Economic Evaluation of Ophthalmic Solutions for Glaucoma Treatment Including Consideration of Clinical Efficacy

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1 Regular Article Jpn J Pharm Health Care Sci 40(9) (2014) Economic Evaluation of Ophthalmic Solutions for Glaucoma Treatment Including Consideration of Clinical Efficacy Takashi Tomita 1, Hiroaki Ikeda 1, *2, Hiroshi Sakurashita 1, Hidetoshi Tsukamoto 3 and Kenji Kihira 1 Department of Pharmaceutical Services, Hiroshima University Hospital 1, Faculty of Pharmaceutical Sciences, Hokuriku University 2, Takayama Eye Clinic 3 Received February 18, 2014 Accepted July 29, 2014 In order to elucidate the cost-effectiveness of various ophthalmic solutions used for the treatment of glaucoma, we compared the daily price for solutions resulting in a 1-mmHg reduction in intraocular pressure (IOP) in glaucoma patients. The IOP reduction achieved by each ophthalmic solution was obtained from the literature and standardized to the reduction achieved by 0.5% timolol maleate. We applied these values to a model patient with a baseline IOP of 24 mmhg, who showed a 20 % reduction (4.8 mmhg) after treatment with 0.5% timolol maleate, and calculated an IOP reduction estimate for each product. The total number of drops per bottle, and the National Health Insurance (NHI) prices of the products were used to calculate the daily price of the ophthalmic solutions. The daily price of solutions resulting in 1-mmHg IOP reduction ranged from 6.7 to 17.0 yen. Further, the daily price distribution was notably different from that of the NHI prices per bottle. The approach used in the current study could be applied to generic products if the clinical data and actual products were obtained, and should be a part of routine glaucoma management. Key words economics, glaucoma, intraocular pressure, daily price, ophthalmic solution Introduction The economic considerations associated with glaucoma therapy often involve a comparison of the prices of ophthalmic solutions. However, several studies have demonstrated significant differences in the efficacy of various glaucoma medications, especially among different categories. 1) The reduction in intraocular pressure (IOP) is usually the primary focus, as opposed to product price. Additionally, the daily dosage of ophthalmic solutions often varies, as well as the total number of drops in an individual bottle of each product. 2-6) Accordingly, a simple comparison of the prices of products could be misleading, and a method for adjusting these factors for the purposes of con- ducting a valid economic evaluation required. In this report, we propose a method for evaluating the economic and clinical aspects of available glaucoma medications that entails the calculation of a daily price, based on the observed IOP reduction for each product. Materials & Methods 1. Ophthalmic solutions evaluated In this retrospective study, we evaluated existing literature on 17 ophthalmic solutions as detailed below: Five prostaglandin analogues: 0.005% latanoprost (Xalatan, Pfizer Japan Inc, Tokyo); % tafluprost (Tapros, Santen * Ho-3, Kanagawa-machi, Kanazawa, Ishikawa , Japan 500

