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Original Research
1.
Introduction
2.
Methods
3.
Patients
4.
Study variables
5.
Results
6.
Discussion
7.
Conclusion
Economical impact associated with a biological therapy prioritization protocol in patients with rheumatoid arthritis in the Hospital of Sagunto Joaquı´n Borra´s-Blasco†, M Dolores-Elvira Castera´, Xavier Cortes, J Dolores Rosique-Robles & F Javier Abad †
Pharmacy Service, Hospital de Sagunto, Valencia, Spain
Background: Until 2010 the cost of biological treatments in Rheumatoid Arthritis (RA) was increasing annually by 15% in our hospital. In 1st January 2011, a Hospital Commission of Biological Therapies involving rheumatology and pharmacy services was created to improve the management of biological drugs and a biological therapy prioritization protocol in RA patients was also established to improve the efficient usage of biological drugs in RA. Objective: To evaluate the economic impact associated with a biological therapy prioritization protocol for RA patients in the Hospital of Sagunto. Methods: Observational, ambispective study comparing the associated cost of RA patients treated with biological drugs in the pre-protocol (2009 -- 2010) versus post-protocol periods (2011 -- 2012). RA patients treated with Abatacept (ABA), Adalimumab (ADA), Etanercept (ETN) or Infliximab (IFX) for at least 6 months during the study period (2009 -- 2012) were included. In 2012, Tocilizumab (TCZ) was also included in the prioritization protocol. Prioritization protocol was established based on both clinical and economical aspects and supervised case by case by our Commission. Cost savings and economic impact were calculated using Spanish official prices. Results: In the pre-protocol period (2009 -- 2010), total expenses were increasing by e110,000, up to e1,761,000 in 2010 (e11,362 pat/year). After protocol implementation, total expenses decreased by 53,676e on the 2010 -- 2011 period, and 149,200e on the 2011 -- 2012 period. On the 2010 -- 2011 period the cost of biological therapy per patient-year decreased 355e (11,007e pat/ year) and additional 653e (up to 10,354e pat/year) by 2012, with a cumulative effect of the protocol implementation of 1,008e per patient-year. In the preprotocol period (2009), the annual cost/patient was 10.812e with ETN, 10.942e with IFX, 12.961e with ADA and 12.739e with ABA. By 1st January 2013, the annual cost per patient was 9,469e with ETN, 10,579e with IFX, 11,117e with ADA, 13,540e with ABA and 14,932e with TCZ. Conclusions: The creation of our Commission of Biological Therapies is key to rational management of RA patients and optimization of resources, allowing us to save 200,000e after 2-year efficiency protocol implementation. Keywords: biological therapies, economic impact, priorization, protocol, rheumatoid arthritis, TNF Expert Opin. Biol. Ther. (2014) 14(11):1561-1567
10.1517/14712598.2014.944895 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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J. Borra´s-Blasco et al.
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Dicle Univ. on 11/07/14 For personal use only.
1.
Introduction
Rheumatoid arthritis (RA) is a chronic, disabling disease with considerable impact on patients’ lives, their families and the society as a whole. The estimated prevalence in Spain is 0.5%, with women-to-men ratio in Spain estimated at 4:1 [1]. RA disease progression implies disabilities and comorbidities that increase the health system economic burden, both in the short and long term. The systematic use of biological antirheumatic drugs has changed the evolution of the disease, achieving a considerable improvement in the management of patients with RA. The use of biological treatments in combination with traditional disease-modifying antirheumatic drugs (DMARDs) demonstrated to be more effective than the available therapies were in the prebiological era. The RA direct therapeutic costs however tripled [2]. Indirect costs related to productivity loss constitute a substantial part of total cost in the patient with RA. Biological drug treatment in patients with RA may contribute to improve their quality of life but also to reduce indirect costs by decreasing lost productivity, surgical procedures and requirements for extended-care facility admission and social service [3]. Therefore, RA is associated with a substantial economic burden, both in direct and indirect costs. There is an increasing need for limiting the pharmaceutical costs of chronic diseases. In 2010, cost of biological drugs for patients with RA represented > 25% of our total hospital drug budget. Furthermore, until 31 December 2010, the cost of biological treatments in RA was increasing annually by 15% in our hospital. In order to improve the cost-effectiveness use of biological drugs in RA, in 1 January 2011, a Hospital Commission of Biological Therapies involving rheumatology and pharmacy services was created to improve the management of biological drugs. The main objectives of the commission were to establish procedures for the rational use of biological drugs, development of therapeutic protocols and establish programs of detecting, recording, assessment and reporting of adverse reactions to biological drugs. Once a biological drug is prescribed, an individualized follow-up program is started in order to improve the efficiency of the biological treatment. A biological therapy prioritization protocol in patients with RA was also established. The aim of this protocol was to set a general framework for the use of these treatments within the hospital, while recognizing that this protocol does not cover all the possible situations, justifying the need for clinical interventions outside it, individually managed through the commission. The purpose of the study is to evaluate the economic impact associated with a biological therapy prioritization protocol for patients with RA in the Hospital of Sagunto. 2.
