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Treatment costs for advanced prostate cancer using luteinizing hormone-releasing hormone agonists: a solid biodegradable leuprorelin implant versus other formulations Aim: To compare treatment costs with alternative luteinizing hormone-releasing hormone (LHRH) agonist preparations and determine whether a leuprorelin solid implant is associated with potential cost savings. Patients & methods: A hypothetical population of 1000 prostate cancer patients was apportioned between the three most commonly-prescribed LHRH agonist preparations. Differentiated annual costs for 1- and 3-monthly formulations were calculated for France, Germany, Italy, Spain, the UK (EU5) and Sweden, and compared with the leuprorelin solid implant. Results: Compared with alternative formulations, leuprorelin solid implants had potential annual cost savings/1000 patients of €353,000 (EU5) and €699,000 (Sweden; 1-month formulations), and €259,000 (EU5) and €300,000 (Sweden; 3-month formulations). Conclusion: The leuprorelin solid implant was associated with potential cost savings compared with the most commonly used LHRH agonist preparations. Keywords: costs • economics • leuprorelin • luteinizing hormone-releasing hormone agonists • prostate cancer
Prostate cancer is the second most common type of cancer among men, with more than 1 million people worldwide diagnosed with the disease during 2012 [1] . This figure is expected to rise to more than 1.4 million cases in 2020 as the global population increases and ages [1] . The incidence of prostate cancer varies geographically, and currently approximately 70% of diagnosed cases are in more developed countries, largely because prostate-specific antigen (PSA) testing is more widespread in these regions [1] . Prostate cancer brings with it a substantial burden of morbidity, mortality and financial cost [2,3] . The total economic cost of prostate cancer in the EU was estimated at €8.43 billion in 2009 [3] , and costs are expected to rise in the future due to increased diagnosis at an earlier stage and increased survival [4] . Hormonal therapy accounts for a substantial proportion of the costs associated with prostate cancer [5] , and one approach to help offset some of the anticipated future
10.2217/cer.15.30 © Davide Meani
increase in overall costs would be to determine whether cost savings can be achieved by using particular formulations of commonly used therapies. Androgen deprivation therapy (ADT) is a mainstay of the management of patients with advanced prostate cancer [6] , and longacting luteinizing hormone-releasing hormone (LHRH) agonists, synthetic analogs of hypothalamic LHRH, are the standardof-care pharmacological therapy for metastatic disease [7] . Several different LHRH agonists are available in various formulations (powders requiring reconstitution, microsphere formulations and solid implants), and with different routes of administration (subcutaneous or intramuscular) and storage requirements [8] . The different products have practical differences (including whether a drug is ready for immediate use or requires reconstitution) that need to be considered in everyday practice [7] . The most commonly used LHRH agonists are leuprorelin and goserelin [8] .
J. Comp. Eff. Res. (2015) 4(5), 447–453
Axel S Merseburger1, Thomas Björk2, James Whitehouse3 & Davide Meani*,4 Department of Urology & Urologic Oncology, Hannover Medical School, Hannover, Germany 2 Department of Surgery & Urology, Skåne University Hospital, Malmö, Sweden 3 Norgine, Norgine House, Widewater Place, Moorhall Road Harefield, Uxbridge, UB9 6NS, UK 4 Sandoz Biopharmaceuticals, Sandoz International GmbH, Industriestraße 25, 83607 Holzkirchen, Germany *Author for correspondence: Tel.: +49 802 4476 4850 Fax: +49 802 4476 2899
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Research Article Merseburger, Björk, Whitehouse & Meani One leuprorelin preparation (Leuprorelin Sandoz®, Leuprone ®, Hexal®, Sandoz/Hexal, Holzkirchen, Germany) [9] with unique pharmaceutical properties is a solid biodegradable subcutaneous implant supplied in a ready-to-use syringe, which was initially approved in Germany in 2007, and is currently available in 23 European countries (36 countries worldwide). Based on sales data, it is estimated that there have been >110,000 patient-years of use with this medicinal product worldwide. The active drug is dispersed in a biodegradable polymer containing lactic acid and glycolic acid (1-month implant; 3.78 mg leuprorelin acetate) or lactic acid alone (3-month implant; 5.25 mg leuprorelin acetate). The implant is inserted into the abdominal wall by subcutaneous injection, where it is hydrolytically degraded to release the drug. Potential benefits of the implant compared with some other LHRH agonist preparations are that it is ready to use, requires no reconstitution and does not need to be stored in a refrigerator. In clinical trials, the leuprorelin solid implant administered every 1 or 3 months was as effective as established leuprorelin microsphere formulations at suppressing testosterone and normalizing PSA levels, and was well tolerated [10,11] . The aim of the current study was to evaluate whether the leuprorelin solid implant was associated with cost savings compared with the most widely used 1- and 3-month LHRH agonist formulations in a European setting. Patients & methods Using simple cost and volume measurements, an analysis was performed to compare costs across various treatments for prostate cancer. A hypothetical population of 1000 patients with prostate cancer were apportioned between the current most commonly prescribed hormonal treatments for advanced prostate cancer. The apportionment was based on the drug market share for 14 EU countries, and was scaled up from the data shown in Figure 1 & Supplementary Figure 1 (see online at www.futuremedicine.com/doi/full/10.2217/cer.15.30) [12] . The top three most common preparations were leuprorelin powder for reconstitution and injection (Eligard®, Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany), leuprorelin microsphere injection (Enantone ®, Takeda Pharma GmbH, Aachen, Germany, other brand names: Trenantone®/Procrin®/Prostap®) and goserelin implant (Zoladex®, AstraZeneca GmbH, Wedel/Schleswig-Holstein, Germany) (Table 1) . Drug costs for 1- and 3-month formulations of these products were calculated for six countries: France, Germany, Italy, Spain, UK (collectively referred to as EU5) and Sweden. Drug cost data for each country
