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An Overview of the Orphan Medicines Market in Turkey
VALUE IN HEALTH REGIONAL ISSUES 4C (2014) 47–52
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/vhri
An Overview of the Orphan Medicines Market in Turkey Güvenç Koçkaya, MD, MsC1,*, Albert I. Wertheimer, MBA, PhD2, Pelin Kilic, MsC3, Pelin Tanyeri, MD4, I˙. Mert Vural, MD3, Akif Akbulat, MD3, Guven Artiran, MD3, Saim Kerman, MD3 1 Health Economics and Policy Association, Ankara, Turkey; 2Temple University, School of Pharmacy, Philadelphia, PA, USA; 3Turkish Medicines and Medical Device Agency, Ankara, Turkey; 4Sakarya University, Medical Faculty, Pharmacology Department, Sakarya, Turkey
AB STR A CT
Background: The health policies of many countries and regions have already defined orphan drugs for rare diseases. Although there is no official definition of orphan drugs in Turkey, all orphan drugs are covered by reimbursement, regardless of their market authorization status. Thus, a pharmacoeconomic analysis does not have to be presented to the Social Security Institution (Sosyal Güvenlik Kurumu) for reimbursement decisions on orphan drugs. Objective: The aim of this study was to shed light on the use of orphan drugs to aid classifications of rare diseases and assessments of orphan drugs in Turkey. Methods: Data for sales of authorized orphan drugs and all other drugs were extracted from the IMS Turkey for 2008, 2009, and 2010. Nonauthorized orphan drug sales data were extracted from records of the Turkish Pharmacists’ Association for the same years. Government prices were obtained from the Sosyal Güvenlik Kurumu.
Results: The European Medicines Agency has classified more than 60 orphan drugs for rare diseases. Of these, 50 entered the Turkish market in recent years, half of which were authorized. The remaining drugs were imported through the early access procedure. Antineoplastic agents accounted for the largest percentage of orphan drugs, with 58% of the total market share. In 2010, there were 18 such agents in use, at a cost of €120 million. Conclusions: Although legislation is not yet in place for orphan drugs in Turkey, recognized pricing and reimbursement policies are in operation. This situation facilitates an analysis of orphan drug prices and reimbursement policies in Turkey.
Introduction
European Union (EU) defines rare diseases as life-threatening or chronically debilitating conditions that affect no more than 5 in 10,000 people [4–6]. Definitions of orphan drugs are used for classifying medicinal products intended to treat rare diseases. The Orphan Drug Act of 1983 defined a pathway through new product development: with data supporting the treatment of a rare disease or condition, a medicine can receive orphan designation status in the United States [7–9]. The EU implemented regional policies in 2000 with the aim of improving research and development in the field of orphan drugs [4,5,10]. According to one study, an application for an orphan status designation from the US Food and Drug Administration (FDA) is perhaps the simplest and most straightforward request that can be made to the FDA [8]. Although the cost of launching orphan drugs for rare diseases is similar to that of launching drugs for common diseases, the low patient numbers increase the price of orphan drugs. Because of the inverse proportion between patient numbers and prices, no alternative health technology exists for many orphan drugs [5]. This is, of course, one bottleneck in the course of orphan drug development. To manage this situation, many countries and regions around the world offer economic incentives to make orphan drug development attractive, especially to small and medium companies [11–13].
It was reported in a recent review that 5400 new molecule entities were in the clinical research process in 2013 [1]. Research on rare diseases is one of the fastest growing areas in medicine in recent years. A total of 1795 projects about rare diseases were reported as being in the development process [1]. This research may increase in the coming years. A substantial part of the research on orphan drugs for rare diseases is led by small pharmaceutical and biotechnology companies because such drugs are potentially easier to get onto the market than are drugs are intended to treat widespread diseases and conditions. This is due to several reasons—for example, the well-known etiology, hence the clinical interest and expertise to treat common diseases, and the fact that common drugs are launched at much lower prices than are orphan drugs. Orphan drugs are intended to be used in a country or region in the same way as regular medications (e.g., antihypertension medications). Although there is high demand for orphan medications for specific diseases, it is much more difficult to design clinical research for orphan drugs than for other drugs because of low numbers of the target patient population. Rare diseases are defined in the United States as diseases or conditions affecting fewer than 200,000 individuals [2,3]. The
Keywords: early access, orphan drugs, Turkey. Copyright & 2014, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.
