Pharmacology and therapeutics
Cost-efficacy of biologic therapies for moderate to severe psoriasis from the perspective of the Taiwanese healthcare system Shu-Hui Wang1,2,3, MD, MS, Ching-Chi Chi4,5, MD, MMS, DPhil (Oxf), and Sindy Hu3,5,6, MD, MS
1 Department of Dermatology, Far Eastern Memorial Hospital, New Taipei, 2 Department of Healthcare Administration, Oriental Institute of Technology, New Taipei, 3Department of Cosmetic Science, Chang Gung University of Science and Technology, Taoyuan, 4Department of Dermatology, Chang Gung Memorial Hospital Chiayi, Chiayi, 5College of Medicine, Chang Gung University, Taoyuan, and 6Department of Dermatology, Chang Gung Memorial Hospital Taoyuan, Taoyuan, Taiwan
Abstract Background Biologic therapies are more effective than conventional therapies in the treatment of psoriasis, but they are also more costly. Objectives The aim of this study was to compare the cost-efficacy of etanercept, adalimumab, and ustekinumab therapies in the treatment of moderate to severe psoriasis in a Taiwanese setting. Methods We conducted a meta-analysis of randomized, placebo-controlled trials to calculate the incremental efficacy of etanercept, adalimumab, and ustekinumab, respectively, in affecting a reduction of ≥75% in score on the Psoriasis Area and Severity Index (PASI 75). The base, best case, and worst case incremental cost-effectiveness ratios (ICERs) for one subject to achieve PASI 75 were calculated for the purposes of economic analysis.
Correspondence Ching-Chi Chi, MD, MMS, DPhil Department of Dermatology Chang Gung Memorial Hospital, Chiayi 6, Section West, Chia-Pu Road Puzih, Chiayi 61363, Taiwan E-mails: [email protected]; [email protected]
Results One-year ICERs per PASI 75 responder were US$ 39,709 (best scenario US$
Conflicts of interest: None.
adalimumab, and ustekinumab, respectively.
36,400; worst scenario US$ 43,680), US$ 23,711 (best scenario US$ 22,633; worst scenario US$ 25,319), and US$ 26,329 (best scenario US$ 24,780; worst scenario US$ 27,623) for etanercept, adalimumab, and ustekinumab, respectively. Two year ICERs per PASI 75 responder were US$ 71,973 (best scenario US$ 65,975; worst scenario US$ 79,170), US$ 62,665 (best scenario US$ 59,817; worst scenario US$ 66,914), and US$ 52,657 (best scenario US$ 49,560; worst scenario US$ 55,427) for etanercept, Conclusions In a Taiwanese setting, adalimumab and ustekinumab had lower 1-year costs per PASI 75 responder than etanercept, and ustekinumab had the lowest 2-year cost per PASI 75 responder.
Introduction Psoriasis is a chronic inflammatory dermatosis affecting 0.23% of the Taiwanese population1,2 or around 53,000 Taiwanese individuals. Approximately 14–17% of psoriatic patients have moderate to severe disease that requires treatment with systemic therapies or phototherapy.1,2 People with psoriasis, especially those with moderate to severe psoriasis, have an increased risk for comorbidities including hypertension, diabetes, hyperlipidemia, and heart disease.1,2 Three biologic therapies for treating moderate to severe psoriasis (etanercept, adalimumab, and ustekinumab) have been approved for reimbursement by Taiwan's Bureau of National Health Insurance (BNHI).3 Etanercept and adalimumab bind and neutralize tumor necrosis factor (TNF),4,5 whereas ustekinumab is a monoclonal ª 2014 The International Society of Dermatology
antibody that blocks interleukin-12 and interleukin-23, which are involved in inflammation and immune response.6 Patients with moderate to severe psoriasis (defined by a Psoriasis Area and Severity Index [PASI] score of ≥10) are eligible for reimbursement if the psoriasis has not responded to regular phototherapy and at least two systemic agents (such as acitretin, methotrexate, and cyclosporine) or if the patient is intolerant of or has a contraindication for these treatments. Before initiating biologic therapy, the dermatologist must obtain preapproval from the BNHI. After examining the application and confirming the patient's eligibility, the BNHI will approve six months of biologic treatment. Dermatologists are required to follow-up the clinical response and may apply for a 6-month extension treatment when this is indicated.3 International Journal of Dermatology 2014, 53, 1151–1156
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Over the past few years, healthcare expenditure has increased as the baby boomer generation has aged and as a result of the introduction of expensive novel health technology. It is therefore important to efficiently allocate the limited resources available for treating chronic diseases such as psoriasis.7 Compared with conventional therapies, biologic therapies are more effective in treating psoriasis, but they are also more expensive. The objective of this study was to compare the cost efficacy of biologic therapies in the treatment of moderate to severe psoriasis in a Taiwanese setting. Materials and methods Meta-analysis A meta-analysis of randomized, placebo-controlled trials was conducted to determine the efficacy of biologic therapies in treating psoriasis. The Cochrane Central Register of Controlled Trials and MEDLINE were searched for relevant trials from the inception of the respective databases to October 2012. Inclusion criteria required that studies referred to randomized, placebo-controlled trials on the efficacy of etanercept, adalimumab, or ustekinumab therapies for moderate to severe psoriasis in adults who adhered to the approved regimens. The approved regimen for etanercept comprised doses of 50 mg twice weekly for 12 