Methods
This study was an observational, ambispective analysis comparing the associated cost of biotreated patients with RA 1562
in the pre-protocol period (2009 -- 2010) versus post-protocol period (2011 -- 2012). By 2011, available biological treatments in our hospital were abatacept (ABA), adalimumab (ADA), etanercept (ETN) or infliximab (IFX). By January 2011, golimumab, certolizumab and tocilizumab (TCZ) were not available in our hospital formulary. Our prioritization protocol of biological therapies in patients with RA was based on the following: 1) EULAR guidelines [4] that indicate patients with RA with inadequate response to conventional DMARD should start their biological treatment with an antiTNF drug, without making any distinction among them. 2) The available evidence also supports that the biological drugs used in RA are not significantly different in efficacy [5]. 3) The National Institute for Health and Care Excellence (NICE) technology appraisal recommendations indicates that in patients with RA, anti-TNF treatment should normally be initiated with the least-expensive drug taking into account administration cost, required dose and product price per dose [6]. 4) Our experience in 18 ETN 25 mg/week selected patients, achieving a total savings of e136.636 while maintaining clinical effectiveness [7]. 5) The intravenous indirect costs associated with IFX and ABA administration [8]. 6) The development of neutralizing antidrug antibodies associated with monoclonal antibodies [9]. 7) Theoretical annual cost of biological RA drugs per patient in Spain. Based on these clinical and cost-effectiveness appointments, ETN was selected as the preferred therapy for both naive and previously biotreated patients. In case patients failed their first subcutaneous anti-TNF (ADA or ETN), they switched to another one (ETN or ADA) following the Consensus Statement of the European League Against Rheumatology and the Spanish Society of Rheumatology on the management of biological therapies in RA [10,11]. According to these consensus, failure to a treatment was defined as not achieving clinical remission (defined as DAS28 < 2.6) or, if remission is unlikely to be achievable, at least low-disease activity (DAS28 < 3.2) within the 3 -- 6 first months of treatment or a failure to maintain this clinical activity. Figure 1 shows the schematic of the Hospital of Sagunto biological therapy prioritization protocol started on 1 January 2011. In 2012, TCZ was further included in the prioritization protocol. This drug was considered as a third-line therapy due to its intravenous administration, label indication and higher theoretical cost per patient-year. All the possible situations are not fully covered by this protocol, justifying the need for clinical interventions outside it, individually managed through the commission.
Expert Opin. Biol. Ther. (2014) 14(11)
Economical impact associated with a biological therapy prioritization protocol in RA patients
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Naïve patient
1st line treatment
2nd line
3rd line
Etanercept
Adalimumab
Abatacept
IFX fail
Etanercept
Adalimumab
ADA fail
Etanercept
Abatacept
ETN fail
Adalimumab
Abatacept
4th line
Abatacept
Figure 1. Biotherapies protocol recommendations of treatment in patients with RA. ADA: Adalimumab; ETN: Etanercept; IFX: Infliximab; RA: Rheumatoid arthritis.
3.
Patients
All available clinical records of patients on biological treatment during the study period (2009 -- 2012) in the Hospital of Sagunto were retrospectively reviewed. Eligible patients were adults diagnosed with RA (ACR 1987 revised criteria), treated with ABA, ADA, ETN or IFX with or without concomitant DMARDs and followed in the Rheumatology Department for at least 6 months during the study period. Patients were excluded if they received any different biological therapy for RA or had a follow-up shorter than 6 months. Enrolled patients could constitute various cases if they received different sequential biological treatments for at least 6 months each during the study period and had an adherence over 90%, measured by our outpatient clinic pharmacy report. 4.
Study variables
Clinical and demographic data were obtained from Rheumatology Department clinical records. The recorded variables were demographics (age, gender and weight) and date of RA diagnosis and biological therapy prescribed (type, dose, starting and ending dates of the treatment). Individualized drug dispensations and correlated dates during the study period were collected from Outpatient Clinic Hospital Pharmacy database. Patient annual (52 weeks) costs were calculated using Spanish official published prices (e2012) of EnbrelÒ (e227.81 per 50 mg), HumiraÒ (e494.61 per 40 mg), OrenciaÒ (e322.80 per 250 mg), RoActemraÒ (e134.30 per 80 mg) and RemicadeÒ (e515.90 per 100 mg). Administered dosages were calculated individually (number of delivered vials/number of weeks of effective treatment), standardized and adjusted to mean percentage of respective Summary of Product Characteristics recommended doses (considered as 100%). For weight-dependent dose treatments (IFX, ABA,
TCZ), their associated costs were calculated using the real dose administered in function of individual patient weight in each drug infusion. Intravenous treatment (IFX, ABA, TCZ) administration costs in daycare hospital (e275 per patient per session) were also taken into account according to the IGP, Catalogo de hospital de dia of the Hospital of Sagunto (Conselleria Sanitat Comunidad Valenciana). 5.