Conflict of interest: The authors have indicated that they have no conflicts of interest with regard to the content of this article. * Address correspondence to: Güvenç Koçkaya, Saglık Ekonomisi ve Politikası Derneğ i, Ufuk Üniversitesi Cad. No:3 The Paragon K:23 Söğ ütözü/Ankar, Turkey. E-mail: [email protected] 2212-1099$36.00 – see front matter Copyright & 2014, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. http://dx.doi.org/10.1016/j.vhri.2014.06.009
48
VALUE IN HEALTH REGIONAL ISSUES 4C (2014) 47–52
The cost of most orphan drugs is higher than that of conventional drugs. In addition, the lack of clinical data on orphan drugs restricts pharmacoeconomic assessments. Both make reimbursement difficult. The first-line approach to aid reimbursement decision making on orphan drugs is to conduct additional assessments after the enactment of orphan drug legislation [14]. One hundred twelve different active substances are listed as orphan drugs by Orphanet [15]. The FDA and the European Medicines Agency (EMA) have already classified a number of rare diseases and orphan drugs, with the EMA authorizing 60 different orphan drugs to date [16,17]. Although there is no official definition of orphan drugs in Turkey, a working group has been established and is used in establishing laws and definitions related to rare diseases. The Turkish Medicines and Medical Device Agency—Türkiye I˙laç ve Tıbbi Cihaz Kurumu (TITCK)—is responsible for the pricing of pharmaceuticals. All drugs in Turkey are subject to a reference pricing policy, with France, Greece, Italy, Portugal, and Spain used as the reference countries since 2006. The Social Security Institution—Sosyal Güvenlik Kurumu (SGK)—is responsible for reimbursement. Two scientific commissions that are responsible for setting opinion for reimbursement operate in the evaluation of such dossiers submitted for the pricing of medicinal products. The Medical and Economic Evaluation Commission assesses all orphan drug applications and conveys its findings to the Reimbursement
Commission, which finalizes the decision made by the Medical and Economic Evaluation Commission. The Medical and Economic Evaluation Commission and the Reimbursement Commission consist of the TITCK, SGK, and the Ministry of Finance. All reimbursement applications submitted to the SGK for conventional drugs must include a pharmacoeconomic analysis [18] (Fig. 1). Orphan drugs are exempted from this requirement. In accordance with the Notification on the Pricing of Medicines, the TITCK sets the price of these drugs using the reference prices, as documented by the official records of the country of manufacture or export (this is considered to be the original price). The SGK reviews orphan drug prices annually and revises them on the basis of their sales volume. All orphan drugs entering the market are reimbursed without any co-payment. Because the TITCK does not have to present a pharmacoeconomic analysis to the SGK for reimbursement decisions of orphan drugs, such drugs may enter the market faster than conventional drugs [19]. However, most of the orphan drugs accessed in the country, which are not licensed by the TITCK, may be in the hands of the responsible physician and the patient in need with the early access procedure defined by the TITCK. This procedure allows physicians to prescribe off-label medications or unlicensed drugs. The TITCK evaluates off-label and unlicensed medication use for each patient through off-label application procedures. A treating
Pharmaceucal Company Makes Applicaon for the License of its Product to TITCK
TITCK Evaluaon of the License
Negave Decision Posive Decision
Pricing Commission Sets the Price Depending on Reference Price Procedures
Product Can Be Distributed in the Market without Reimbursement
Pharmaceucal Company Makes Applicaon for the Reimbursement of Product to SGK
Generics
Originals
Is the price under 5% of cheapest generic?
MEEC Evaluates the Applicaon and Makes the Decision
Yes
Reimbursement Commiee Finalizes the Decision
Negave Decision
Posive Desicion
Product Will Be Reimbursed by SGK with the Desired Discount Rate
Fig. 1 – Overview of licensed product market access in Turkey [17]. MEEC, Medical and Economic Evaluation Commission; SGK, _ Sosyal Güvenlik Kurumu; TITCK, Türkiye Ilaç ve Tıbbi Cihaz Kurumu.
49
VALUE IN HEALTH REGIONAL ISSUES 4C (2014) 47–52
Table 1 – List of orphan medicines in the Turkish market (year 2010). Authorized
Nonauthorized
Agalsidase beta Azasitidine Bosentan Busulfan Dasatinib Deferasirox Everolimus Imatinib Laronidase Lenalidomide Miglustat Nilotinib Pegvisomant Sildenafil
Arsenic trioxide
Sorafenib Sunitinib Temsirolimus Thalidomide
Betaine anhydrous (INN) cystadane powder Carglumic acid Clofarabine Eculizumab Ibuprofen Idursulfase Mecasermin Mitotane Nelarabine N-acetylgalactosamine-4-sulfatase (Galsulfase) Nitisinone Plerixafor Recombinant human acid alpha-glucosidase (Alglucosidase alpha) Rufinamide Sapropterin dihydrochloride Trabectedin
physician who wants to prescribe an off-label or unlicensed pharmaceutical is obliged to apply to the TITCK for named patient approval. The TITCK then evaluates each application on the basis of published scientific evidence and the advice of scientific committees. When the TITCK approves the use of an off-label or unlicensed medicine, the Turkish Pharmacists’ Association—Türk Eczacıları Birlig˘i—is then responsible for importing the drug, and the cost is directly covered by the SGK’s reimbursement scheme, with price margins updated every 6 months [20]. This illustrates that there are both licensed and unlicensed orphan drugs on the Turkish market and that all orphan drugs are covered by a reimbursement scheme, whether licensed or not. The aim of this study was to shed light on the use of orphan drugs in Turkey to aid further classifications of rare diseases and assessments of orphan drugs in the country.