weeks, followed by 25 mg twice weekly or 50 mg once weekly. The approved weight-based regimen for adalimumab is 80 mg at week 0 followed by 40 mg every other week. The approved regimen for ustekinumab is 45 mg at weeks 0 and 4, followed by 45 mg every 12 weeks.3 Trials that did not adhere to an approved regimen were excluded. If a trial included an arm using an approved regimen and another arm using an unapproved regimen, we extracted data from the approved regimen and placebo arms only. Although a double dose of ustekinumab (i.e. 90 mg at weeks 0 and 4, followed by 90 mg every 12 weeks) is recommended for patients weighing >100 kg,6 Taiwan's BNHI does not reimburse this regimen. Therefore, we considered only the ustekinumab 45 mg regimen in this meta-analysis. The efficacy outcome was the proportion of participants achieving a reduction of ≥75% in PASI score (PASI 75) at the end of the placebo-controlled period. We calculated the incremental efficacy (IE) of each biologic therapy according to the gain in the proportion of participants achieving PASI 75 after biologic treatment compared with those on placebo treatment (IE represents the proportion of participants achieving PASI 75 in the biologics group minus the proportion of participants achieving PASI 75 in the placebo group). We used intention-to-treat (ITT) analysis to calculate the proportion of participants achieving PASI 75 based on all randomized participants. All randomized participants for whom data on PASI 75 were missing were considered to represent treatment failures. We conducted a meta-analysis to obtain the International Journal of Dermatology 2014, 53, 1151–1156
IE and 95% confidence interval (CI) using the Mantel–Haenszel method.8 Review Manager Version 5.1 (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark) was used for meta-analysis.
Cost-efficacy analysis For the cost-efficacy analysis, we considered the direct costs of reimbursement for drugs dispensed according to the approved regimens. Taiwan's BNHI reimburses biologics at a fixed price which is subject to adjustment every several years. Therefore, the reimbursed drug price is very constant. We used the cost of reimbursement in effect in February 2013 for the present study.9 We compared the incremental cost-effectiveness ratios (ICERs) of the biologic therapies. The ICER represents the ratio of the increase in costs to the therapy's IE ([cost of biologic cost of placebo]/[proportion of participants achieving PASI 75 in the biologic group–proportion of participants achieving PASI 75 in the placebo group]). The costs of placebo were assumed to be nil. The ICER represents the incremental cost for one subject to achieve PASI 75. A biologic therapy is more cost-effective if it has a lower ICER. We calculated 1-year (52-week) and 2-year (104-week) base case ICERs per participant achieving PASI 75. In addition to the base case ICER derived from the IE, worst and best scenario ICERs were calculated based on, respectively, the lower and upper 95% confidence limits of the IE. The range between the worst and best scenario ICERs can be regarded as the 95% CI of the ICER and was used to compare the ICERs of different biologic therapies.
Results Incremental efficacy
A total of 1430 records were identified by searching the databases. Two additional records were obtained from a pharmaceutical company. After filtering the studies to remove duplicates and exclude those that did not use approved regimens, lacked a placebo group, or did not report relevant outcomes, 13 trials were included in the meta-analysis.10–22 All of the included trials were found to be of high quality when appraised using the Cochrane Collaboration's tool for assessing risk for bias in randomized trials and were of low heterogeneity.8 The efficacy outcomes of the 13 trials are summarized in Table 1. A meta-analysis (Fig. 1) showed the IEs to PASI 75 to be 44% (95% CI 40–48%), 63% (95% CI 59–66%), and 64% (95% CI 61–68%) for etanercept, adalimumab, and ustekinumab, respectively. Cost-efficacy
As Table 2 shows, both adalimumab and ustekinumab had favorable 1-year ICERs (ICER of adalimumab: US$ ª 2014 The International Society of Dermatology
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Pharmacology and therapeutics
Table 1 Efficacy outcome data reported in the included trials (n = 13)
Trial, authors (year) Etanercept trials Leonardi et al. (2003)10 Papp et al. (2005)11 Tyring et al. (2006)12 Bagel et al. (2012)13 Adalimumab trials Gordon et al. (2006)14 Menter et al. (2008)15 Saurat et al. (2008)16 Asahina et al. (2010)17 Ustekinumab trials Papp et al. (2008)19 Leonardi et al. (2008)18 Tsai et al. (2011)20 Igarashi et al. (2012)21 Zheng et al. (2012)22
Intervention
Randomized participants, n
Timing of outcome assessment
Participants achieving PASI 75, n (%)
Etanercept Placebo Etanercept Placebo Etanercept Placebo Etanercept Placebo
168 168 203 204 311 309 62 62
Week 12
81 6 94 6 147 15 37 3
(48) (4) (46) (3) (47) (5) (59) (5)
Adalimumab Placebo Adalimumab Placebo Adalimumab Placebo Adalimumab Placebo
46 52 814 398 108 53 43 46
Week 12
24 2 578 26 86 10 27 2
(52) (4) (71) (7) (80) (19) (63) (4)
409 410 255 255 61 60 65 33 160 162
Week 12
273 15 171 8 41 3 38 2 132 18
(67) (4) (67) (3) (67) (5) (58) (6) (83) (11)
Ustekinumab Placebo Ustekinumab Placebo Ustekinumab Placebo Ustekinumab Placebo Ustekinumab Placebo
45 mg 45 mg 45 mg 45 mg 45 mg
Week 12 Week 12 Week 12
Week 16 Week 16 Week 16
Week 12 Week 12 Week 12 Week 12
PASI 75, reduction of ≥75% in score on the Psoriasis Area and Severity Index.
