An Overview of the Orphan Medicines Market in Turkey Güvenç Koçkaya, MD, Msc1,*, Albert I
VALUE IN HEALTH REGIONAL ISSUES 4C (2014) 47– 52
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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
1Health 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
ABSTRACT
Background: The health policies of many countries and regions have Results: The European Medicines Agency has classified more than 60 already defined orphan drugs for rare diseases. Although there is no orphan drugs for rare diseases. Of these, 50 entered the Turkish official definition of orphan drugs in Turkey, all orphan drugs are market in recent years, half of which were authorized. The remaining covered by reimbursement, regardless of their market authorization drugs were imported through the early access procedure. Antineo- status. Thus, a pharmacoeconomic analysis does not have to be plastic agents accounted for the largest percentage of orphan drugs, presented to the Social Security Institution (Sosyal Güvenlik Kurumu) with 58% of the total market share. In 2010, there were 18 such agents for reimbursement decisions on orphan drugs. Objective: The aim of in use, at a cost of €120 million. Conclusions: Although legislation is this study was to shed light on the use of orphan drugs to aid not yet in place for orphan drugs in Turkey, recognized pricing and classifications of rare diseases and assessments of orphan drugs in reimbursement policies are in operation. This situation facilitates an Turkey. Methods: Data for sales of authorized orphan drugs and all analysis of orphan drug prices and reimbursement policies in Turkey. other drugs were extracted from the IMS Turkey for 2008, 2009, and Keywords: early access, orphan drugs, Turkey. 2010. Nonauthorized orphan drug sales data were extracted from records of the Turkish Pharmacists’ Association for the same years. Copyright & 2014, International Society for Pharmacoeconomics and Government prices were obtained from the Sosyal Güvenlik Kurumu. Outcomes Research (ISPOR). Published by Elsevier Inc.
fi Introduction European Union (EU) de nes rare diseases as life-threatening or chronically debilitating conditions that affect no more than 5 in It was reported in a recent review that 5400 new molecule entities 10,000 people [4–6].Definitions of orphan drugs are used for were in the clinical research process in 2013 [1]. Research on rare classifying medicinal products intended to treat rare diseases. diseases is one of the fastest growing areas in medicine in recent The Orphan Drug Act of 1983 defined a pathway through new years. A total of 1795 projects about rare diseases were reported product development: with data supporting the treatment of a as being in the development process [1]. This research may rare disease or condition, a medicine can receive orphan desig- increase in the coming years. A substantial part of the research nation status in the United States [7–9]. The EU implemented on orphan drugs for rare diseases is led by small pharmaceutical regional policies in 2000 with the aim of improving research and and biotechnology companies because such drugs are potentially development in the field of orphan drugs [4,5,10]. According to one easier to get onto the market than are drugs are intended to treat study, an application for an orphan status designation from the widespread diseases and conditions. This is due to several US Food and Drug Administration (FDA) is perhaps the simplest reasons—for example, the well-known etiology, hence the clin- and most straightforward request that can be made to the FDA [8]. ical interest and expertise to treat common diseases, and the fact Although the cost of launching orphan drugs for rare diseases that common drugs are launched at much lower prices than are is similar to that of launching drugs for common diseases, the orphan drugs. Orphan drugs are intended to be used in a country low patient numbers increase the price of orphan drugs. Because or region in the same way as regular medications (e.g., antihy- of the inverse proportion between patient numbers and prices, no pertension medications). Although there is high demand for alternative health technology exists for many orphan drugs [5]. orphan medications for specific diseases, it is much more difficult This is, of course, one bottleneck in the course of orphan drug to design clinical research for orphan drugs than for other drugs development. To manage this situation, many countries and because of low numbers of the target patient population. regions around the world offer economic incentives to make Rare diseases are defined in the United States as diseases or orphan drug development attractive, especially to small and conditions affecting fewer than 200,000 individuals [2,3]. The medium companies [11–13].