Methods The study included orphan drugs recognized by the EU and published by the EMA. Sales information of the orphan drugs authorized by the TITCK was extracted from IMS Turkey for 2008, 2009, and 2010. Sales information of nonauthorized orphan drugs was extracted from the records of the TITCK. Published government prices for authorized and unauthorized drugs were extracted from the Web sites of the TITCK and the SGK, respectively. The average exchange rates between the euro and the
Turkish lira were estimated as 1.90, 2.15, and 1.99 for 2008, 2009, and 2010, respectively. Orphan drug consumption depending on monetary value and volume (number of boxes/units) in years was analyzed using Microsoft Excel 2010. A detailed search of the PubMed database for articles published before 2012 was conducted. The following key words were used: “orphan medicines” and “Turkey,” “orphan drugs” and “Turkey,” “orphan drug” and “Turkey,” and “orphan drug market” and “Turkey.” Eight relevant published articles were found, none of which was related to the Turkish orphan medicines market.
Results Of 60 different orphan drugs defined by the EMA, 50 entered the Turkish market in recent years. Half of these were authorized. The remaining drugs (preauthorization phase) were imported. All the drugs are fully reimbursed at present. In 2008, there were 14 authorized and 19 nonauthorized orphan drugs on the market. In 2010, there were 18 authorized and 17 nonauthorized orphan drugs (Table 1). As an example, lenalidomide, which was not authorized in 2009, was placed on the market in 2010. Its total market value increased from €148 million to €208 million between 2008 and 2010. There was a similar peak in units. Between 2008 and 2010, the units and value of all nonauthorized drugs increased more than those of authorized drugs (234% and 43%, respectively, and 71% and 24%, respectively) (Table 2 and Fig. 2). The average cost per unit was €1187 in 2008. It decreased to €1002 in 2011. The reduction in the average unit cost was caused by a decrease in the average unit cost of authorized orphan medicines from €1137 to €878 in the 3 years. The decrease was approximately 22%. The average unit price of unauthorized orphan medicines, however, rose from €1885 to €1894 in the 3 years. In parallel, the difference between the average unit cost of authorized and unauthorized medicines increased from €747 to €1016 in this period. The ratio between the average unit cost of authorized and unauthorized medicines rose from 1.65 to 2.15. In other words, the average unit cost of unauthorized orphan medicines was 65% and 115% greater than the average unit cost of authorized orphan medicines in 2008 and 2011, respectively. Antineoplastic agents accounted for the highest percentage of orphan drugs. In 2010, 18 antineoplastic agents had 58% share of the total orphan drug market, at a value of €120 million. These were followed by alimentary tract and metabolism medicines (Table 3). Darasirox had the highest unit percentage among the authorized medicines, but imatinib had the highest value. Among all unauthorized medicines, galsulfase had the highest unit and market share. In addition, five authorized and unauthorized orphan drugs shared 78% and 86% of the total orphan drug market, respectively (Tables 4 and 5). Interesting findings were obtained for lenalidomide, which was an unauthorized drug. Lenalidomide was imported in the preauthorization phase in 2009 (409 units consumed) through to the first
Table 2 – Units of and expenditures on orphan medicines. Years
2008 2009 2010
License status
Units
Expenditures (€)
Average unit cost (€)
Total (€)
Average unit cost in total (€)
Licensed Unlicensed Licensed Unlicensed Licensed Unlicensed
106,676 7,624 147,543 17,554 182,509 25,484
121,368,283 14,374,237 147,141,530 35,296,693 160,245,988 48,272,702
1137 1885 997 2010 878
135,742,519
1187
182,438,223
1105
208,518,690
1002
50
VALUE IN HEALTH REGIONAL ISSUES 4C (2014) 47–52
Fig. 2 – Changes in units and expenditures from 2008 to 2010.
quarter of 2010 (207 units consumed). Easy access of the patient population to this orphan drug was ensured in the preauthorization phase, and sales of lenalidomide rose to 866 units in the remaining three quarters of 2010. Thus, sales of the drug could be 1154 units if we extrapolate the three-quarter sales to 1 year with the estimation. Moreover, the price for reimbursement changed within these years. In 2009, when it was available through the easy access procedure, the reimbursement price of lenalidomide was €5301 to €6448, depending on the package size. After the drug was launched in 2010, the price fell to €3920 to €4523 because of reimbursement discounts. The total unit sales of lenalidomide, however, increased by 180%, and its total market value rose by 70% following the decreased reimbursement price after the launch. According to IMS data, the total market value of reimbursed medicines increased from €6.6 billion to €7.4 billion from 2008 to 2010. The market share of orphan drugs of the total market increased from 2% to 3%, a rise of nearly 50%, the highest increase among all medicinal product categories. It is noted that there are 1268 different molecules in the positive list for reimbursement (€7.4 billion) according to the SGK positive list. Based on these data, the average market value of the molecules was calculated as €5.8 million each for 2010. However, the average market value of orphan molecules was calculated as €7.5 million for 2010.