23,711 in the base case, US$ 22,633 in the best scenario, US$ 25,319 in the worst scenario; ICER of ustekinumab 45 mg: US$ 26,329 in the base case, US$ 24,780 in the best scenario, US$ 27,623 in the worst scenario). Etanercept had a higher ICER of US$ 39,709 in the base case, US$ 36,400 in the best scenario, and US$ 43,680 in the worst scenario. Ustekinumab had the most favorable 2-year ICER (US$ 52,657 in the base case, US$ 49,560 in the best scenario, US$ 55,247 in the worst scenario), followed by adalimumab (US$ 62,665 in the base case, US$ 59,817 in the best scenario, US$ 66,914 in the worst scenario). The 2-year ICER of etanercept was US$ 71,973 in the base case, US$ 65,975 in the best scenario, and US$ 79,170 in the worst scenario. Discussion The present study represents the first economic analysis of the efficacy of biologic therapies in moderate to severe psoriasis in a Taiwanese setting. This study found that ª 2014 The International Society of Dermatology
adalimumab and ustekinumab had lower 1-year costs per PASI 75 responder, and ustekinumab had the lowest 2-year cost per PASI 75 responder. Etanercept had higher costs per PASI 75 responder. The ITT approach is considered the best way to assess treatment efficacy because it maintains prognostic balance generated by the original randomization and best mimics actual practice, in which patients may drop out or switch treatments.8 A few of the trials included did not use the ITT approach,10–12,14 and several previous economic analyses on the use of biologic therapies for psoriasis also have not used the ITT approach to obtain efficacy estimates.23–25 The present study used the ITT approach to recalculate outcome data and thus provides less biased cost-efficacy estimates. The present economic analysis was based on PASI 75 response at the end of the induction phase of the biologic therapy (weeks 12–16), which is a widely used treatment goal and is applied in many clinical trials as a primary endpoint.26 The efficacy of biologics may change with time. However, for ethical reasons, placebo-treated International Journal of Dermatology 2014, 53, 1151–1156
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Figure 1 Meta-analysis of data reported in 13 trials on a reduction of ≥75% in score on the Psoriasis Area and Severity Index. M-H, Mantel–Haenszel method; 95% CI, 95% confidence interval Table 2 Incremental cost-effectiveness ratio (ICER) per one participant achieving a reduction of ≥75% in score on the Psoriasis Area and Severity Index 1 year ICER, US$
2 year ICER, US$
Biologic
Base case
Best scenario
Worst scenario
Base case
Best scenario
Worst scenario
Etanercept Adalimumab Ustekinumab
39 709 23 711 26 329
36 400 22 633 24 780
43 680 25 319 27 623
71 973 62 665 52 657
65 975 59 817 49 560
79 170 66 914 55 247
participants in all clinical trials were switched to active biologic treatments after weeks 12–16. It is therefore impossible to obtain placebo-controlled data on long-term IE. Furthermore, expert consensus and regulating bodies have advised that the PASI response at the end of the induction phase should be used to judge whether or not the treatment goal has been achieved and to assess whether the treatment should be adjusted.3,26. International Journal of Dermatology 2014, 53, 1151–1156
The ustekinumab 90 mg regimen is recommended for use in patients weighing >100 kg because it is more effective than the ustekinumab 45 mg regimen in such patients.6 Taiwan's BNHI reimburses only for ustekinumab 45 mg regimens. However, only 5% of participants in the Taiwanese trial weighed >100 kg,20 and the proportion of PASI 75 responders on an ustekinumab 45 mg regimen was found to remain within the range of 49–54% in subjects weighing >100 kg.6 ª 2014 The International Society of Dermatology
Wang et al.