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 Derneği, Ufuk Üniversitesi Cad. No:3 The Paragon K:23 Söğütözü/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 conven- Commission, which finalizes the decision made by the Medical tional drugs. In addition, the lack of clinical data on orphan drugs and Economic Evaluation Commission. The Medical and Economic restricts pharmacoeconomic assessments. Both make reimburse- Evaluation Commission and the Reimbursement Commission ment difficult. The first-line approach to aid reimbursement consist of the TITCK, SGK, and the Ministry of Finance. All decision making on orphan drugs is to conduct additional assess- reimbursement applications submitted to the SGK for conven- ments after the enactment of orphan drug legislation [14]. tional drugs must include a pharmacoeconomic analysis [18] One hundred twelve different active substances are listed as (Fig. 1). Orphan drugs are exempted from this requirement. In orphan drugs by Orphanet [15]. The FDA and the European Medi- accordance with the Notification on the Pricing of Medicines, the cines Agency (EMA) have already classified a number of rare diseases TITCK sets the price of these drugs using the reference prices, as and orphan drugs, with the EMA authorizing 60 different orphan documented by the official records of the country of manufacture drugs to date [16,17]. Although there is no official definition of or export (this is considered to be the original price). The SGK orphan drugs in Turkey, a working group has been established and is reviews orphan drug prices annually and revises them on the used in establishing laws and definitions related to rare diseases. basis of their sales volume. All orphan drugs entering the market The Turkish Medicines and Medical Device Agency—Türkiye are reimbursed without any co-payment. Because the TITCK does I˙laç ve Tıbbi Cihaz Kurumu (TITCK)—is responsible for the pricing not have to present a pharmacoeconomic analysis to the SGK for of pharmaceuticals. All drugs in Turkey are subject to a reference reimbursement decisions of orphan drugs, such drugs may enter pricing policy, with France, Greece, Italy, Portugal, and Spain used the market faster than conventional drugs [19]. as the reference countries since 2006. The Social Security Institu- However, most of the orphan drugs accessed in the country, tion—Sosyal Güvenlik Kurumu (SGK)—is responsible for reim- which are not licensed by the TITCK, may be in the hands of the bursement. Two scientific commissions that are responsible for responsible physician and the patient in need with the early setting opinion for reimbursement operate in the evaluation of access procedure defined by the TITCK. This procedure allows such dossiers submitted for the pricing of medicinal products. The physicians to prescribe off-label medications or unlicensed drugs. Medical and Economic Evaluation Commission assesses all orphan The TITCK evaluates off-label and unlicensed medication use for drug applications and conveys its findings to the Reimbursement each patient through off-label application procedures. A treating
Pharmaceu cal Company Makes Applica on for the License of its Product to TITCK
TITCK Evalua on of the License
Nega ve Decision
Posi ve Decision
Pricing Commission Sets the Price Depending on Reference Price Procedures
Product Can Be Distributed in the Market without Reimbursement
Pharmaceu cal Company Makes Applica on for the Reimbursement of Product to SGK
Generics Originals
Is the price under 5% of cheapest generic? MEEC Evaluates the Applica on and Makes the Decision
Yes Reimbursement Commi ee Finalizes the Decision
Nega ve Decision Posi ve 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. VALUE IN HEALTH REGIONAL ISSUES 4C (2014) 47– 52 49
Table 1 – List of orphan medicines in the Turkish Turkish lira were estimated as 1.90, 2.15, and 1.99 for 2008, 2009, market (year 2010). and 2010, respectively. Orphan drug consumption depending on monetary value and volume (number of boxes/units) in years was Authorized Nonauthorized analyzed using Microsoft Excel 2010. A detailed search of the PubMed database for articles pub- Agalsidase Arsenic trioxide lished before 2012 was conducted. The following key words were beta used: “orphan medicines” and “Turkey,”“orphan drugs” and Azasitidine Betaine anhydrous (INN) cystadane powder “Turkey,”“orphan drug” and “Turkey,” and “orphan drug market” Bosentan Carglumic acid and “Turkey.” Eight relevant published articles were found, none Busulfan Clofarabine of which was related to the Turkish orphan medicines market. Dasatinib Eculizumab Deferasirox Ibuprofen Everolimus Idursulfase Imatinib Mecasermin Results Laronidase Mitotane Of 60 different orphan drugs defined by the EMA, 50 entered the Lenalidomide Nelarabine Turkish market in recent years. Half of these were authorized. Miglustat N-acetylgalactosamine-4-sulfatase (Galsulfase) The