Conclusions and Discussion The findings of this study provide unique information on the orphan drug market in Turkey. Based on the literature search, to the best of our knowledge, this is the first study examining the
economic impact of orphan drugs on Turkey. The current findings should be of use to private and public stakeholders responsible for decision making relating to Turkey’s orphan drug market. Similar to regulatory and reimbursement procedures, market access procedures for orphan drugs are more complex than those for conventional drugs. Although the United States and the EU have defined rare diseases and orphan drugs, the definitions are not the same. Different definitions may affect all market access schemes in the United States and the EU and cause disagreements between stakeholders. Nevertheless, it is better to have some sort of definition than no definition. Orphan drug regulations have been in force in the EU for more than 10 years. The average market share of orphan drugs in the EU was cited recently as 2% to 3% [21], making it the same as in Turkey. The budget impact of all orphan drugs was mostly lower than that of common drugs, whereas the average budget impact of orphan molecules was higher than that of conventional molecules. Today, 50 molecules are available for patients with rare diseases in Turkey, with a market share of approximately 3% [22]. The market share, however, may increase in coming years with the prospective launch of new orphan drugs because the average orphan molecule market value is 30% higher than that of the average market value of conventional drug molecules. The value of Turkey’s orphan drug market increased by 40% between 2008 and 2010. In the same given time, the consumption of total orphan drug units increased by 82%. The difference between the units and market value in these years might be due to public price cuts, with mandatory discount rates increasing from 20.5% to 32.5% between 2008 and 2010. In addition, reference prices might have changed.
Table 3 – Expenditures on orphan medicines in various diseases areas. Orphan medicine/disease area Antineoplastic agents Alimentary and metabolism medicines Others Cardiovascular system Systemic endocrinology Urogenital and sex hormones Nervous system
Year 2008 (€)
Year 2009 (€)
Year 2010 (€)
95,096,278,89 13,312,231,05 14,896,114,74 12,358,488,11 79,406,84 0.00 0.00
108,864,374,02 30,521,111,84 27,418,393,49 14,876,912,49 714,876,05 42,555,35 0.00
120,993,262,64 38,648,694,19 29,275,317,09 17,538,804,04 1,498,708,99 563,537,69 366,00
VALUE IN HEALTH REGIONAL ISSUES 4C (2014) 47–52
Table 4 – Expenditures of top five authorized and nonauthorized orphan medicines. Medicine
Authorized Imatinib Deferasirox Bosentan Sunitinib Dasatinib Total top five Nonauthorized N-acetylgalactosamine-4-sulfatase (Galsulfase) Idursulfase Eculizumab Nitisinone Recombinant human acid alphaglucosidase Total top five
Expenditure (€)
58,321,077 29,275,317 17,294,108 12,741,874 8,931,977 126,564,353 18,220,410 11,148,800 6,665,400 2,773,472 2,731,850
Table 5 – Units of top five licensed and unlicensed orphan medicines.
Authorized Deferasirox Imatinib Everolimus Thalidomide Azacitidine Total top five Nonauthorized N-acetylgalactosamine-4-sulfatase (Galsulfase) Recombinant human acid alpha-glucosidase (Alglucosidase alpha) Idursurfase Eculizumab Nitisinone Total
evaluations by the TITCK earlier and the removal of these after licensing of the drug. The authorized drug reimbursement process likely also enhanced patient access to the drug. Against all odds, this discrepancy is in need of further assessment. Although orphan drug legislation is not yet established in Turkey, pricing and reimbursement policies for this particular group of drugs are already in place. As noted in an earlier study, incentives to develop orphan drugs do not yet exist in Turkey; however, procedures are in place to facilitate access to orphan drugs [22]. As a result, patients can access treatment in a rapid and equitable manner [22]. This study facilitates additional analyses of orphan drug prices and reimbursement in Turkey. Further evaluation of prices of authorized and unauthorized orphan drugs could be carried out on a case-by-case basis. The latter would shed light on the diverse pricing and reimbursement policies of countries worldwide. R EF E R EN C ES
41,539,932
However, the average unit cost for authorized orphan drugs decreased in the 3 years, whereas the average unit cost of unauthorized orphan drugs increased. The former may be the result of changes in reference prices and reimbursement discounts. Unlike authorized drugs, unauthorized orphan drugs are imported and not subject to reference pricing and reimbursement discounts by the Türk Eczacıları Birliği. A detailed analysis could shed light on the source of differences between the average unit cost of authorized and unauthorized orphan drugs. As noted earlier, the TITCK governs access to unauthorized orphan drugs in Turkey, and patients considered to be in dire need have access to unauthorized drugs under existing regulations for unauthorized human medicinal products. The total sales of orphan drugs may be boosted after licensing these products, as seen in the case of lenalidomide, for which total unit sales increased by 180% following its launch in Turkey. The source of this increase is unclear. It also remains unclear whether patients who need lenalidomide actually have access to the drug. The increase in the total unit sales of lenalidomide after its launch may be due to stringent scientific and technical
Medicine
51
Units
65,770 32,452 20,003 16,177 13,608 148,010 10,179 4,967 3,328 1,449 1,232 21,155
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Available from: http://www.edak.org.tr/www/ekler/ odemeusulesaslari_klavuz.pdf. [Accessed October 7, 2011]. [20] Koçkaya G, Polat M, Vural I˙M, et al. Off-label and unlicensed oncology medicine use in Turkey: a retrospective analysis of computer records of the Turkish Ministry of Health. J Pharm Health Serv Res 2011;2:53–7.