Concomitant psoriatic arthritis is present in 8–15% of people affected by psoriasis.2,27 In such patients, treatment with etanercept and adalimumab is preferable because these drugs have additional efficacy in arthritis.4,5 The present economic analysis considered only the clinical response of skin lesions, but biologic therapies for psoriasis have additional benefits in improving quality of life and emotional well-being. All three biologics have been found to improve patients’ quality of life.28–30 In addition, etanercept has been found to improve fatigue and depression in line with improvements in joint and skin symptoms.12. In conclusion, in this Taiwanese setting, the 1-year costs per PASI 75 responder of adalimumab and ustekinumab were lower than that of etanercept, and ustekinumab had the lowest 2-year cost per PASI 75 responder. This economic analysis may serve as a reference to help clinicians and healthcare payers to allocate the limited healthcare resources available for treating psoriasis in the most efficient way possible.
Cost-efficacy of biologics for psoriasis
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Acknowledgment The authors thank Professor Fenella Wojnarowska, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK, for her comments on the manuscript. References 1 Tsai TF, Wang TS, Hung ST, et al. Epidemiology and comorbidities of psoriasis patients in a national database in Taiwan. J Dermatol Sci 2011; 63: 40–46. 2 Chang YT, Chen TJ, Liu PC, et al. Epidemiological study of psoriasis in the national health insurance database in Taiwan. Acta Derm Venereol 2009; 89: 262–266. 3 Bureau of National Health Insurance. Regulations for Reimbursed Immunologic Agents for Treating Psoriasis. Taipei: National Health Insurance Administration, Ministry of Health and Welfare, 2012. 4 Immunex Corp. Prescribing Information for Enbrel. Thousand Oaks, CA: Immunex Corp, 2011. 5 Abbott Laboratories, Inc. Prescribing Information for Humira. North Chicago, IL: Abbott Laboratories, Inc., 2012. 6 Janssen Biotech, Inc. Prescribing Information for Stelara. Horsham, PA: Janssen Biotech, Inc., 2012. 7 Chi CC. Evidence-based dermatology. Dermatologica Sinica 2013; 31: 2–6. 8 Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Chichester: Wiley-Blackwell, 2008. 9 Bureau of National Health Insurance. Queries on Reimbursed Medicines [WWW document]Available from: http://www.nhi.gov.tw/query/query1.aspx?menu=
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21&menu_id=713&webdata_id=3510&WD_ID=851. [Accessed September 12, 2012.] Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349: 2014–2022. Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol 2005; 152: 1304–1312. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomized phase III trial. Lancet 2006; 367: 29–35. Bagel J, Lynde C, Tyring S, et al. Moderate to severe plaque psoriasis with scalp involvement: a randomized, double-blind, placebo-controlled study of etanercept. J Am Acad Dermatol 2012; 67: 86–92. Gordon KB, Langley RG, Leonardi C, et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol 2006; 55: 598–606. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol 2008; 58: 106–115. Saurat JH, Stingl G, Dubertret L, et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: 558–566. Asahina A, Nakagawa H, Etoh T, et al. Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study. J Dermatol 2010; 37: 299– 310. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371: 1665–1674. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: 1675–1684. Tsai TF, Ho JC, Song M, et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci 2011; 63: 154–163. Igarashi A, Kato T, Kato M, et al. Japanese Ustekinumab Study. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: longterm results from a phase II/III clinical trial. J Dermatol 2012; 39: 242–252.
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22 Zheng M, Zhu XT, Song M, et al. A randomized, double-blind, placebo-controlled study of ustekinumab in Chinese patients with moderate to severe plaque psoriasis: LOTUS trial results. J Dermatol 2012; 39: 238–239. 23 Nelson AA, Pearce DJ, Fleischer AB Jr, et al. Cost-effectiveness of biologic treatments for psoriasis based on subjective and objective efficacy measures assessed over a 12-week treatment period. J Am Acad Dermatol 2008; 58: 125–135. 24 Ferrandiz C, Garcia A, Blasco AJ, et al. Cost-efficacy of adalimumab, etanercept, infliximab and ustekinumab for moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol 2012; 26: 768–777. 25 Igarashi A, Kuwabara H, Fahrbach K, et al. Cost-efficacy comparison of biological therapies for patients with moderate to severe psoriasis in Japan. J Dermatolog Treat 2013; 24: 351–355. 26 Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a
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European consensus. Arch Dermatol Res 2011; 303: 1–10. Winchester R. Psoriatic arthritis. In: Wolff K, Goldsmith LA, Katz SI, et al., eds. Fitzpatrick's Dermatology in General Medicine, 7th edn. New York, NY: McGraw Hill, 2008: 194–207. Krueger GG, Langley RG, Finlay AY, et al. Patient-reported outcomes of psoriasis improvement with etanercept therapy: results of a randomized phase III trial. Br J Dermatol 2005; 153: 1192–1199. Revicki D, Willian MK, Saurat JH, et al. Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis. Br J Dermatol 2008; 158: 549–557. Lebwohl M, Papp K, Han C, et al. Ustekinumab improves health-related quality of life in patients with moderateto-severe psoriasis: results from the PHOENIX 1 trial. Br J Dermatol 2010; 162: 137–146.