Results
During the study period, 186 patients were included in the analysis constituting 214 cases. Seventy-eight percent were women, mean age 58.5 ± 10.8 years, mean duration on treatment 4.1 ± 2.5 years. In 2009, total expenses were e1,648,790 among the 143 patients (e11,530 per patient-year). After 1 year, total expenses were increasing by e112,379 (+7%), up to e1,761,169 among the 155 patients in 2010 (e11,362 per patient-year), treating 12 additional patients. After protocol implementation, the total included patients decreased by 4 in 2011 and additional 3 in 2012. After adjusting by the number of patients, expenses decreased by e53,676 (-3%) in the 2010 -- 2011 period and by e149,200 (-9%) in the 2011 -2012 period with a total expenses of e1,532,425 among the 148 remaining patients by the end of 2012 (Figure 2). In the 2010 -- 2011 period, the mean cost of biological therapy per patient-year decreased by e355 (e11,007 per patientyear) among the 151 patients and additional savings of e653 (up to e10,354 per patient-year) 1 year later (2012), with a cumulative effect of the protocol implementation of e1008 per patient-year (Figure 3). Figure 4 shows theoretical and mean annualized cost evolution per drug. At the end of the pre-protocol period (1 January 2011), the mean annual cost per naive patient was e10,632 (SD e2215) with ETN, e10,574 (SD e3414) with IFX, e12,711 (SD e1482) with ADA and e13,086 (SD
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-53,673 (-3%) -149,210 (-9%)
2010
€ 1,681,632
2011
2010 total costs adjusted per 2012 n of patients
€ 1,662,047 Actual costs
2010 total costs adjusted per 20112 n of patients
€ 1,715,720
€ 1,532,422 Actual costs
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Dicle Univ. on 11/07/14 For personal use only.
Actual costs
€ 1,761,169 € 1,761,169
2012
Figure 2. Total expenses evolution by year (dark columns) and associated savings, adjusted by the actual number (n) of patients treated.
e1985) with ABA. In the post-protocol period (1 January 2013), the mean annual cost per naive patient was e9469 (SD e3023) with ETN, e10,579 (SD e4332) with IFX, e11,117 (SD e1950) with ADA and e13,540 (e1607) with ABA. Furthermore, we calculated the mean cost of TCZ for patients treated during 2012, being e14,932 (SD e2722) per patient-year. Total associated intravenous biological drugs administration annual costs were e79,571 in the pre-protocol period among 43 patients. This cost diminished up to e67,731 in the post-protocol period (37 patients). However, TCZ administration costs were e28,084 in 2012 among the 10 treated patients. 6.
Discussion
By 2013 RA prevalence in Spain was estimated in 0.5% of total population. Biotreated patients were estimated around 8 -- 10% of patients with RA, with an associated direct expense of e180,000,000 per year. Data regarding the cost and efficiency of these therapies are important for physicians and healthcare systems, as the choice of more efficient treatments may involve major savings. The aim of this study was to evaluate whether the creating of a multidisciplinary Hospital Commission of Biological Therapies would increase efficiency and cost savings over the usual management of patients with RA without Hospital Commission of Biological Therapies intervention. The function of this commission is the development of strategies that ensure adequate selection, cost-effectiveness and management of their biological treatments in order to achieve the best care in patients with RA. Here, we present the effect of a therapy prioritization protocol 1564
in patients with RA as a tool to improve the cost-effectiveness usage of biological drugs in our patients with RA. After 2-year protocol implementation, we obtained a cumulative cost saving of e202,876 and the cost of biological therapy per patient-year decreased by e1008. Among subcutaneous treatments, representing 71% of patients, this decrease was more pronounced, mainly due to dose optimizations, rated in e167,394 among ETN patients and e40,157 among ADA patients. The effect of ETN and ADA dose optimization was shown when we compared with respective theoretical costs, representing a saving per patient and year with ETN of e1312 (-12.6%) and e2377 (-20.0%) in 2011 and 2012, respectively, and of e1087 (-8.4%) in 2011 and e1743 (-13.5%) in 2012 with ADA. Furthermore, no patient was treated with increased doses of ETN and ADA during the study period. In our presented data, the cost savings associated with ETN are greater than the ADA ones due to dose titration of 50% in ETN; 15 patients with RA were given ETN 25 mg/week on 31 December 2012 [7] compared with around 38% in ADA patients; 6 patients with RA were given ADA 40 mg/3 weeks [12]. For IFX patients, no dose titration was observed. However, IFX required an increased dose in 66% (5 mg/kg) in three cases. No dose titration or dose escalation was observed for ABA and TCZ. Similar data about dose titration have been reported in other studies published in the literature. Raffeiner et al. concluded that switching to a low-dose maintenance regimen reduced annual treatment costs by an average of e562,000 annually relative to the standard-dose regimen in 109 patients, while maintaining clinical and radiological remission in up to 81.6% of low-dose patients for a mean of 2.59 years [13].
Expert Opin. Biol. Ther. (2014) 14(11)
Economical impact associated with a biological therapy prioritization protocol in RA patients
2009
€ 11,530
€ 11,362
2010
€ -355 (-3%) € 11,007
2011
€ 10,354
2012
€ -1,008 (-9%)
Figure 3. Mean cost of biological therapy per patient-year. +1,648 (+17%)
+1,109 (+12%)
+4,071 (+43%) 14,453
Etanercept
12,905 13,540
10,550 10,579
10,574
Adalimumab
Infliximab
2012
2011
2010
2009
Label
2012
2011
2012
2011
2010
2009
9,320
Label
2012
2011
2010
2009
9,469
10,942
2010
10,632 10,534
13,086 12,739
2009
10,812
12,961 12,711 12,860 11,773 11,117
Label
11,846
Label
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€ -653 (-6%)
Abatacept
Figure 4. Annual cost/patient by biological drug therapy.
The objective of the PRESERVE trial was to assess whether low-disease activity (DAS28 < 3.2) could be sustained with reduced doses or withdrawal of ETN in patients with moderately active RA disease (DAS28 > 3.2). This study shows that patients with moderate RA treated with ETN 50 mg/week who achieved low-disease activity and decreased their doses to ETN 25 mg/week maintained good control of clinical and radiographic progression after 1 year. However, patients who discontinued treatment showed poorer control of radiographic progression and clinical control of RA. Therefore, low-disease activity in certain patients with moderate RA can be maintained with a combination of MTX and low-dose ETN [14].