[21] Picavet E, Dooms M, Cassiman D, Simoens S. PHP28 drugs for rare diseases: influence of orphan designation status on price. Value Health 2011;14:A338. [22] Kılıc P, Kockaya G, Yemsen O, et al. Orphan drug regulations in Turkey. J Pharm Health Serv Res 2013;4:151–3.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/vhri
An Overview of the Orphan Medicines Market in Turkey Güvenç Koçkaya, MD, MsC1,*, Albert I. Wertheimer, MBA, PhD2, Pelin Kilic, MsC3, Pelin Tanyeri, MD4, I˙. Mert Vural, MD3, Akif Akbulat, MD3, Guven Artiran, MD3, Saim Kerman, MD3 1 Health Economics and Policy Association, Ankara, Turkey; 2Temple University, School of Pharmacy, Philadelphia, PA, USA; 3Turkish Medicines and Medical Device Agency, Ankara, Turkey; 4Sakarya University, Medical Faculty, Pharmacology Department, Sakarya, Turkey
AB STR A CT
Background: The health policies of many countries and regions have already defined orphan drugs for rare diseases. Although there is no official definition of orphan drugs in Turkey, all orphan drugs are covered by reimbursement, regardless of their market authorization status. Thus, a pharmacoeconomic analysis does not have to be presented to the Social Security Institution (Sosyal Güvenlik Kurumu) for reimbursement decisions on orphan drugs. Objective: The aim of this study was to shed light on the use of orphan drugs to aid classifications of rare diseases and assessments of orphan drugs in Turkey. Methods: Data for sales of authorized orphan drugs and all other drugs were extracted from the IMS Turkey for 2008, 2009, and 2010. Nonauthorized orphan drug sales data were extracted from records of the Turkish Pharmacists’ Association for the same years. Government prices were obtained from the Sosyal Güvenlik Kurumu.
Results: The European Medicines Agency has classified more than 60 orphan drugs for rare diseases. Of these, 50 entered the Turkish market in recent years, half of which were authorized. The remaining drugs were imported through the early access procedure. Antineoplastic agents accounted for the largest percentage of orphan drugs, with 58% of the total market share. In 2010, there were 18 such agents in use, at a cost of €120 million. Conclusions: Although legislation is not yet in place for orphan drugs in Turkey, recognized pricing and reimbursement policies are in operation. This situation facilitates an analysis of orphan drug prices and reimbursement policies in Turkey.
Introduction
European Union (EU) defines rare diseases as life-threatening or chronically debilitating conditions that affect no more than 5 in 10,000 people [4–6]. Definitions of orphan drugs are used for classifying medicinal products intended to treat rare diseases. The Orphan Drug Act of 1983 defined a pathway through new product development: with data supporting the treatment of a rare disease or condition, a medicine can receive orphan designation status in the United States [7–9]. The EU implemented regional policies in 2000 with the aim of improving research and development in the field of orphan drugs [4,5,10]. According to one study, an application for an orphan status designation from the US Food and Drug Administration (FDA) is perhaps the simplest and most straightforward request that can be made to the FDA [8]. Although the cost of launching orphan drugs for rare diseases is similar to that of launching drugs for common diseases, the low patient numbers increase the price of orphan drugs. Because of the inverse proportion between patient numbers and prices, no alternative health technology exists for many orphan drugs [5]. This is, of course, one bottleneck in the course of orphan drug development. To manage this situation, many countries and regions around the world offer economic incentives to make orphan drug development attractive, especially to small and medium companies [11–13].
It was reported in a recent review that 5400 new molecule entities were in the clinical research process in 2013 [1]. Research on rare diseases is one of the fastest growing areas in medicine in recent years. A total of 1795 projects about rare diseases were reported as being in the development process [1]. This research may increase in the coming years. A substantial part of the research on orphan drugs for rare diseases is led by small pharmaceutical and biotechnology companies because such drugs are potentially easier to get onto the market than are drugs are intended to treat widespread diseases and conditions. This is due to several reasons—for example, the well-known etiology, hence the clinical interest and expertise to treat common diseases, and the fact that common drugs are launched at much lower prices than are orphan drugs. Orphan drugs are intended to be used in a country or region in the same way as regular medications (e.g., antihypertension medications). Although there is high demand for orphan medications for specific diseases, it is much more difficult to design clinical research for orphan drugs than for other drugs because of low numbers of the target patient population. Rare diseases are defined in the United States as diseases or conditions affecting fewer than 200,000 individuals [2,3]. The
Keywords: early access, orphan drugs, Turkey. Copyright & 2014, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.