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Cost-efficacy of biologic therapies for moderate to severe psoriasis from the perspective of the Taiwanese healthcare system Shu-Hui Wang1,2,3, MD, MS, Ching-Chi Chi4,5, MD, MMS, DPhil (Oxf), and Sindy Hu3,5,6, MD, MS
1 Department of Dermatology, Far Eastern Memorial Hospital, New Taipei, 2 Department of Healthcare Administration, Oriental Institute of Technology, New Taipei, 3Department of Cosmetic Science, Chang Gung University of Science and Technology, Taoyuan, 4Department of Dermatology, Chang Gung Memorial Hospital Chiayi, Chiayi, 5College of Medicine, Chang Gung University, Taoyuan, and 6Department of Dermatology, Chang Gung Memorial Hospital Taoyuan, Taoyuan, Taiwan
Abstract Background Biologic therapies are more effective than conventional therapies in the treatment of psoriasis, but they are also more costly. Objectives The aim of this study was to compare the cost-efficacy of etanercept, adalimumab, and ustekinumab therapies in the treatment of moderate to severe psoriasis in a Taiwanese setting. Methods We conducted a meta-analysis of randomized, placebo-controlled trials to calculate the incremental efficacy of etanercept, adalimumab, and ustekinumab, respectively, in affecting a reduction of ≥75% in score on the Psoriasis Area and Severity Index (PASI 75). The base, best case, and worst case incremental cost-effectiveness ratios (ICERs) for one subject to achieve PASI 75 were calculated for the purposes of economic analysis.
Correspondence Ching-Chi Chi, MD, MMS, DPhil Department of Dermatology Chang Gung Memorial Hospital, Chiayi 6, Section West, Chia-Pu Road Puzih, Chiayi 61363, Taiwan E-mails: [email protected]; [email protected]
Results One-year ICERs per PASI 75 responder were US$ 39,709 (best scenario US$
Conflicts of interest: None.
adalimumab, and ustekinumab, respectively.
36,400; worst scenario US$ 43,680), US$ 23,711 (best scenario US$ 22,633; worst scenario US$ 25,319), and US$ 26,329 (best scenario US$ 24,780; worst scenario US$ 27,623) for etanercept, adalimumab, and ustekinumab, respectively. Two year ICERs per PASI 75 responder were US$ 71,973 (best scenario US$ 65,975; worst scenario US$ 79,170), US$ 62,665 (best scenario US$ 59,817; worst scenario US$ 66,914), and US$ 52,657 (best scenario US$ 49,560; worst scenario US$ 55,427) for etanercept, Conclusions In a Taiwanese setting, adalimumab and ustekinumab had lower 1-year costs per PASI 75 responder than etanercept, and ustekinumab had the lowest 2-year cost per PASI 75 responder.
Introduction Psoriasis is a chronic inflammatory dermatosis affecting 0.23% of the Taiwanese population1,2 or around 53,000 Taiwanese individuals. Approximately 14–17% of psoriatic patients have moderate to severe disease that requires treatment with systemic therapies or phototherapy.1,2 People with psoriasis, especially those with moderate to severe psoriasis, have an increased risk for comorbidities including hypertension, diabetes, hyperlipidemia, and heart disease.1,2 Three biologic therapies for treating moderate to severe psoriasis (etanercept, adalimumab, and ustekinumab) have been approved for reimbursement by Taiwan's Bureau of National Health Insurance (BNHI).3 Etanercept and adalimumab bind and neutralize tumor necrosis factor (TNF),4,5 whereas ustekinumab is a monoclonal ª 2014 The International Society of Dermatology
antibody that blocks interleukin-12 and interleukin-23, which are involved in inflammation and immune response.6 Patients with moderate to severe psoriasis (defined by a Psoriasis Area and Severity Index [PASI] score of ≥10) are eligible for reimbursement if the psoriasis has not responded to regular phototherapy and at least two systemic agents (such as acitretin, methotrexate, and cyclosporine) or if the patient is intolerant of or has a contraindication for these treatments. Before initiating biologic therapy, the dermatologist must obtain preapproval from the BNHI. After examining the application and confirming the patient's eligibility, the BNHI will approve six months of biologic treatment. Dermatologists are required to follow-up the clinical response and may apply for a 6-month extension treatment when this is indicated.3 International Journal of Dermatology 2014, 53, 1151–1156