Intravenous-treated patients’ (29% of patients) mean cost remained almost invariable due to nonallowance of dose increases and rational selection and follow-up of patients in 2011. When we evaluated the mean cost per patient by drug 1 year after the end of the present study (31 December 2012), ETN remained with the lowest cost per patient-year followed by IFX (increased cost of 12% vs ETN), ADA (increased cost of 17%), ABA (increased cost of 47%) and TCZ; this is the highest cost per patient-year with an increased cost of 54%. In a cross-sectional study conducted in a Spanish hospital in which information from patients with RA treated with
Expert Opin. Biol. Ther. (2014) 14(11)
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J. Borra´s-Blasco et al.
anti-TNF drugs under conventional and modified doses were collected, the authors showed that the percentage of patients with reduced doses was 27 for ETN patients and 25% for ADA patients. In this study, the mean annual cost of ETN compared with the theoretical costs was decreased in e1223.6 (-10.3%) with ETN and e839.7 (-6.5%) with ADA [15]. Schabert et al. estimated the annual cost per treated patient from the payer perspective for ETN, ADA and IFX in adults with RA. The results of the study showed similar trends to our findings, estimating the annual TNF-blocker cost per treated patient to be lowest for ETN, followed by ADA and then IFX [16]. Ramı´rez-Herra´iz et al. assessed mean doses of ADA, ETN and IFX in patients with RA under clinical practice, correlated the doses with their effectiveness and evaluated the cost implications in two different Spanish hospitals. Among patients clinically controlled, 36.73% of ADA cases and 52.83% of those treated with ETN remained in reduced doses. By contrast, IFX required an increased dose to achieve clinical control in 76.32% of cases, reporting mean annual costs of ADA of e11,963, of e10,095 in IFX patients and of e9595 in case of ETN-treated patients similar to our findings [17]. As shown herein, the development of a therapy prioritization protocol supported by a Hospital Commission and based on i) EULAR guidelines [4]; ii) similar biological drug clinical efficacy [5]; iii) NICE biological treatment recommendations [6]; iv) our experience in the use of ETN 25 mg/week in selected patients [7]; v) intravenous administration indirect cost; vi) differential immunogenicity profiles of biological RA drugs [9]; and vii) theoretical annual cost of biological
RA drugs per patient in Spain provided key insights into the cost-effective management of our patients with RA treated with biological drugs. It is difficult to compare our findings with previous works. To our knowledge, this is the first published study that evaluates the economic impact of a commission and protocol prioritization in biological patients for patients with RA. In order to confirm our results, it would be desirable for other studies to be published. Considering these results, further studies in another inflammatory diseases (ankylosing spondylitis or psoriatic arthropathy) are being conducted in our hospital. 7.
Conclusion
The creation of our Commission of Biological Therapies is key to rational management of patients with RA and optimization of resources. Our decision of treatment prioritization according to our experience of use and cost-effectiveness rationale allowed us to save e200,000 after 2-year protocol implementation.
Declaration of interest The hospital pharmacy of Sagunto was paid consultancy fees by Pfizer. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Bibliography Carmona L, Villaverde V, Herna´ndez-Garcı´a C, et al. The prevalence of rheumatoid arthritis in the general population of pain. Rheumatology 2002;41:88-95
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Modena V, Bianchi G, Roccatello D. Cost-effectiveness of biologic treatmentfor rheumatoid arthritis in clinical practice: an achievable target? Autoimmun Rev 2013;12:835-8
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Furuya H, Kasama T, Isozaki T, et al. Effect of TNF antagonists on the productivity of daily work of patients with rheumatoid arthritis. J Multidiscip Healthc 2013;6:25-30
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Smolen J, Landewe R, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010;69:964-75
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Singh JA, Christensen R, Wells GA, et al. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ 2009;181:787-96 National Institute for Health and Care Excellence Technology Appraisal 130: rheumatoid arthritis - adalimumab, etanercept and infliximab: guidance. Review 2010. Available from: http://www.nice.org.uk/nicemedia/pdf/ ta130guidance.pdf Borra´s-Blasco J, Gracia-Perez A, Rosique-obles JD, et al. Clinical and economic impact of the use of etanercept 25 mg once weekly in rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis patients. Expert Opin Biol Ther 2014;14:145-50 Ollendorf DA, Lidsky L. Infliximab drug and infusion costs among patients
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with Crohn’s disease in a commercially-insured setting. Am J Ther 2006;13:502-6 9.