Conflict of interest: The authors have indicated that they have no conflicts of interest with regard to the content of this article. * Address correspondence to: Güvenç Koçkaya, Saglık Ekonomisi ve Politikası Derneğ i, Ufuk Üniversitesi Cad. No:3 The Paragon K:23 Söğ ütözü/Ankar, Turkey. E-mail: [email protected] 2212-1099$36.00 – see front matter Copyright & 2014, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. http://dx.doi.org/10.1016/j.vhri.2014.06.009
48
VALUE IN HEALTH REGIONAL ISSUES 4C (2014) 47–52
The cost of most orphan drugs is higher than that of conventional drugs. In addition, the lack of clinical data on orphan drugs restricts pharmacoeconomic assessments. Both make reimbursement difficult. The first-line approach to aid reimbursement decision making on orphan drugs is to conduct additional assessments after the enactment of orphan drug legislation [14]. One hundred twelve different active substances are listed as orphan drugs by Orphanet [15]. The FDA and the European Medicines Agency (EMA) have already classified a number of rare diseases and orphan drugs, with the EMA authorizing 60 different orphan drugs to date [16,17]. Although there is no official definition of orphan drugs in Turkey, a working group has been established and is used in establishing laws and definitions related to rare diseases. The Turkish Medicines and Medical Device Agency—Türkiye I˙laç ve Tıbbi Cihaz Kurumu (TITCK)—is responsible for the pricing of pharmaceuticals. All drugs in Turkey are subject to a reference pricing policy, with France, Greece, Italy, Portugal, and Spain used as the reference countries since 2006. The Social Security Institution—Sosyal Güvenlik Kurumu (SGK)—is responsible for reimbursement. Two scientific commissions that are responsible for setting opinion for reimbursement operate in the evaluation of such dossiers submitted for the pricing of medicinal products. The Medical and Economic Evaluation Commission assesses all orphan drug applications and conveys its findings to the Reimbursement
Commission, which finalizes the decision made by the Medical and Economic Evaluation Commission. The Medical and Economic Evaluation Commission and the Reimbursement Commission consist of the TITCK, SGK, and the Ministry of Finance. All reimbursement applications submitted to the SGK for conventional drugs must include a pharmacoeconomic analysis [18] (Fig. 1). Orphan drugs are exempted from this requirement. In accordance with the Notification on the Pricing of Medicines, the TITCK sets the price of these drugs using the reference prices, as documented by the official records of the country of manufacture or export (this is considered to be the original price). The SGK reviews orphan drug prices annually and revises them on the basis of their sales volume. All orphan drugs entering the market are reimbursed without any co-payment. Because the TITCK does not have to present a pharmacoeconomic analysis to the SGK for reimbursement decisions of orphan drugs, such drugs may enter the market faster than conventional drugs [19]. However, most of the orphan drugs accessed in the country, which are not licensed by the TITCK, may be in the hands of the responsible physician and the patient in need with the early access procedure defined by the TITCK. This procedure allows physicians to prescribe off-label medications or unlicensed drugs. The TITCK evaluates off-label and unlicensed medication use for each patient through off-label application procedures. A treating
Pharmaceucal Company Makes Applicaon for the License of its Product to TITCK
TITCK Evaluaon of the License
Negave Decision Posive Decision
Pricing Commission Sets the Price Depending on Reference Price Procedures
Product Can Be Distributed in the Market without Reimbursement
Pharmaceucal Company Makes Applicaon for the Reimbursement of Product to SGK
Generics
Originals
Is the price under 5% of cheapest generic?
MEEC Evaluates the Applicaon and Makes the Decision
Yes
Reimbursement Commiee Finalizes the Decision
Negave Decision
Posive Desicion
Product Will Be Reimbursed by SGK with the Desired Discount Rate
Fig. 1 – Overview of licensed product market access in Turkey [17]. MEEC, Medical and Economic Evaluation Commission; SGK, _ Sosyal Güvenlik Kurumu; TITCK, Türkiye Ilaç ve Tıbbi Cihaz Kurumu.
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Table 1 – List of orphan medicines in the Turkish market (year 2010). Authorized
Nonauthorized
Agalsidase beta Azasitidine Bosentan Busulfan Dasatinib Deferasirox Everolimus Imatinib Laronidase Lenalidomide Miglustat Nilotinib Pegvisomant Sildenafil
Arsenic trioxide
Sorafenib Sunitinib Temsirolimus Thalidomide
Betaine anhydrous (INN) cystadane powder Carglumic acid Clofarabine Eculizumab Ibuprofen Idursulfase Mecasermin Mitotane Nelarabine N-acetylgalactosamine-4-sulfatase (Galsulfase) Nitisinone Plerixafor Recombinant human acid alpha-glucosidase (Alglucosidase alpha) Rufinamide Sapropterin dihydrochloride Trabectedin
physician who wants to prescribe an off-label or unlicensed pharmaceutical is obliged to apply to the TITCK for named patient approval. The TITCK then evaluates each application on the basis of published scientific evidence and the advice of scientific committees. When the TITCK approves the use of an off-label or unlicensed medicine, the Turkish Pharmacists’ Association—Türk Eczacıları Birlig˘i—is then responsible for importing the drug, and the cost is directly covered by the SGK’s reimbursement scheme, with price margins updated every 6 months [20]. This illustrates that there are both licensed and unlicensed orphan drugs on the Turkish market and that all orphan drugs are covered by a reimbursement scheme, whether licensed or not. The aim of this study was to shed light on the use of orphan drugs in Turkey to aid further classifications of rare diseases and assessments of orphan drugs in the country.
