 for velaglucerase alfa to €2,163 for ofatumumab, with an average cost of €7,032 for all the drugs.

Table 3: Prevalence, target population, estimation of the prevalence in Spain and estimation of the monthly pharmacological cost per patient.

Figure 3 shows the correlation between the estimated monthly pharmacological cost per patient and the prevalence of the disease. In general terms, the estimated monthly pharmacological cost was higher when the prevalence of the disease was lower and vice versa.

Figure 3: Monthly pharmacological cost per patient and estimated prevalence of rare diseases.

The NICE and SMC economic evaluation reports of the orphan drugs marketed in Spain between 2010 and 2015 are shown in Table 4. During this period, the SMC prepared 16 reports, whereas the NICE prepared 7. The ICERs of the study drugs in these reports ranged from −£13,295 to £1,232,645/QALY, with a mean ICER of £121,072/QALY for all the study drugs. ICERs below the threshold of £20,000-30,000/ QALY were found in 36.8% of the evaluations [19]. With respect to the occurrence of some mode of a patient access scheme (PAS)-type agreement in the evaluations, 70% of them considered a final PAS after knowing the value of the ICER, whereas 47.4% procured a PAS agreement before the calculation of the ICER.

Table 4: Economic evaluation reports from NICE and SMC in commercialized orphan drugs in Spain.

The final recommendations provided by the corresponding evaluating agencies were positive in 65.2% of the reports, compared to 34.8% negative. Of the latter, 37.5% were negative because economic information was not provided to the evaluating organisation.

Only one orphan drug (NexoBrid®) marketed in Spain during this period was not reported on by the two organisations.

The European regulation on orphan drugs established in 2000 (141/2000) [7] has encouraged the development of therapies for rare diseases, which has in turn led to an increase in the number of authorisations [20]. Since that year, there has been a continued increase in the number of new authorisations for orphan drugs in Europe [7]. The results of the present study indicate that this growing trend continued through 2015. Despite the incentivising regulation, only 31.2% of the drugs authorised by the EC during this period were marketed in Spain. In addition, the waiting period until commercialisation was very long, with an average of more than 500 days, meaning nearly a year and a half elapsed before the drugs could be marketed. These results are in line with other Spanish studies that determined that the period from approval by the EMA to the first prescription is 24 months [21].

In more than half of the cases (56%) in the current analysis, EC approvals of orphan drugs considered some type of conditional or exceptional circumstances. These approvals were mostly related to the small population of patients who participated in the clinical trials and always related to the prevalence of the disease and the measures of effectiveness achieved. This finding demonstrates that health authorities positively value the discovery of effective drugs to treat cancer and that they are open to authorisation based on early positive data [22]. The results additionally show that oncological drugs were much more often authorised than other therapeutic groups during the study period in Europe in general and in Spain in particular. This finding has also been observed in other studies [5,6,23]. The reason that this area is better developed may be that new diagnostic techniques can differentiate among different subtypes of cancer, thereby allowing orphan designation of low-prevalence subtypes [24]. Moreover, in the area of oncology, drugs are used to alleviate disease, such that the potential benefits can be very high because they imply patient survival, whereas in other rare diseases, drug administration is chronic and only produces limited improvement of the disease [25].

The majority of the clinical trials of orphan drugs approved in Spain were phase III (57.7%), randomised (79.1%) and/or double blind (54.2%), differing little from non-orphan drug trials in terms of the methodologies used [26,27].

The numbers of patients participating in the trials were low, meaning that it was challenging to obtain robust evidence regarding efficacy and safety and these numbers were quite different from the sample sizes observed in clinical trials of non-orphan drugs [27].

There was an increasing tendency to evaluate the quality of life of the patients in the clinical trials (62.4%), in contrast to other series studied [28]. This trend reflects the growing intention to provide evidence in this area, which is so important for rare diseases, where an increase in quality of life is often as important as achieving high treatment efficacy [29].