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were obtained from the following sources: UK [13] , Germany [14] , France [15] , Italy [16] , Spain [17] and Sweden [18] . The total cost for a 1-year treatment period using each product was calculated for the population of 1000 patients, to give a base cost for the current situation. Costs were reported in Euros. The cost calculations for these products included the preparation time for Enantone (3 min [19] ) and Eligard (4 min, according to Eligard preparation video instructions) but not the time to come to room temperature (approximately additional 20–30 min for Eligard). It was assumed that products were prepared by a nurse, and a proxy for the cost of the nurse for each market was calculated based on wages on the PayScale website [20] multiplied by the preparation time. This was added to the total costs for each market. The additional time was totalized to provide an estimate of potentially avoidable time wastage. An analysis was then performed for a hypothetical scenario in which all 1000 patients from each market were switched to the leuprorelin solid implant (Leuprorelin-Sandoz®). The cost of the solid implant was calculated for each market. For those markets where it is not yet available, the lowest price from comparator products available in that specific market was used. The total cost of the leuprorelin solid implant for the hypothetical population of 1000 patients for each market was calculated, and compared with the total costs for the three comparator products. In addition, the labor time (h) potentially saved by using the ready-to-use leuprorelin solid implant was estimated. Results Drug cost data per country are summarized in Table 2. The cost analysis based on the 1-month formulations found that, compared with using the top three LHRH agonist preparations, use of the leuprorelin solid implant was associated with a potential cost saving per 1000 patients of €353,000 for the EU5 market and €699,000 for Sweden over the 1-year timeframe (Figure 2A) . When 3-month formulations were considered, the leuprorelin solid implant was associated with a potential annual cost saving per 1000 patients of €259,000 for the EU5 market and €300,000 for Sweden (Figure 2B) . The leuprorelin solid implant was also associated with a reduction in labor time compared with use of the top three LHRH agonist formulations, because it required less preparation time than some of the alternative formulations. It was estimated that the leuprorelin implant saved a total of approximately 30 h of labor time per 1000 patients per year in each market (177 h across all six markets combined). To place these results in a wider context, data from
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Prostate cancer treatment costs: leuprorelin solid implant
2012 regarding the unit sales and expenditure for leuprorelin and goserelin in the various markets were considered (Supplementary Figure 2) . If the total unit sales were priced using the average cost per unit of the leuprorelin solid implant, it suggested the potential to save an average of about €53 million and €42 million using the 1- and 3-month implants, respectively, across the six markets included in the analysis. Discussion This study found that the use of a solid leuprorelin implant formulation was associated with substantial cost and time savings compared with other LHRH agonist preparations in common use for the treatment of advanced prostate cancer. The cost of prostate cancer is high. Across the EU, prostate cancer was responsible for 7% of overall cancer costs in 2009, associated with total costs of over €8 billion [3] . Another European study (covering France, Germany, Italy, Spain and the UK) found that the mean direct costs per patient during the first year after diagnosis ranged from €3256 in Spain to €5851 in France [21] . In France, initial treatments account for up to 80% of the direct costs from the healthcare payer’s perspective [22] , while a UK study found that hormonal therapy accounted for approximately twothirds of the total costs associated with prostate cancer during a 5-year period [5] . The costs associated with prostate cancer are likely to rise in the future, as men’s life expectancy increases, diagnosis improves and new therapies emerge. In addition, men are remaining on ADT for longer than in the past [23] . It is therefore increasingly important that cost-effective therapeutic measures are used, and consideration should be given to ways of reducing costs where possible, without adversely affecting clinical outcomes. LHRH agonists are currently the main form of ADT used in men with advanced and metastatic prostate cancer [7] , and given this key role, they inevitably account for a substantial proportion of the costs associated with the treatment of the disease. Several different LHRH agonists are available in a variety of slow-release formulations which are administered at intervals of 1, 3, 4 or 6 months. The most commonly prescribed LHRH agonist products in the EU in 2011 were goserelin (administered as a subcutaneous implant), and two different leuprorelin products, including a microsphere formulation and formulations that require reconstitution prior to injection (Table 1) . One of the alternative LHRH agonist options available in some European countries is a solid implant formulation of leuprorelin that is supplied ready-to-use in a prefilled syringe. This avoids the
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2%
25% 61%
Leuprorelin Goserelin Triptorelin Buserelin
Figure 1. Global luteinizing hormone-releasing hormone agonist market in 2011, according to molecule. Data taken from [12] .