remaining drugs (preauthorization phase) were imported. All Nilotinib Nitisinone the drugs are fully reimbursed at present. Pegvisomant Plerixafor In 2008, there were 14 authorized and 19 nonauthorized Sildenafil Recombinant human acid alpha-glucosidase orphan drugs on the market. In 2010, there were 18 authorized (Alglucosidase alpha) and 17 nonauthorized orphan drugs (Table 1). As an example, Sorafenib Rufinamide lenalidomide, which was not authorized in 2009, was placed on Sunitinib Sapropterin dihydrochloride the market in 2010. Its total market value increased from €148 Temsirolimus Trabectedin million to €208 million between 2008 and 2010. There was a Thalidomide similar peak in units. Between 2008 and 2010, the units and value of all nonauthorized drugs increased more than those of author- ized drugs (234% and 43%, respectively, and 71% and 24%, physician who wants to prescribe an off-label or unlicensed respectively) (Table 2 and Fig. 2). pharmaceutical is obliged to apply to the TITCK for named The average cost per unit was €1187 in 2008. It decreased to patient approval. The TITCK then evaluates each application on €1002 in 2011. The reduction in the average unit cost was caused the basis of published scientific evidence and the advice of by a decrease in the average unit cost of authorized orphan scientific committees. When the TITCK approves the use of an medicines from €1137 to €878 in the 3 years. The decrease was off-label or unlicensed medicine, the Turkish Pharmacists’ Asso- approximately 22%. The average unit price of unauthorized ciation—Türk Eczacıları Birlig˘i—is then responsible for importing orphan medicines, however, rose from €1885 to €1894 in the 3 the drug, and the cost is directly covered by the SGK’s reimburse- years. In parallel, the difference between the average unit cost of ment scheme, with price margins updated every 6 months [20]. authorized and unauthorized medicines increased from €747 to This illustrates that there are both licensed and unlicensed €1016 in this period. The ratio between the average unit cost of orphan drugs on the Turkish market and that all orphan drugs authorized and unauthorized medicines rose from 1.65 to 2.15. In are covered by a reimbursement scheme, whether licensed or other words, the average unit cost of unauthorized orphan not. The aim of this study was to shed light on the use of orphan medicines was 65% and 115% greater than the average unit cost drugs in Turkey to aid further classifications of rare diseases and of authorized orphan medicines in 2008 and 2011, respectively. assessments of orphan drugs in the country. 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 Methods were followed by alimentary tract and metabolism medicines (Table 3). Darasirox had the highest unit percentage among the The study included orphan drugs recognized by the EU and authorized medicines, but imatinib had the highest value. Among published by the EMA. Sales information of the orphan drugs all unauthorized medicines, galsulfase had the highest unit and authorized by the TITCK was extracted from IMS Turkey for 2008, market share. In addition, five authorized and unauthorized 2009, and 2010. Sales information of nonauthorized orphan drugs orphan drugs shared 78% and 86% of the total orphan drug was extracted from the records of the TITCK. Published govern- market, respectively (Tables 4 and 5). ment prices for authorized and unauthorized drugs were Interesting findings were obtained for lenalidomide, which was extracted from the Web sites of the TITCK and the SGK, respec- an unauthorized drug. Lenalidomide was imported in the preau- tively. The average exchange rates between the euro and the thorization phase in 2009 (409 units consumed) through to the first
Table 2 – Units of and expenditures on orphan medicines. Years License status Units Expenditures (€) Average unit Total (€) Average unit cost cost (€) in total (€)
2008 Licensed 106,676 121,368,283 1137 135,742,519 1187 Unlicensed 7,624 14,374,237 1885 2009 Licensed 147,543 147,141,530 997 182,438,223 1105 Unlicensed 17,554 35,296,693 2010 2010 Licensed 182,509 160,245,988 878 208,518,690 1002 Unlicensed 25,484 48,272,702 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 economic impact of orphan drugs on Turkey. The current findings population to this orphan drug was ensured in the preauthorization should be of use to private and public stakeholders responsible for phase, and sales of lenalidomide rose to 866 units in the remaining decision making relating to Turkey’s orphan drug market. three quarters of 2010. Thus, sales of the drug could be 1154 units if Similar to regulatory and reimbursement procedures, market we extrapolate the three-quarter sales to 1 year with the estima- access procedures for orphan drugs are more complex than those tion. Moreover, the price for reimbursement changed within these for conventional drugs. Although the United