2 Vol 40,No 9(2014) Pharmaceutical Co, Ltd, Osaka); 0.004% % travo- prost (Travatanz, Alcon Japan Ltd, Tokyo); 0.03% bimatoprost (Lumigan, Senju Pharmaceutical Co, Ltd, Osaka); and 0.12% isopropyl unoprostone (Rescula, R-Tech Ueno, Ltd, Tokyo). Two carbonic anhydrase inhibitors: 1% % brinzo- lamaide (Azopt, Alcon Japan Ltd); and 1% dorzolamide (Trusopt, MSD KK, Tokyo). An α2-adrenergic receptor agonist: 0.1% brimonidine tartrate (Aiphagan, Senju Pharmaceutical Co, Ltd). Eight β-adrenergic receptor antagonists (β-blockers): 0.25% nipradilol (Hypadil Kowa, Kowa Company, Ltd, Nagoya); 0.5% % levobuno- lol (Mirol, Kyorin Pharmaceutical Co, Ltd, Tokyo); 0.5% timolol maleate (Timoptol, Timoptol -XE, MSD KK, and Rysmon TG, Wakamoto Pharmaceutical Co, Ltd, Tokyo); 0.5% betaxolol (Betoptic, Alcon Japan Ltd); 2% carteolol (Mikelan and Mikelan LA, Otsuka Pharmaceutical Co, Ltd, Tokyo). An α-adrenergic receptor antagonist (α- blocker): 0.01% bunazosin (Detantol, Santen Pharmaceutical Co, Ltd). 2. Literature search and selection criteria Literature search: For evaluation of IOP reduction, we searched for literature addressing the assessment of the products included on the study. First, we identified Japanese Phase III studies of each product from the product labels, as well as the Pharmaceutical Interview Forms, which served the detailed product information provided by manufacture. If the design of the study did not meet inclusion criteria or the results of the study were not published, we searched the eligible studies from the Ichushi Web, which is the Japan's medical-literature database from the Japan Medical Abstract Society, and MEDLINE using PubMed. Selection criteria: The retrospective data analysis included published literature that met the following inclusion criteria: 1) The study population was comprised of glaucoma patients who had no prior treatment history, or who had adhered to a sufficient washout period before starting the study treatment. 2) The IOP for the respective ophthalmic solution was measured for 1 3 months after starting treatment. 3) The study involved the use of 0.5% timolol maleate or other drugs that were compared to 0.5% timolol maleate in other literature. 3. The IOP reduction of each product relative to timolol maleate To calculate the relative IOP reduction, we hypothesized a glaucoma patient with an IOP of 24 mmhg, whose IOP reduction was 20% (4.8 mmhg) after 0.5% timolol maleate treatment. The IOP reduction of each product was adjusted to a rate to the reduction observed following treatment with 0.5% timolol maleate (Equations 1 & 2). If studies of a study drug that involved a comparison to timolol maleate could be identified, the IOP reduction of the ophthalmic solution was calculated using Equation 2a (directly calculated IOP reduction). In cases where no publications that compared the study drug to timolol maleate could be found, the IOP reductions were calculated using Equation 2b (indirectly calculated IOP reduction). 501

3 Jpn J Pharm Health Care Sci Equation 1 IOP reduction rate = IOP baseline IOP :test medication arm IOP baseline IOP :competitor arm Where IOP = Difference in IOP before versus after treatment Equation 2 Estimated IOP reduction of each drug a. For agents WITH prior comparison to 0.5% timolol maleate (direct calculation): 4.8 IOP reduction rate (vs timolol) b. For agents WITHOUT prior comparison to 0.5% timolol maleate (indirect calculation): 4.8 IOP reduction rate (vs competitor) IOP reduction rate of "competitor" (vs timolol) If IOPs were measured twice a day or more, we chose the IOP measured at approximately 2 hours after drug instillation. 4. Daily price per 1-mmHg IOP reduction The theoretical daily price of each product was calculated as previously reported. 4, 6, 7) Briefly, the total number of drops in one bottle of each product was calculated by counting each drop dispensed at room temperature. All calculations were performed in triplicate by a single investigator. The price of one drop was calculated by dividing the price of one bottle (at the National Health Insurance (NHI) price as of April 2013) by the average total number of drops per bottle. The daily price was then calculated by multiplying the cost of one drop by the number of drops indicated for daily instillation (one drop for each eye per use). Results Eleven studies were identified that compared one of the ophthalmic solutions included in the current study with 0.5% timolol maleate. 1, 8-17) Additionally, two such studies were identified that included 0.005% latanoprost, 18, 19) as well as one study that involved 2% carteolol. 20) No published study for 1% dorzolamide met the study criteria, due largely to the fact that in Japan, 2% % dorzol- amide was not approved for clinical use because the phase III data revealed 1% % and 2% % dorzol- amide had equivalent efficacy. 21) Therefore, the values reported in a study that compared 2% % dor- zolamide with 0.5% timolol maleate were used for our calculations. 22) The average baseline IOP values in the clinical studies selected ranged from 22.1 to 27.9 mmhg, while the IOP reduction ranged from 15.0 to 31.9%, and the length of the study period varied from 28 to 90 days (Table 1). The estimated IOP reduction in our hypothetical patient ranged from 4.0 to 7.2 mmhg. The NHI price for a bottle of each product ranged from 1,443 to 2,449 yen. The number of drops per 2.5-mL bottle ranged from 62 to 101 drops, while the average number of drops in a 5-mL bottle ranged from 120 to 191 (Table 2). The daily price calculated using the price of a drop and the number of drops per daily instillation ranged from 37.2 to 72.6 yen. The daily price of a 1-mmHg reduction in IOP (theoretical daily price divided by the estimated IOP reduction) was 6.7 to 17.0 yen (Fig 1). Discussion The effectiveness of various categories of ophthalmic solutions differs widely with decreasing 502