Methods The study included orphan drugs recognized by the EU and published by the EMA. Sales information of the orphan drugs authorized by the TITCK was extracted from IMS Turkey for 2008, 2009, and 2010. Sales information of nonauthorized orphan drugs was extracted from the records of the TITCK. Published government prices for authorized and unauthorized drugs were extracted from the Web sites of the TITCK and the SGK, respectively. The average exchange rates between the euro and the
Turkish lira were estimated as 1.90, 2.15, and 1.99 for 2008, 2009, and 2010, respectively. Orphan drug consumption depending on monetary value and volume (number of boxes/units) in years was analyzed using Microsoft Excel 2010. A detailed search of the PubMed database for articles published before 2012 was conducted. The following key words were used: “orphan medicines” and “Turkey,” “orphan drugs” and “Turkey,” “orphan drug” and “Turkey,” and “orphan drug market” and “Turkey.” Eight relevant published articles were found, none of which was related to the Turkish orphan medicines market.
Results Of 60 different orphan drugs defined by the EMA, 50 entered the Turkish market in recent years. Half of these were authorized. The remaining drugs (preauthorization phase) were imported. All the drugs are fully reimbursed at present. In 2008, there were 14 authorized and 19 nonauthorized orphan drugs on the market. In 2010, there were 18 authorized and 17 nonauthorized orphan drugs (Table 1). As an example, lenalidomide, which was not authorized in 2009, was placed on the market in 2010. Its total market value increased from €148 million to €208 million between 2008 and 2010. There was a similar peak in units. Between 2008 and 2010, the units and value of all nonauthorized drugs increased more than those of authorized drugs (234% and 43%, respectively, and 71% and 24%, respectively) (Table 2 and Fig. 2). The average cost per unit was €1187 in 2008. It decreased to €1002 in 2011. The reduction in the average unit cost was caused by a decrease in the average unit cost of authorized orphan medicines from €1137 to €878 in the 3 years. The decrease was approximately 22%. The average unit price of unauthorized orphan medicines, however, rose from €1885 to €1894 in the 3 years. In parallel, the difference between the average unit cost of authorized and unauthorized medicines increased from €747 to €1016 in this period. The ratio between the average unit cost of authorized and unauthorized medicines rose from 1.65 to 2.15. In other words, the average unit cost of unauthorized orphan medicines was 65% and 115% greater than the average unit cost of authorized orphan medicines in 2008 and 2011, respectively. Antineoplastic agents accounted for the highest percentage of orphan drugs. In 2010, 18 antineoplastic agents had 58% share of the total orphan drug market, at a value of €120 million. These were followed by alimentary tract and metabolism medicines (Table 3). Darasirox had the highest unit percentage among the authorized medicines, but imatinib had the highest value. Among all unauthorized medicines, galsulfase had the highest unit and market share. In addition, five authorized and unauthorized orphan drugs shared 78% and 86% of the total orphan drug market, respectively (Tables 4 and 5). Interesting findings were obtained for lenalidomide, which was an unauthorized drug. Lenalidomide was imported in the preauthorization phase in 2009 (409 units consumed) through to the first
Table 2 – Units of and expenditures on orphan medicines. Years
2008 2009 2010
License status
Units
Expenditures (€)
Average unit cost (€)
Total (€)
Average unit cost in total (€)
Licensed Unlicensed Licensed Unlicensed Licensed Unlicensed
106,676 7,624 147,543 17,554 182,509 25,484
121,368,283 14,374,237 147,141,530 35,296,693 160,245,988 48,272,702
1137 1885 997 2010 878
135,742,519
1187
182,438,223
1105
208,518,690
1002
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Fig. 2 – Changes in units and expenditures from 2008 to 2010.
quarter of 2010 (207 units consumed). Easy access of the patient population to this orphan drug was ensured in the preauthorization phase, and sales of lenalidomide rose to 866 units in the remaining three quarters of 2010. Thus, sales of the drug could be 1154 units if we extrapolate the three-quarter sales to 1 year with the estimation. Moreover, the price for reimbursement changed within these years. In 2009, when it was available through the easy access procedure, the reimbursement price of lenalidomide was €5301 to €6448, depending on the package size. After the drug was launched in 2010, the price fell to €3920 to €4523 because of reimbursement discounts. The total unit sales of lenalidomide, however, increased by 180%, and its total market value rose by 70% following the decreased reimbursement price after the launch. According to IMS data, the total market value of reimbursed medicines increased from €6.6 billion to €7.4 billion from 2008 to 2010. The market share of orphan drugs of the total market increased from 2% to 3%, a rise of nearly 50%, the highest increase among all medicinal product categories. It is noted that there are 1268 different molecules in the positive list for reimbursement (€7.4 billion) according to the SGK positive list. Based on these data, the average market value of the molecules was calculated as €5.8 million each for 2010. However, the average market value of orphan molecules was calculated as €7.5 million for 2010.