need for preparation and reconstitution which some other leuprorelin formulations require, and this could save time for healthcare workers and patients. Indeed, the current study suggests that if the leuprorelin solid implant was used instead of the current top three LHRH agonists, 30 h of labor time could be saved per 1000 patients over a 1- year period. Our study also found that over the 1-year timeframe, use of the 1-month or 3-month solid leuprorelin implant could lead to average cost savings of €353,000 and €259,000, respectively, per 1000 patients across Germany, France, Italy, Spain and the UK, and savings of €699,000 and €300,000 per 1000 patients in Sweden. Extrapolating the estimated savings to the number of units of leuprorelin and goserelin sold in 2012, the 1-month and 3-month leuprorelin solid implants could potentially save an average of €53 million and €42 million, respectively, across the six markets included in the analysis. It is important that economic benefits should not be at the expense of clinical effectiveness. The overall efficacy and tolerability profiles of the different LHRH agonist formulations are largely accepted to be similar, although direct head-to-head comparisons are often lacking and observations are generally based on noncomparative evaluation [7] . Nevertheless, clinical trials have established that the leuprorelin solid implant administered every 1 or 3 months is as effective at suppressing testosterone and normalizing PSA levels as traditional microsphere leuprorelin formulations, and has a similar tolerability profile [10] . Furthermore, patients who switched from a range of standard LHRH agonist therapies to the leuprorelin implant experienced significant improvements in testosterone and PSA levels after the switch [11] . Taken together with the cost analysis data, this suggests that cost and time savings could be achieved by using the
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Research Article Merseburger, Björk, Whitehouse & Meani
Table 1. Top three most commonly prescribed luteinizing hormone-releasing hormone agonist products in the EU. Generic name Brand name
Dosing interval, strength and formulation
1 month
3 months
Goserelin
Zoladex®
3.6 mg; implant in prefilled syringe for sc. injection
10.8 mg; implant in prefilled syringe for sc. injection
Leuprorelin
Enantone® / Trenantone® / Procrin® /Prostap®
3.75 mg; microsphere powder in prefilled syringe for sc. and/or im. injection
11.25 mg; microsphere powder in prefilled syringe for sc. and/or im. injection
Leuprorelin
Eligard®
7.5 mg; powder and liquid gel for mixing prior to sc. injection; forms a solid implant
22.5 mg; powder and liquid gel for mixing prior to sc. injection; forms a solid implant
im.: Intramuscular; sc.: Subcutaneous.
leuprorelin implant, without any sacrifice of clinical effectiveness. One of the limitations of the current study was that the hypothetical population was restricted to 1000 patients per market. Although a preliminary extrapolation to the full market was explored, further research is needed to assess potential savings for the entire prostate cancer patient population in the individual countries and across the wider market. The study used a 1-year treatment period, and data for a longer timeframe would also be useful. The analysis was limited to comparisons with LHRH agonist formulations administered at 1- and 3-month intervals (formulations prescribed most widely in the countries considered in the analysis), and did not consider other LHRH agonist formulations that are administered at 6- or 12-month intervals (Leuprorelin Sandoz is not available in 6- or 12-monthly formulations), or other ADT modalities or orchiectomy (not within the scope of the current analysis). Furthermore, an exten-
sive analysis of the comparative effectiveness, and cost–effectiveness, of the leuprorelin solid implant and other alternatives is currently limited by a paucity of data, and is beyond the scope of the current study. Nevertheless, this area could potentially be addressed in the future by performing a Markov model-based sensitivity analysis which incorporates effectiveness outcomes over a longer time horizon. It should also be noted that the leuprorelin solid implant is not currently available for use in France, Spain or the UK. Our results are in concordance with a study from Italy in which leuprorelin 22.5 mg proved to be the most cost-effective treatment compared with leuprorelin 11.25 mg, triptorelin 11.25 mg, buserelin 9.9 mg and goserelin 10.8 mg [24] . Nonetheless, the performed analysis does suggest the potential for considerable savings through the use of the leuprorelin solid implant. Such savings could release funds for other elements of the management of patients with prostate cancer, including expensive