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Over the past few years, healthcare expenditure has increased as the baby boomer generation has aged and as a result of the introduction of expensive novel health technology. It is therefore important to efficiently allocate the limited resources available for treating chronic diseases such as psoriasis.7 Compared with conventional therapies, biologic therapies are more effective in treating psoriasis, but they are also more expensive. The objective of this study was to compare the cost efficacy of biologic therapies in the treatment of moderate to severe psoriasis in a Taiwanese setting. Materials and methods Meta-analysis A meta-analysis of randomized, placebo-controlled trials was conducted to determine the efficacy of biologic therapies in treating psoriasis. The Cochrane Central Register of Controlled Trials and MEDLINE were searched for relevant trials from the inception of the respective databases to October 2012. Inclusion criteria required that studies referred to randomized, placebo-controlled trials on the efficacy of etanercept, adalimumab, or ustekinumab therapies for moderate to severe psoriasis in adults who adhered to the approved regimens. The approved regimen for etanercept comprised doses of 50 mg twice weekly for 12 weeks, followed by 25 mg twice weekly or 50 mg once weekly. The approved weight-based regimen for adalimumab is 80 mg at week 0 followed by 40 mg every other week. The approved regimen for ustekinumab is 45 mg at weeks 0 and 4, followed by 45 mg every 12 weeks.3 Trials that did not adhere to an approved regimen were excluded. If a trial included an arm using an approved regimen and another arm using an unapproved regimen, we extracted data from the approved regimen and placebo arms only. Although a double dose of ustekinumab (i.e. 90 mg at weeks 0 and 4, followed by 90 mg every 12 weeks) is recommended for patients weighing >100 kg,6 Taiwan's BNHI does not reimburse this regimen. Therefore, we considered only the ustekinumab 45 mg regimen in this meta-analysis. The efficacy outcome was the proportion of participants achieving a reduction of ≥75% in PASI score (PASI 75) at the end of the placebo-controlled period. We calculated the incremental efficacy (IE) of each biologic therapy according to the gain in the proportion of participants achieving PASI 75 after biologic treatment compared with those on placebo treatment (IE represents the proportion of participants achieving PASI 75 in the biologics group minus the proportion of participants achieving PASI 75 in the placebo group). We used intention-to-treat (ITT) analysis to calculate the proportion of participants achieving PASI 75 based on all randomized participants. All randomized participants for whom data on PASI 75 were missing were considered to represent treatment failures. We conducted a meta-analysis to obtain the International Journal of Dermatology 2014, 53, 1151–1156
IE and 95% confidence interval (CI) using the Mantel–Haenszel method.8 Review Manager Version 5.1 (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark) was used for meta-analysis.
Cost-efficacy analysis For the cost-efficacy analysis, we considered the direct costs of reimbursement for drugs dispensed according to the approved regimens. Taiwan's BNHI reimburses biologics at a fixed price which is subject to adjustment every several years. Therefore, the reimbursed drug price is very constant. We used the cost of reimbursement in effect in February 2013 for the present study.9 We compared the incremental cost-effectiveness ratios (ICERs) of the biologic therapies. The ICER represents the ratio of the increase in costs to the therapy's IE ([cost of biologic cost of placebo]/[proportion of participants achieving PASI 75 in the biologic group–proportion of participants achieving PASI 75 in the placebo group]). The costs of placebo were assumed to be nil. The ICER represents the incremental cost for one subject to achieve PASI 75. A biologic therapy is more cost-effective if it has a lower ICER. We calculated 1-year (52-week) and 2-year (104-week) base case ICERs per participant achieving PASI 75. In addition to the base case ICER derived from the IE, worst and best scenario ICERs were calculated based on, respectively, the lower and upper 95% confidence limits of the IE. The range between the worst and best scenario ICERs can be regarded as the 95% CI of the ICER and was used to compare the ICERs of different biologic therapies.