Conclusions and Discussion The findings of this study provide unique information on the orphan drug market in Turkey. Based on the literature search, to the best of our knowledge, this is the first study examining the
economic impact of orphan drugs on Turkey. The current findings should be of use to private and public stakeholders responsible for decision making relating to Turkey’s orphan drug market. Similar to regulatory and reimbursement procedures, market access procedures for orphan drugs are more complex than those for conventional drugs. Although the United States and the EU have defined rare diseases and orphan drugs, the definitions are not the same. Different definitions may affect all market access schemes in the United States and the EU and cause disagreements between stakeholders. Nevertheless, it is better to have some sort of definition than no definition. Orphan drug regulations have been in force in the EU for more than 10 years. The average market share of orphan drugs in the EU was cited recently as 2% to 3% [21], making it the same as in Turkey. The budget impact of all orphan drugs was mostly lower than that of common drugs, whereas the average budget impact of orphan molecules was higher than that of conventional molecules. Today, 50 molecules are available for patients with rare diseases in Turkey, with a market share of approximately 3% [22]. The market share, however, may increase in coming years with the prospective launch of new orphan drugs because the average orphan molecule market value is 30% higher than that of the average market value of conventional drug molecules. The value of Turkey’s orphan drug market increased by 40% between 2008 and 2010. In the same given time, the consumption of total orphan drug units increased by 82%. The difference between the units and market value in these years might be due to public price cuts, with mandatory discount rates increasing from 20.5% to 32.5% between 2008 and 2010. In addition, reference prices might have changed.
Table 3 – Expenditures on orphan medicines in various diseases areas. Orphan medicine/disease area Antineoplastic agents Alimentary and metabolism medicines Others Cardiovascular system Systemic endocrinology Urogenital and sex hormones Nervous system
Year 2008 (€)
Year 2009 (€)
Year 2010 (€)
95,096,278,89 13,312,231,05 14,896,114,74 12,358,488,11 79,406,84 0.00 0.00
108,864,374,02 30,521,111,84 27,418,393,49 14,876,912,49 714,876,05 42,555,35 0.00
120,993,262,64 38,648,694,19 29,275,317,09 17,538,804,04 1,498,708,99 563,537,69 366,00
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Table 4 – Expenditures of top five authorized and nonauthorized orphan medicines. Medicine
Authorized Imatinib Deferasirox Bosentan Sunitinib Dasatinib Total top five Nonauthorized N-acetylgalactosamine-4-sulfatase (Galsulfase) Idursulfase Eculizumab Nitisinone Recombinant human acid alphaglucosidase Total top five
Expenditure (€)
58,321,077 29,275,317 17,294,108 12,741,874 8,931,977 126,564,353 18,220,410 11,148,800 6,665,400 2,773,472 2,731,850
Table 5 – Units of top five licensed and unlicensed orphan medicines.
Authorized Deferasirox Imatinib Everolimus Thalidomide Azacitidine Total top five Nonauthorized N-acetylgalactosamine-4-sulfatase (Galsulfase) Recombinant human acid alpha-glucosidase (Alglucosidase alpha) Idursurfase Eculizumab Nitisinone Total
evaluations by the TITCK earlier and the removal of these after licensing of the drug. The authorized drug reimbursement process likely also enhanced patient access to the drug. Against all odds, this discrepancy is in need of further assessment. Although orphan drug legislation is not yet established in Turkey, pricing and reimbursement policies for this particular group of drugs are already in place. As noted in an earlier study, incentives to develop orphan drugs do not yet exist in Turkey; however, procedures are in place to facilitate access to orphan drugs [22]. As a result, patients can access treatment in a rapid and equitable manner [22]. This study facilitates additional analyses of orphan drug prices and reimbursement in Turkey. Further evaluation of prices of authorized and unauthorized orphan drugs could be carried out on a case-by-case basis. The latter would shed light on the diverse pricing and reimbursement policies of countries worldwide. R EF E R EN C ES
41,539,932
However, the average unit cost for authorized orphan drugs decreased in the 3 years, whereas the average unit cost of unauthorized orphan drugs increased. The former may be the result of changes in reference prices and reimbursement discounts. Unlike authorized drugs, unauthorized orphan drugs are imported and not subject to reference pricing and reimbursement discounts by the Türk Eczacıları Birliği. A detailed analysis could shed light on the source of differences between the average unit cost of authorized and unauthorized orphan drugs. As noted earlier, the TITCK governs access to unauthorized orphan drugs in Turkey, and patients considered to be in dire need have access to unauthorized drugs under existing regulations for unauthorized human medicinal products. The total sales of orphan drugs may be boosted after licensing these products, as seen in the case of lenalidomide, for which total unit sales increased by 180% following its launch in Turkey. The source of this increase is unclear. It also remains unclear whether patients who need lenalidomide actually have access to the drug. The increase in the total unit sales of lenalidomide after its launch may be due to stringent scientific and technical
Medicine
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Units
65,770 32,452 20,003 16,177 13,608 148,010 10,179 4,967 3,328 1,449 1,232 21,155
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