Table 2. Costs associated with luteinizing hormone-releasing hormone agonist treatment. Country
Zoladex®
Enantone®
Eligard®
Leuprorelin-Sandoz®
1-month formulations UK
€911.92
€1055.59
€0.00
€911.92
Germany
€2340.48
€2108.16
€2247.48
€1585.20
France
€1663.44
€1646.04
€1486.68
€1486.68
Italy
€2340.72
€2134.20
€1797.24
€1600.68
Spain
€1275.72
€1909.44
€1936.80
€1275.72
Sweden
€2157.72
€1964.28
€1987.08
€1358.76
3-month formulations
450
UK
€1098.98
€1055.59
€0.00
€1055.59
Germany
€2047.72
€1970.72
€1843.40
€1537.20
France
€1520.52
€1504.60
€1358.32
€1358.32
Italy
€2369.40
€1840.56
€1549.96
€1380.44
Spain
€1523.72
€1388.84
€1412.88
€1388.84
Sweden
€1318.92
€1598.40
€1375.84
€1125.20
J. Comp. Eff. Res. (2015) 4(5)
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Prostate cancer treatment costs: leuprorelin solid implant
€2,500,000
€2,500,000
€2,000,000
€2,000,000
€1,500,000
€1,500,000
€1,000,000
€1,000,000
€500,000
€500,000
€0
UK
Germany France
Italy
Spain
Sweden
Top three LHRHa
Leuprorelin-Sandoz®
€0
UK
Germany France Top three LHRHa
Research Article
Italy
Spain
Sweden
Leuprorelin-Sandoz®
Figure 2. Mean annual total costs per 1000 patients based on the use of 1-month formulations (A) or 3-month formulations (B) of the solid leuprorelin implant versus the top three luteinizing hormone-releasing hormone agonists. LHRHa: Luteinizing hormone-releasing hormone agonist.
novel therapeutic innovations. Conclusion & future perspective Recent advances in the development of new LHRH agonist formulations represent an opportunity to reduce future costs associated with prostate cancer. Although further studies are warranted, our preliminary analysis suggests that the use of the leuprorelin solid implant could be associated with substantial cost and time savings compared with the most commonly used alternative LHRH agonist preparations. Given
the substantial impact of advanced prostate cancer on healthcare resources, treatments that could potentially reduce the economic burden of the disease should be of future interest to clinicians and healthcare decision-makers. Financial & competing interests disclosure This study was funded by Sandoz International GmbH, Germany. AS Merseburger has been a study investigator for Novartis, Bayer, Pfizer, Wyeth, Ipsen, TEVA, Astellas, Janssen and GSK; a speaker for Janssen, GSK, Ipsen, Novartis, Astel-
Executive summary Background • Luteinizing hormone-releasing hormone (LHRH) agonists, such as leuprorelin and goserelin, are central to the management of patients with advanced prostate cancer. • The leuprorelin solid implant administered every 1 or 3 months is as effective as leuprorelin microsphere formulations in patients with advanced prostate cancer. This cost analysis compared treatment costs between the most commonly used LHRH agonist preparations and the leuprorelin solid implant.
Patients & methods • The analysis was based on a hypothetical population of 1000 prostate cancer patients apportioned between the three most commonly prescribed LHRH preparations. • Costs were calculated based on using 1- or 3-month formulations for a 1-year treatment period in France, Germany, Italy, Spain, UK (EU5) and Sweden, and were compared with the cost of the leuprorelin solid implant.
Results • Compared with the alternative LHRH agonist preparations, the leuprorelin solid implant was associated with potential annual cost savings per 1000 patients of €353,000 (1-month formulations) and €259,000 (3-month formulations) for the EU5, and €699,000 and €300,000, respectively, in Sweden. • Use of the ready-to-use leuprorelin solid implant (in a prefilled syringe), was associated with potential annual labor time savings of 30 h/1000 patients compared with the alternative preparations, some of which require reconstitution prior to administration.
Conclusion • In patients with prostate cancer, use of the leuprorelin solid implant could be associated with substantial cost and time savings compared with the most commonly used alternative LHRH agonist preparations.
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Research Article Merseburger, Björk, Whitehouse & Meani las, Bayer, Sanofi Aventis, TEVA and Hexal; an advisory board member for Ipsen, Novartis, Astellas, Janssen, Bayer, Pfizer and TEVA; received grants from Wyeth, and EU Horizon 2020. D Meani is an employee of Sandoz International GmbH, Germany. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors acknowledge the assistance of David P Figgitt, Content Ed Net, funded by Sandoz International GmbH, in the preparation of this manuscript.
Ethical conduct of research
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