Results Incremental efficacy
A total of 1430 records were identified by searching the databases. Two additional records were obtained from a pharmaceutical company. After filtering the studies to remove duplicates and exclude those that did not use approved regimens, lacked a placebo group, or did not report relevant outcomes, 13 trials were included in the meta-analysis.10–22 All of the included trials were found to be of high quality when appraised using the Cochrane Collaboration's tool for assessing risk for bias in randomized trials and were of low heterogeneity.8 The efficacy outcomes of the 13 trials are summarized in Table 1. A meta-analysis (Fig. 1) showed the IEs to PASI 75 to be 44% (95% CI 40–48%), 63% (95% CI 59–66%), and 64% (95% CI 61–68%) for etanercept, adalimumab, and ustekinumab, respectively. Cost-efficacy
As Table 2 shows, both adalimumab and ustekinumab had favorable 1-year ICERs (ICER of adalimumab: US$ ª 2014 The International Society of Dermatology
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Cost-efficacy of biologics for psoriasis
Pharmacology and therapeutics
Table 1 Efficacy outcome data reported in the included trials (n = 13)
Trial, authors (year) Etanercept trials Leonardi et al. (2003)10 Papp et al. (2005)11 Tyring et al. (2006)12 Bagel et al. (2012)13 Adalimumab trials Gordon et al. (2006)14 Menter et al. (2008)15 Saurat et al. (2008)16 Asahina et al. (2010)17 Ustekinumab trials Papp et al. (2008)19 Leonardi et al. (2008)18 Tsai et al. (2011)20 Igarashi et al. (2012)21 Zheng et al. (2012)22
Intervention
Randomized participants, n
Timing of outcome assessment
Participants achieving PASI 75, n (%)
Etanercept Placebo Etanercept Placebo Etanercept Placebo Etanercept Placebo
168 168 203 204 311 309 62 62
Week 12
81 6 94 6 147 15 37 3
(48) (4) (46) (3) (47) (5) (59) (5)
Adalimumab Placebo Adalimumab Placebo Adalimumab Placebo Adalimumab Placebo
46 52 814 398 108 53 43 46
Week 12
24 2 578 26 86 10 27 2
(52) (4) (71) (7) (80) (19) (63) (4)
409 410 255 255 61 60 65 33 160 162
Week 12
273 15 171 8 41 3 38 2 132 18
(67) (4) (67) (3) (67) (5) (58) (6) (83) (11)
Ustekinumab Placebo Ustekinumab Placebo Ustekinumab Placebo Ustekinumab Placebo Ustekinumab Placebo
45 mg 45 mg 45 mg 45 mg 45 mg
Week 12 Week 12 Week 12
Week 16 Week 16 Week 16
Week 12 Week 12 Week 12 Week 12
PASI 75, reduction of ≥75% in score on the Psoriasis Area and Severity Index.
23,711 in the base case, US$ 22,633 in the best scenario, US$ 25,319 in the worst scenario; ICER of ustekinumab 45 mg: US$ 26,329 in the base case, US$ 24,780 in the best scenario, US$ 27,623 in the worst scenario). Etanercept had a higher ICER of US$ 39,709 in the base case, US$ 36,400 in the best scenario, and US$ 43,680 in the worst scenario. Ustekinumab had the most favorable 2-year ICER (US$ 52,657 in the base case, US$ 49,560 in the best scenario, US$ 55,247 in the worst scenario), followed by adalimumab (US$ 62,665 in the base case, US$ 59,817 in the best scenario, US$ 66,914 in the worst scenario). The 2-year ICER of etanercept was US$ 71,973 in the base case, US$ 65,975 in the best scenario, and US$ 79,170 in the worst scenario. Discussion The present study represents the first economic analysis of the efficacy of biologic therapies in moderate to severe psoriasis in a Taiwanese setting. This study found that ª 2014 The International Society of Dermatology
adalimumab and ustekinumab had lower 1-year costs per PASI 75 responder, and ustekinumab had the lowest 2-year cost per PASI 75 responder. Etanercept had higher costs per PASI 75 responder. The ITT approach is considered the best way to assess treatment efficacy because it maintains prognostic balance generated by the original randomization and best mimics actual practice, in which patients may drop out or switch treatments.8 A few of the trials included did not use the ITT approach,10–12,14 and several previous economic analyses on the use of biologic therapies for psoriasis also have not used the ITT approach to obtain efficacy estimates.23–25 The present study used the ITT approach to recalculate outcome data and thus provides less biased cost-efficacy estimates. The present economic analysis was based on PASI 75 response at the end of the induction phase of the biologic therapy (weeks 12–16), which is a widely used treatment goal and is applied in many clinical trials as a primary endpoint.26 The efficacy of biologics may change with time. However, for ethical reasons, placebo-treated International Journal of Dermatology 2014, 53, 1151–1156
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Cost-efficacy of biologics for psoriasis
Figure 1 Meta-analysis of data reported in 13 trials on a reduction of ≥75% in score on the Psoriasis Area and Severity Index. M-H, Mantel–Haenszel method; 95% CI, 95% confidence interval Table 2 Incremental cost-effectiveness ratio (ICER) per one participant achieving a reduction of ≥75% in score on the Psoriasis Area and Severity Index 1 year ICER, US$
2 year ICER, US$
Biologic
Base case
Best scenario
Worst scenario
Base case
Best scenario
Worst scenario
Etanercept Adalimumab Ustekinumab
39 709 23 711 26 329
36 400 22 633 24 780
43 680 25 319 27 623
71 973 62 665 52 657
65 975 59 817 49 560
79 170 66 914 55 247
participants in all clinical trials were switched to active biologic treatments after weeks 12–16. It is therefore impossible to obtain placebo-controlled data on long-term IE. Furthermore, expert consensus and regulating bodies have advised that the PASI response at the end of the induction phase should be used to judge whether or not the treatment goal has been achieved and to assess whether the treatment should be adjusted.3,26. International Journal of Dermatology 2014, 53, 1151–1156
The ustekinumab 90 mg regimen is recommended for use in patients weighing >100 kg because it is more effective than the ustekinumab 45 mg regimen in such patients.6 Taiwan's BNHI reimburses only for ustekinumab 45 mg regimens. However, only 5% of participants in the Taiwanese trial weighed >100 kg,20 and the proportion of PASI 75 responders on an ustekinumab 45 mg regimen was found to remain within the range of 49–54% in subjects weighing >100 kg.6 ª 2014 The International Society of Dermatology
Wang et al.