Radstake TR, Svenson M, Eijsbouts AM, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis 2009;68:1739-45
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Tornero Molina J, Sanmartı´ Sala R, Rodrı´guez Valverde V, et al. [Update of the Consensus Statement of the Spanish Society of Rheumatology on the management of biologic therapies in rheumatoid arthritis]. Reumatol Clin 2010;6:23-36
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Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-
Economical impact associated with a biological therapy prioritization protocol in RA patients
(PRESERVE): a randomized controlled trial. Lancet 2013;381:918-29
modifying antirheumatic drugs. Ann Rheum Dis 2010;69:964-75
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Borra´s-Blasco J, Gracia-Perez A, Rosique-Robles JD, et al. Adalimumab dose reduction in rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis patients in sustained clinical remission. Ann Rheum Dis 2014;73:Suppl 2
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Raffeiner B, Botsios C, Sfriso P, et al. The effects of low dose etanercept on disease control and radiographic progression in moderate to severe rheumatoid arthritis. Arthritis Rheum 2010;62:S120
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Smolen JS, Nash P, Durez P, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis
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de la Torre I, Valor L, Nieto JC, et al. Anti-TNF treatments in rheumatoidarthritis: economic impact of dosage modification. Expert Rev Pharmacoecon Outcomes Res 2013;13:407-14
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Schabert VF, Watson C, Joseph GJ, et al. Costs of tumor necrosis factor blockers per treated patient using real-world drug data in a managed care population. J Manag Care Pharm 2013;19:621-30
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Ramı´rez-Herra´iz E, Escudero-Vilaplana V, Alan˜o´n-Plaza E, et al. Efficiency of adalimumab, etanercept and infliximab in rheumatoid arthritis patients: dosing patterns and
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effectiveness in daily clinical practice. Clin Exp Rheumatol 2013;31:559-65
Affiliation
Joaquı´n Borra´s-Blasco†1 PharmD PhD, M Dolores-Elvira Castera´1 PharmD, Xavier Cortes2 MD, J Dolores Rosique-Robles1 PharmD PhD & F Javier Abad1 PharmD PhD † Author for correspondence 1 Specialist in Hospital Pharmacy, Pharmacy Service, Hospital de Sagunto, Avda Ramon y Cajal s/n Sagunto 46520, Valencia, Spain Tel: +34 962653809; Fax: +34 962659428; E-mail: [email protected] 2 Internal Medicine Service, Hospital de Sagunto, Spain
1567
Original Research
1.
Introduction
2.
Methods
3.
Patients
4.
Study variables
5.
Results
6.
Discussion
7.
Conclusion
Economical impact associated with a biological therapy prioritization protocol in patients with rheumatoid arthritis in the Hospital of Sagunto Joaquı´n Borra´s-Blasco†, M Dolores-Elvira Castera´, Xavier Cortes, J Dolores Rosique-Robles & F Javier Abad †
Pharmacy Service, Hospital de Sagunto, Valencia, Spain
Background: Until 2010 the cost of biological treatments in Rheumatoid Arthritis (RA) was increasing annually by 15% in our hospital. In 1st January 2011, a Hospital Commission of Biological Therapies involving rheumatology and pharmacy services was created to improve the management of biological drugs and a biological therapy prioritization protocol in RA patients was also established to improve the efficient usage of biological drugs in RA. Objective: To evaluate the economic impact associated with a biological therapy prioritization protocol for RA patients in the Hospital of Sagunto. Methods: Observational, ambispective study comparing the associated cost of RA patients treated with biological drugs in the pre-protocol (2009 -- 2010) versus post-protocol periods (2011 -- 2012). RA patients treated with Abatacept (ABA), Adalimumab (ADA), Etanercept (ETN) or Infliximab (IFX) for at least 6 months during the study period (2009 -- 2012) were included. In 2012, Tocilizumab (TCZ) was also included in the prioritization protocol. Prioritization protocol was established based on both clinical and economical aspects and supervised case by case by our Commission. Cost savings and economic impact were calculated using Spanish official prices. Results: In the pre-protocol period (2009 -- 2010), total expenses were increasing by e110,000, up to e1,761,000 in 2010 (e11,362 pat/year). After protocol implementation, total expenses decreased by 53,676e on the 2010 -- 2011 period, and 149,200e on the 2011 -- 2012 period. On the 2010 -- 2011 period the cost of biological therapy per patient-year decreased 355e (11,007e pat/ year) and additional 653e (up to 10,354e pat/year) by 2012, with a cumulative effect of the protocol implementation of 1,008e per patient-year. In the preprotocol period (2009), the annual cost/patient was 10.812e with ETN, 10.942e with IFX, 12.961e with ADA and 12.739e with ABA. By 1st January 2013, the annual cost per patient was 9,469e with ETN, 10,579e with IFX, 11,117e with ADA, 13,540e with ABA and 14,932e with TCZ. Conclusions: The creation of our Commission of Biological Therapies is key to rational management of RA patients and optimization of resources, allowing us to save 200,000e after 2-year efficiency protocol implementation. Keywords: biological therapies, economic impact, priorization, protocol, rheumatoid arthritis, TNF Expert Opin. Biol. Ther. (2014) 14(11):1561-1567
10.1517/14712598.2014.944895 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
1561
J. Borra´s-Blasco et al.
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Dicle Univ. on 11/07/14 For personal use only.
1.