4 Vol 40,No 9(2014) Table 1 Estimated IOP reduction Study drug Competitor IOP evaluation Baseline IOP (mmhg) Study drug/ competitor Δ IOP (mmhg) Study drug/ competitor IOP reduction rate (vs competitor) IOP reduction rate (vs timolol) Estimated IOP reduction (mmhg) 0.005% Latanoprost qd 0.5% Timolol maleate bid 12- am 9: week before instillation % Tafluprost qd 0.005% Latanoprost qd am 9:00-11:00 week * % Travoprost qd 0.005% Latanoprost qd 12- am 12: week am 8:00 instillation * % Bimatoprost qd 0.005% Latanoprost qd 12- am 12: week am 8:00 instillation * % Isopropyl 12-4 hours later after unoprostone week morning instillation % Brinzolamide 12- am 10: tartrate week am 8:00 instillation % Dorzolamide 3-2 hours after instillation tid 0.5% Timolol maleate bid month on am 9: % Brimonidine 4-2 hours after tartrate week morning instillation % Nipradilol hours after week morning instillation % Levobunolol 12- before week morning instillation % Timolol maleate hours after GFS a) qd 0.5% Timolol maleate bid week morning instillation % Timolol maleate hours after TSG b) qd 0.5% Timolol maleate bid week morning instillation % Betaxolol 12-3 hours week after instillation % Carteolol 90- over 1 hour after day morning instillation % Carteolol 60- am 11: Alg c) qd 2% Carteolol bid day 2 hours after instillation * % Bunazosin hours after morning Bid 0.5% Timolol maleate bid week instillation * INDIRECTLY calculated IOP reduction. a) GFS: gel-forming solution, b) TSG: thermo-setting gel, c) Alg: formulation containing alginic acid. qd: quaque die, once daily, bid: bis in die, twice daily, tid: ter in die, three times daily. Reference 503

5 Jpn J Pharm Health Care Sci Table 2 Daily price of each ophthalmic solution Product Dosing frequency Price per bottle (yen) Drops per bottle Price per drop (yen) Daily price (yen) 0.005% Latanoprost Xalatan qd 1, ± ± ± % Tafluprost Tapros qd 2, ± ± ± % Travoprost Travatanz qd 2, ± ± ± % Bimatoprost Lumigan qd 2, ± ± ± % Isopropyl unoprostone Rescula bid 1, ± ± ± 2.3 1% Brinzolamide Azopt bid 2, ± ± ± 3.7 1% Dorzolamide Trusopt tid 1, ± ± ± % Brimonidine tartrate Aiphagan bid 2, ± ± ± % Nipradilol Hypadil Kowa bid 1, ± ± ± % Levobunolol Mirol bid 2, ± ± ± % Timolol maleate Timoptol bid 1, ± ± ± % Timolol maleate GFS a) Timoptol -XE qd 1, ± ± ± % Timolol maleate TSG b) Rysmon TG qd 1, ± ± ± % Betaxolol Betoptic bid 1, ± ± ± 3.3 2% Carteolol Mikelan bid 1, ± ± ± 1.0 2% Carteolol Alg c) Mikelan LA qd 1, ± ± ± % Bunazosin Detantol bid 1, ± ± ± 3.2 a) GFS: gel-forming solution, b) TSG: thermo-setting gel, c) Alg: formulation containing alginic acid. qd: quaque die, once daily, bid: bis in die, twice daily, tid: ter in die, three times daily. Each value for drops per bottle, price per drop and daily price is presented as mean ± standard deviation. Fig. 1 Daily price of solutions resulting in a 1-mmHg IOP reduction Open bars: prostagrandin analogues, closed bars: carbonic anhydrase inhibitors, dotted bar: α2-adrenergic receptor agonist, hatched bars: β-adrenergic receptor antagonists, shaded bar: α-adrenergic receptor antagonist. a) Timolol GFS: gel-forming solution, b) Timolol TSG: thermo-setting gel, c) Carteolol Alg: formulation containing alginic acid. IOP. 1, 17, 22) For example, 0.01% % bunazosin was reported to reduce IOP by 15%, while 0.5% % betax- olol was reported to reduce IOP by 20%. 15, 17) However, baseline IOP differed by 1.5 mmhg between the two studies. In the current study, we used 0.5% % timolol maleate as the basis for comparison in our hypothetical patient model. The estimated IOP reduction achieved in the model was 4.0 mmhg for both 0.01% bunazosin and 0.5% betaxalol (Table 1). Generally, a comparison of the efficacy of two or more drugs based on different study results is not accurate. However, the 504