Concomitant psoriatic arthritis is present in 8–15% of people affected by psoriasis.2,27 In such patients, treatment with etanercept and adalimumab is preferable because these drugs have additional efficacy in arthritis.4,5 The present economic analysis considered only the clinical response of skin lesions, but biologic therapies for psoriasis have additional benefits in improving quality of life and emotional well-being. All three biologics have been found to improve patients’ quality of life.28–30 In addition, etanercept has been found to improve fatigue and depression in line with improvements in joint and skin symptoms.12. In conclusion, in this Taiwanese setting, the 1-year costs per PASI 75 responder of adalimumab and ustekinumab were lower than that of etanercept, and ustekinumab had the lowest 2-year cost per PASI 75 responder. This economic analysis may serve as a reference to help clinicians and healthcare payers to allocate the limited healthcare resources available for treating psoriasis in the most efficient way possible.
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Acknowledgment The authors thank Professor Fenella Wojnarowska, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK, for her comments on the manuscript. References 1 Tsai TF, Wang TS, Hung ST, et al. Epidemiology and comorbidities of psoriasis patients in a national database in Taiwan. J Dermatol Sci 2011; 63: 40–46. 2 Chang YT, Chen TJ, Liu PC, et al. Epidemiological study of psoriasis in the national health insurance database in Taiwan. Acta Derm Venereol 2009; 89: 262–266. 3 Bureau of National Health Insurance. Regulations for Reimbursed Immunologic Agents for Treating Psoriasis. Taipei: National Health Insurance Administration, Ministry of Health and Welfare, 2012. 4 Immunex Corp. Prescribing Information for Enbrel. Thousand Oaks, CA: Immunex Corp, 2011. 5 Abbott Laboratories, Inc. Prescribing Information for Humira. North Chicago, IL: Abbott Laboratories, Inc., 2012. 6 Janssen Biotech, Inc. Prescribing Information for Stelara. Horsham, PA: Janssen Biotech, Inc., 2012. 7 Chi CC. Evidence-based dermatology. Dermatologica Sinica 2013; 31: 2–6. 8 Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Chichester: Wiley-Blackwell, 2008. 9 Bureau of National Health Insurance. Queries on Reimbursed Medicines [WWW document]Available from: http://www.nhi.gov.tw/query/query1.aspx?menu=
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21&menu_id=713&webdata_id=3510&WD_ID=851. [Accessed September 12, 2012.] Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349: 2014–2022. Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol 2005; 152: 1304–1312. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomized phase III trial. Lancet 2006; 367: 29–35. Bagel J, Lynde C, Tyring S, et al. Moderate to severe plaque psoriasis with scalp involvement: a randomized, double-blind, placebo-controlled study of etanercept. J Am Acad Dermatol 2012; 67: 86–92. Gordon KB, Langley RG, Leonardi C, et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol 2006; 55: 598–606. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol 2008; 58: 106–115. Saurat JH, Stingl G, Dubertret L, et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: 558–566. Asahina A, Nakagawa H, Etoh T, et al. Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study. J Dermatol 2010; 37: 299– 310. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371: 1665–1674. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: 1675–1684. Tsai TF, Ho JC, Song M, et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci 2011; 63: 154–163. Igarashi A, Kato T, Kato M, et al. Japanese Ustekinumab Study. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: longterm results from a phase II/III clinical trial. J Dermatol 2012; 39: 242–252.
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22 Zheng M, Zhu XT, Song M, et al. A randomized, double-blind, placebo-controlled study of ustekinumab in Chinese patients with moderate to severe plaque psoriasis: LOTUS trial results. J Dermatol 2012; 39: 238–239. 23 Nelson AA, Pearce DJ, Fleischer AB Jr, et al. Cost-effectiveness of biologic treatments for psoriasis based on subjective and objective efficacy measures assessed over a 12-week treatment period. J Am Acad Dermatol 2008; 58: 125–135. 24 Ferrandiz C, Garcia A, Blasco AJ, et al. Cost-efficacy of adalimumab, etanercept, infliximab and ustekinumab for moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol 2012; 26: 768–777. 25 Igarashi A, Kuwabara H, Fahrbach K, et al. Cost-efficacy comparison of biological therapies for patients with moderate to severe psoriasis in Japan. J Dermatolog Treat 2013; 24: 351–355. 26 Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a
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