Introduction
Rheumatoid arthritis (RA) is a chronic, disabling disease with considerable impact on patients’ lives, their families and the society as a whole. The estimated prevalence in Spain is 0.5%, with women-to-men ratio in Spain estimated at 4:1 [1]. RA disease progression implies disabilities and comorbidities that increase the health system economic burden, both in the short and long term. The systematic use of biological antirheumatic drugs has changed the evolution of the disease, achieving a considerable improvement in the management of patients with RA. The use of biological treatments in combination with traditional disease-modifying antirheumatic drugs (DMARDs) demonstrated to be more effective than the available therapies were in the prebiological era. The RA direct therapeutic costs however tripled [2]. Indirect costs related to productivity loss constitute a substantial part of total cost in the patient with RA. Biological drug treatment in patients with RA may contribute to improve their quality of life but also to reduce indirect costs by decreasing lost productivity, surgical procedures and requirements for extended-care facility admission and social service [3]. Therefore, RA is associated with a substantial economic burden, both in direct and indirect costs. There is an increasing need for limiting the pharmaceutical costs of chronic diseases. In 2010, cost of biological drugs for patients with RA represented > 25% of our total hospital drug budget. Furthermore, until 31 December 2010, the cost of biological treatments in RA was increasing annually by 15% in our hospital. In order to improve the cost-effectiveness use of biological drugs in RA, in 1 January 2011, a Hospital Commission of Biological Therapies involving rheumatology and pharmacy services was created to improve the management of biological drugs. The main objectives of the commission were to establish procedures for the rational use of biological drugs, development of therapeutic protocols and establish programs of detecting, recording, assessment and reporting of adverse reactions to biological drugs. Once a biological drug is prescribed, an individualized follow-up program is started in order to improve the efficiency of the biological treatment. A biological therapy prioritization protocol in patients with RA was also established. The aim of this protocol was to set a general framework for the use of these treatments within the hospital, while recognizing that this protocol does not cover all the possible situations, justifying the need for clinical interventions outside it, individually managed through the commission. The purpose of the study is to evaluate the economic impact associated with a biological therapy prioritization protocol for patients with RA in the Hospital of Sagunto. 2.
Methods
This study was an observational, ambispective analysis comparing the associated cost of biotreated patients with RA 1562
in the pre-protocol period (2009 -- 2010) versus post-protocol period (2011 -- 2012). By 2011, available biological treatments in our hospital were abatacept (ABA), adalimumab (ADA), etanercept (ETN) or infliximab (IFX). By January 2011, golimumab, certolizumab and tocilizumab (TCZ) were not available in our hospital formulary. Our prioritization protocol of biological therapies in patients with RA was based on the following: 1) EULAR guidelines [4] that indicate patients with RA with inadequate response to conventional DMARD should start their biological treatment with an antiTNF drug, without making any distinction among them. 2) The available evidence also supports that the biological drugs used in RA are not significantly different in efficacy [5]. 3) The National Institute for Health and Care Excellence (NICE) technology appraisal recommendations indicates that in patients with RA, anti-TNF treatment should normally be initiated with the least-expensive drug taking into account administration cost, required dose and product price per dose [6]. 4) Our experience in 18 ETN 25 mg/week selected patients, achieving a total savings of e136.636 while maintaining clinical effectiveness [7]. 5) The intravenous indirect costs associated with IFX and ABA administration [8]. 6) The development of neutralizing antidrug antibodies associated with monoclonal antibodies [9]. 7) Theoretical annual cost of biological RA drugs per patient in Spain. Based on these clinical and cost-effectiveness appointments, ETN was selected as the preferred therapy for both naive and previously biotreated patients. In case patients failed their first subcutaneous anti-TNF (ADA or ETN), they switched to another one (ETN or ADA) following the Consensus Statement of the European League Against Rheumatology and the Spanish Society of Rheumatology on the management of biological therapies in RA [10,11]. According to these consensus, failure to a treatment was defined as not achieving clinical remission (defined as DAS28 < 2.6) or, if remission is unlikely to be achievable, at least low-disease activity (DAS28 < 3.2) within the 3 -- 6 first months of treatment or a failure to maintain this clinical activity. Figure 1 shows the schematic of the Hospital of Sagunto biological therapy prioritization protocol started on 1 January 2011. In 2012, TCZ was further included in the prioritization protocol. This drug was considered as a third-line therapy due to its intravenous administration, label indication and higher theoretical cost per patient-year. All the possible situations are not fully covered by this protocol, justifying the need for clinical interventions outside it, individually managed through the commission.
Expert Opin. Biol. Ther. (2014) 14(11)
Economical impact associated with a biological therapy prioritization protocol in RA patients
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Naïve patient
1st line treatment
2nd line
3rd line
Etanercept
Adalimumab
Abatacept
IFX fail
Etanercept
Adalimumab
ADA fail
Etanercept
Abatacept
ETN fail
Adalimumab
Abatacept
4th line
Abatacept
Figure 1. Biotherapies protocol recommendations of treatment in patients with RA. ADA: Adalimumab; ETN: Etanercept; IFX: Infliximab; RA: Rheumatoid arthritis.
3.
Patients
All available clinical records of patients on biological treatment during the study period (2009 -- 2012) in the Hospital of Sagunto were retrospectively reviewed. Eligible patients were adults diagnosed with RA (ACR 1987 revised criteria), treated with ABA, ADA, ETN or IFX with or without concomitant DMARDs and followed in the Rheumatology Department for at least 6 months during the study period. Patients were excluded if they received any different biological therapy for RA or had a follow-up shorter than 6 months. Enrolled patients could constitute various cases if they received different sequential biological treatments for at least 6 months each during the study period and had an adherence over 90%, measured by our outpatient clinic pharmacy report. 4.