6 Vol 40,No 9(2014) values obtained in the current study were consistent with the level of IOP reduction noted in clinical practice. Hence, the results suggest the validity of our model for the evaluation of IOP reduction. Additionally, the economic evaluations of ophthalmic solutions are generally accomplished by comparing the price per bottle. Notably, factors that can influence the volume of one drop, such as the bottle shape, nozzle design, or fluid properties of the solution affect the total number of drops per bottle. Further, differences in the usable duration of one bottle could cause discrepancies between the daily price and the price of one bottle. For example, the price per bottle of a prostaglandin analog was relatively high, but the daily price was comparable to that of other categories of ophthalmic solutions (Table 2). We calculated the daily price of a 1-mmHg IOP reduction, and discovered that the resulting distribution of values was notably different from the NHI price per bottle. In this study, we evaluated only innovator products with a single active ingredient. However, the method should be applicable to generic products or a fixed-dose combination of products if the clinical data and actual products are obtained. The generic ophthalmic solution products had the same active ingredients, but had different additives or were marketed in different containers. A number of factors limited the current study. Despite attempts to standardize the IOP included by using measurements taken 2 hours after drug instillation, two of the studies included in this analysis only measured IOP prior to drug instillation. As well, we typically included the IOP obtained at 8 12 weeks, but three studies only provided the IOP measured at 4 weeks. The standardization of the design employed in drug development studies should also be considered. Additional method validation is required; however, we believe the economic evaluation of available treatments should be a routine component of glaucoma management. Conflict of Interest The authors have no conflicts of interest to disclose. References 1) Stewart WC, Sine C, Cate E, Minno CG, Hunt HH, Daily cost of β-adrenergic blocker therapy, Arch Ophthalmol, 1997, 115, ) Ikeda H, Sato E, Kitaura T, Fukuchi H, Kimura Y, Kihira K, Daily cost of ophthalmic solutions for treating glaucoma in Japan, Jpn J Ophthalmol, 2001, 45, ) Rouland JF, Le Pen C, Gouveia Pinto C, Berto P, Berdeaux G, Cost-minimisation study of dorzolamide versus brinzolamide in the treatment of ocular hypertension and primary open-angle glaucoma in four European countries, Pharmacoeconomics, 2003, 21, ) Ikeda H, Practice of pharmaceutical care -therapeutic drug monitoring and pharmacoeconomics of glaucoma-, Yakugaku Zasshi, 2007, 127, ) Mishima H, Masuda K, Araie M, Kitazawa Y, Shiose Y, Azuma I, Mizogami K, Ogawa N, Phase III clinical study on PhXA41 ophthalmic solution on primary open angle glaucoma and ocular hypertension, A multicenter, double-blind comparison with 0.5% timolol maleate, Jpn Rev Clin Ophthalmol, 1996, 90, ) Ball SF, Schneider E, Cost of β-adrenergic receptor blocking agent for ocular hypertension, Arch Ophthalmol, 1992, 110, ) Tomita T, Sakurashita H, Ikeda H, Tsukamoto H, Kihira K, Usable period and daily cost of prostaglandin-like agent ophthalmic solutions, Atarashii Ganka (J Eye), 2011, 28, ) Azuma I, Masuda K, Kitazawa Y, Takase M, Yamamura H, Double-masked comparative study of UF-021 and timolol ophthalmic solutions in patients 505

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