In recent years, the annual pharmaceutical budget for orphan drugs, accounting for 2.5% of spending in 2007 and 3.3% in 2010, with an upward prediction of 6.6% for 2020 [9,20]. This increase represents a challenge for ensuring the sustainability of health care systems. The present study shows that orphan drugs marketed in Spain for rare diseases with a lower prevalence are associated with higher pharmacological costs. This trend has already been described previously [10,23,30,31]. Even so, the calculation of the number of patients in Spain based on prevalence data for rare diseases and the general population of Spain may be obtained more reliably with the recent creation of a registry that includes the number of people affected in the country [32].

Economic evaluations are tools that help with health decisionmaking by identifying interventions that produce the greatest health outcomes with the given resources. In Spain, there is no organisation that systematically evaluates the efficiency of drugs. The current study therefore analysed information from the economic evaluations issued by two institutions in the United Kingdom that are pioneers in evaluating efficiency and that serve as models for countries where routine evaluations are not yet available. The ICER data from the evaluation reports showed a wide range (−£13,295 to £1,232,654/QALY), which coincides with the findings of another published study [33].

Of the evaluations, 36.8% had ICER values that would be considered efficient according to the NICE criterion [19], although in general, it is thought that these drugs are not cost-effective [12].

Strategies have been developed in recent years to help health decision-makers evaluate the effects of new oncology drugs under the conditions of daily clinical practice [34]. The evaluation of effectiveness [35], linked to PAS-type agreements, has become increasingly more common in recent years. The presence of PAS-type agreements for the recommendation of positive financing for the drugs included in this study highlights the importance of these payment strategies for reaching agreements on orphan drugs [34].

In Spain, health authorities have a growing concern about the impact of rare diseases in the population in terms of costs and quality of life. As an example, the Spanish Ministry of Health has developed a strategy in rare diseases for the National Health system with the implication of central and local stakeholders and also patient advocacy groups. The strategy includes the need of developing registries of patients, prevention campaigns and early diagnostic [36].

The limited availability of economic evaluations of these drugs [37,38] is one of the limitations of the present study. In addition, the assessments provided by the NICE and the SMC reports are not transparent regarding the determination of the ICER [9], making it difficult to perform comparisons and draw conclusions. What the reports do highlight is the importance of these types of agreements for favouring patient access to these therapies. Another issue to consider is that drug prices in England and Scotland are not necessarily comparable to those in Spain, which limits extrapolation of the results. Even so, both the NICE and the SMC evaluations are good guides and references and permit the conclusion that in general, orphan drugs have ICERs well above the widely considered efficiency thresholds and this circumstance is likely to be present in other countries.

The results from this study highlight the need for establishing mechanisms to speed the approval of orphan drugs and to reduce the variability in the approval by enhancing the transparency of price and reimbursement decisions.

Although there have been legislative measures that promote the development of therapies for rare diseases, these therapies account for 31.2% of commercialisation in Spain, with time intervals from national authorisation to commercialisation that, on average, exceed a year and a half. This lag has a great impact on the expectations of patients who are delayed from being able to benefit from therapies for diseases for which there are often no alternatives available.

The scientific evidence generated for each orphan drug that has EC approval is sound and of high quality, including mostly phase III, randomised, double-blind and open-label clinical trials, although in many cases, the numbers of patients in the clinical trials are limited. An inverse correlation is observed between the number of patients affected and the monthly pharmacological cost per patient for these drugs.

The ICERs in the analysed reports show a great deal of variability, with 63% of the assessments being above the recognised thresholds and with a mean value exceeding £100,000/QALY.

We wish to acknowledge the University Carlos III, Madrid for providing a framework to this work.

All authors have completed the ICMJE uniform disclosure form at www. icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; at the time of the study, JAS and TD were employees of Eli Lilly and hold Eli Lilly shares; no other relationships or activities that could appear to have influenced the submitted work.

No funding was provided. This study was fully developed as part of a Master’s Thesis conducted at the Universidad Carlos III de Madrid (UCIIIM).

MN, BG, JAS and TD designed the study, developed the methodology and wrote the manuscript. MN and BG collected the data and performed the analysis.

At the time this work was developed, MN and BG were students at Universidad Carlos III de Madrid (UCIIIM). JAS and TD are invited professors at Universidad Carlos III de Madrid (UCIIIM).

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