Study variables
Clinical and demographic data were obtained from Rheumatology Department clinical records. The recorded variables were demographics (age, gender and weight) and date of RA diagnosis and biological therapy prescribed (type, dose, starting and ending dates of the treatment). Individualized drug dispensations and correlated dates during the study period were collected from Outpatient Clinic Hospital Pharmacy database. Patient annual (52 weeks) costs were calculated using Spanish official published prices (e2012) of EnbrelÒ (e227.81 per 50 mg), HumiraÒ (e494.61 per 40 mg), OrenciaÒ (e322.80 per 250 mg), RoActemraÒ (e134.30 per 80 mg) and RemicadeÒ (e515.90 per 100 mg). Administered dosages were calculated individually (number of delivered vials/number of weeks of effective treatment), standardized and adjusted to mean percentage of respective Summary of Product Characteristics recommended doses (considered as 100%). For weight-dependent dose treatments (IFX, ABA,
TCZ), their associated costs were calculated using the real dose administered in function of individual patient weight in each drug infusion. Intravenous treatment (IFX, ABA, TCZ) administration costs in daycare hospital (e275 per patient per session) were also taken into account according to the IGP, Catalogo de hospital de dia of the Hospital of Sagunto (Conselleria Sanitat Comunidad Valenciana). 5.
Results
During the study period, 186 patients were included in the analysis constituting 214 cases. Seventy-eight percent were women, mean age 58.5 ± 10.8 years, mean duration on treatment 4.1 ± 2.5 years. In 2009, total expenses were e1,648,790 among the 143 patients (e11,530 per patient-year). After 1 year, total expenses were increasing by e112,379 (+7%), up to e1,761,169 among the 155 patients in 2010 (e11,362 per patient-year), treating 12 additional patients. After protocol implementation, the total included patients decreased by 4 in 2011 and additional 3 in 2012. After adjusting by the number of patients, expenses decreased by e53,676 (-3%) in the 2010 -- 2011 period and by e149,200 (-9%) in the 2011 -2012 period with a total expenses of e1,532,425 among the 148 remaining patients by the end of 2012 (Figure 2). In the 2010 -- 2011 period, the mean cost of biological therapy per patient-year decreased by e355 (e11,007 per patientyear) among the 151 patients and additional savings of e653 (up to e10,354 per patient-year) 1 year later (2012), with a cumulative effect of the protocol implementation of e1008 per patient-year (Figure 3). Figure 4 shows theoretical and mean annualized cost evolution per drug. At the end of the pre-protocol period (1 January 2011), the mean annual cost per naive patient was e10,632 (SD e2215) with ETN, e10,574 (SD e3414) with IFX, e12,711 (SD e1482) with ADA and e13,086 (SD
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-53,673 (-3%) -149,210 (-9%)
2010
€ 1,681,632
2011
2010 total costs adjusted per 2012 n of patients
€ 1,662,047 Actual costs
2010 total costs adjusted per 20112 n of patients
€ 1,715,720
€ 1,532,422 Actual costs
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Actual costs
€ 1,761,169 € 1,761,169
2012
Figure 2. Total expenses evolution by year (dark columns) and associated savings, adjusted by the actual number (n) of patients treated.
e1985) with ABA. In the post-protocol period (1 January 2013), the mean annual cost per naive patient was e9469 (SD e3023) with ETN, e10,579 (SD e4332) with IFX, e11,117 (SD e1950) with ADA and e13,540 (e1607) with ABA. Furthermore, we calculated the mean cost of TCZ for patients treated during 2012, being e14,932 (SD e2722) per patient-year. Total associated intravenous biological drugs administration annual costs were e79,571 in the pre-protocol period among 43 patients. This cost diminished up to e67,731 in the post-protocol period (37 patients). However, TCZ administration costs were e28,084 in 2012 among the 10 treated patients. 6.
Discussion
By 2013 RA prevalence in Spain was estimated in 0.5% of total population. Biotreated patients were estimated around 8 -- 10% of patients with RA, with an associated direct expense of e180,000,000 per year. Data regarding the cost and efficiency of these therapies are important for physicians and healthcare systems, as the choice of more efficient treatments may involve major savings. The aim of this study was to evaluate whether the creating of a multidisciplinary Hospital Commission of Biological Therapies would increase efficiency and cost savings over the usual management of patients with RA without Hospital Commission of Biological Therapies intervention. The function of this commission is the development of strategies that ensure adequate selection, cost-effectiveness and management of their biological treatments in order to achieve the best care in patients with RA. Here, we present the effect of a therapy prioritization protocol 1564
in patients with RA as a tool to improve the cost-effectiveness usage of biological drugs in our patients with RA. After 2-year protocol implementation, we obtained a cumulative cost saving of e202,876 and the cost of biological therapy per patient-year decreased by e1008. Among subcutaneous treatments, representing 71% of patients, this decrease was more pronounced, mainly due to dose optimizations, rated in e167,394 among ETN patients and e40,157 among ADA patients. The effect of ETN and ADA dose optimization was shown when we compared with respective theoretical costs, representing a saving per patient and year with ETN of e1312 (-12.6%) and e2377 (-20.0%) in 2011 and 2012, respectively, and of e1087 (-8.4%) in 2011 and e1743 (-13.5%) in 2012 with ADA. Furthermore, no patient was treated with increased doses of ETN and ADA during the study period. In our presented data, the cost savings associated with ETN are greater than the ADA ones due to dose titration of 50% in ETN; 15 patients with RA were given ETN 25 mg/week on 31 December 2012 [7] compared with around 38% in ADA patients; 6 patients with RA were given ADA 40 mg/3 weeks [12]. For IFX patients, no dose titration was observed. However, IFX required an increased dose in 66% (5 mg/kg) in three cases. No dose titration or dose escalation was observed for ABA and TCZ. Similar data about dose titration have been reported in other studies published in the literature. Raffeiner et al. concluded that switching to a low-dose maintenance regimen reduced annual treatment costs by an average of e562,000 annually relative to the standard-dose regimen in 109 patients, while maintaining clinical and radiological remission in up to 81.6% of low-dose patients for a mean of 2.59 years [13].