States and the EU years. In 2009, when it was available through the easy access have defined rare diseases and orphan drugs, the definitions are procedure, the reimbursement price of lenalidomide was €5301 to not the same. Different definitions may affect all market access €6448, depending on the package size. After the drug was launched schemes in the United States and the EU and cause disagree- in 2010, the price fell to €3920 to €4523 because of reimbursement ments between stakeholders. Nevertheless, it is better to have discounts. The total unit sales of lenalidomide, however, increased some sort of definition than no definition. by 180%, and its total market value rose by 70% following the Orphan drug regulations have been in force in the EU for more decreased reimbursement price after the launch. than 10 years. The average market share of orphan drugs in the According to IMS data, the total market value of reimbursed EU was cited recently as 2% to 3% [21], making it the same as in medicines increased from €6.6 billion to €7.4 billion from 2008 to Turkey. The budget impact of all orphan drugs was mostly lower 2010. The market share of orphan drugs of the total market than that of common drugs, whereas the average budget impact increased from 2% to 3%, a rise of nearly 50%, the highest of orphan molecules was higher than that of conventional increase among all medicinal product categories. molecules. Today, 50 molecules are available for patients with It is noted that there are 1268 different molecules in the positive rare diseases in Turkey, with a market share of approximately 3% list for reimbursement (€7.4 billion) according to the SGK positive list. [22]. The market share, however, may increase in coming years Based on these data, the average market value of the molecules was with the prospective launch of new orphan drugs because the calculated as €5.8 million each for 2010. However, the average market average orphan molecule market value is 30% higher than that of value of orphan molecules was calculated as €7.5 million for 2010. 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 Conclusions and Discussion between the units and market value in these years might be The findings of this study provide unique information on the due to public price cuts, with mandatory discount rates increasing orphan drug market in Turkey. Based on the literature search, to from 20.5% to 32.5% between 2008 and 2010. In addition, reference the best of our knowledge, this is the first study examining the prices might have changed.
Table 3 – Expenditures on orphan medicines in various diseases areas. Orphan medicine/disease area Year 2008 (€) Year 2009 (€) Year 2010 (€)
Antineoplastic agents 95,096,278,89 108,864,374,02 120,993,262,64 Alimentary and metabolism medicines 13,312,231,05 30,521,111,84 38,648,694,19 Others 14,896,114,74 27,418,393,49 29,275,317,09 Cardiovascular system 12,358,488,11 14,876,912,49 17,538,804,04 Systemic endocrinology 79,406,84 714,876,05 1,498,708,99 Urogenital and sex hormones 0.00 42,555,35 563,537,69 Nervous system 0.00 0.00 366,00 VALUE IN HEALTH REGIONAL ISSUES 4C (2014) 47– 52 51
Table 4 – Expenditures of top five authorized and evaluations by the TITCK earlier and the removal of these nonauthorized orphan medicines. after licensing of the drug. The authorized drug reimburse- ment process likely also enhanced patient access to the drug. Medicine Expenditure Against all odds, this discrepancy is in need of further € ( ) assessment. Although orphan drug legislation is not yet established in Authorized Turkey, pricing and reimbursement policies for this particular Imatinib 58,321,077 group of drugs are already in place. As noted in an earlier study, Deferasirox 29,275,317 incentives to develop orphan drugs do not yet exist in Turkey; Bosentan 17,294,108 however, procedures are in place to facilitate access to orphan Sunitinib 12,741,874 drugs [22]. As a result, patients can access treatment in a rapid Dasatinib 8,931,977 and equitable manner [22]. This study facilitates additional Total top five 126,564,353 analyses of orphan drug prices and reimbursement in Turkey. Nonauthorized Further evaluation of prices of authorized and unauthorized N-acetylgalactosamine-4-sulfatase 18,220,410 orphan drugs could be carried out on a case-by-case basis. The (Galsulfase) latter would shed light on the diverse pricing and reimbursement Idursulfase 11,148,800 policies of countries worldwide. Eculizumab 6,665,400 Nitisinone 2,773,472 Recombinant human acid alpha- 2,731,850 REFERENCES glucosidase Total top five 41,539,932 [1] Analysis Group. Innovation in the biopharmaceutical pipeline: a multidimensional view. Available from: http://www.phrma.org/sites/ default/files/pdf/2013innovationinthebiopharmaceuticalpipeline- However, the average unit cost for authorized orphan drugs analysisgroupfinal.pdf. 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