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Economical impact associated with a biological therapy prioritization protocol in RA patients
2009
€ 11,530
€ 11,362
2010
€ -355 (-3%) € 11,007
2011
€ 10,354
2012
€ -1,008 (-9%)
Figure 3. Mean cost of biological therapy per patient-year. +1,648 (+17%)
+1,109 (+12%)
+4,071 (+43%) 14,453
Etanercept
12,905 13,540
10,550 10,579
10,574
Adalimumab
Infliximab
2012
2011
2010
2009
Label
2012
2011
2012
2011
2010
2009
9,320
Label
2012
2011
2010
2009
9,469
10,942
2010
10,632 10,534
13,086 12,739
2009
10,812
12,961 12,711 12,860 11,773 11,117
Label
11,846
Label
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€ -653 (-6%)
Abatacept
Figure 4. Annual cost/patient by biological drug therapy.
The objective of the PRESERVE trial was to assess whether low-disease activity (DAS28 < 3.2) could be sustained with reduced doses or withdrawal of ETN in patients with moderately active RA disease (DAS28 > 3.2). This study shows that patients with moderate RA treated with ETN 50 mg/week who achieved low-disease activity and decreased their doses to ETN 25 mg/week maintained good control of clinical and radiographic progression after 1 year. However, patients who discontinued treatment showed poorer control of radiographic progression and clinical control of RA. Therefore, low-disease activity in certain patients with moderate RA can be maintained with a combination of MTX and low-dose ETN [14].
Intravenous-treated patients’ (29% of patients) mean cost remained almost invariable due to nonallowance of dose increases and rational selection and follow-up of patients in 2011. When we evaluated the mean cost per patient by drug 1 year after the end of the present study (31 December 2012), ETN remained with the lowest cost per patient-year followed by IFX (increased cost of 12% vs ETN), ADA (increased cost of 17%), ABA (increased cost of 47%) and TCZ; this is the highest cost per patient-year with an increased cost of 54%. In a cross-sectional study conducted in a Spanish hospital in which information from patients with RA treated with
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anti-TNF drugs under conventional and modified doses were collected, the authors showed that the percentage of patients with reduced doses was 27 for ETN patients and 25% for ADA patients. In this study, the mean annual cost of ETN compared with the theoretical costs was decreased in e1223.6 (-10.3%) with ETN and e839.7 (-6.5%) with ADA [15]. Schabert et al. estimated the annual cost per treated patient from the payer perspective for ETN, ADA and IFX in adults with RA. The results of the study showed similar trends to our findings, estimating the annual TNF-blocker cost per treated patient to be lowest for ETN, followed by ADA and then IFX [16]. Ramı´rez-Herra´iz et al. assessed mean doses of ADA, ETN and IFX in patients with RA under clinical practice, correlated the doses with their effectiveness and evaluated the cost implications in two different Spanish hospitals. Among patients clinically controlled, 36.73% of ADA cases and 52.83% of those treated with ETN remained in reduced doses. By contrast, IFX required an increased dose to achieve clinical control in 76.32% of cases, reporting mean annual costs of ADA of e11,963, of e10,095 in IFX patients and of e9595 in case of ETN-treated patients similar to our findings [17]. As shown herein, the development of a therapy prioritization protocol supported by a Hospital Commission and based on i) EULAR guidelines [4]; ii) similar biological drug clinical efficacy [5]; iii) NICE biological treatment recommendations [6]; iv) our experience in the use of ETN 25 mg/week in selected patients [7]; v) intravenous administration indirect cost; vi) differential immunogenicity profiles of biological RA drugs [9]; and vii) theoretical annual cost of biological
RA drugs per patient in Spain provided key insights into the cost-effective management of our patients with RA treated with biological drugs. It is difficult to compare our findings with previous works. To our knowledge, this is the first published study that evaluates the economic impact of a commission and protocol prioritization in biological patients for patients with RA. In order to confirm our results, it would be desirable for other studies to be published. Considering these results, further studies in another inflammatory diseases (ankylosing spondylitis or psoriatic arthropathy) are being conducted in our hospital. 7.
Conclusion
The creation of our Commission of Biological Therapies is key to rational management of patients with RA and optimization of resources. Our decision of treatment prioritization according to our experience of use and cost-effectiveness rationale allowed us to save e200,000 after 2-year protocol implementation.
Declaration of interest The hospital pharmacy of Sagunto was paid consultancy fees by Pfizer. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Affiliation
Joaquı´n Borra´s-Blasco†1 PharmD PhD, M Dolores-Elvira Castera´1 PharmD, Xavier Cortes2 MD, J Dolores Rosique-Robles1 PharmD PhD & F Javier Abad1 PharmD PhD † Author for correspondence 1 Specialist in Hospital Pharmacy, Pharmacy Service, Hospital de Sagunto, Avda Ramon y Cajal s/n Sagunto 46520, Valencia, Spain Tel: +34 962653809; Fax: +34 962659428; E-mail: [email protected] 2 Internal Medicine Service, Hospital de Sagunto, Spain
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