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Pages 335-342 (June - July 2021)
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Vol. 17. Issue 6.
Pages 335-342 (June - July 2021)
Original Article
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Cost evolution of biological drugs in rheumatoid arthritis patients in a tertiary hospital: Influential factors on price
Evolución del coste de medicamentos biológicos en pacientes con artritis reumatoide en un hospital terciario. Factores influyentes en dicha evolución
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Mariángeles González Fernándeza,
Corresponding author
, Elena Villamañánb, Inmaculada Jiménez-Nácherb, Francisco Morenob, Chamaida Plasenciac, Francisco Gayád, Alicia Herrerob, Alejandro Balsac
a Pharmacy Department, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain
b Pharmacy Department, La Paz University Hospital, Madrid, Spain
c Rheumatology Department, La Paz University Hospital, Madrid, Spain
d Biostatistic Department, La Paz University Hospital, Madrid, Spain
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Statistics
Figures (2)
Tables (7)
Table 1. Characteristics of patients.
Table 2. Economic data evolution per drug from 2009 to 2017 in rheumatoid arthritis.
Table 3. Official discounts and negotiated rebates from 2009 to 2017.
Table 4a. Clinical characteristics of patients according to the optimizations of their treatments.
Table 4b. Number of active patients and % patients with optimized therapies per drug.
Table 5. Calculation of different factors that have an impact on costs in 2017.
Table 6. Quantification of influential factor that affect on treatment costs in rheumatoid arthritis.
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Abstract
Objective

To assess the evolution of cost per patient/year and the cost per patient/year/drug in patients with rheumatoid arthritis (RA) receiving biological treatments. To analyze and quantify the factors influencing this evolution, such as the optimization of the biological drugs, the use of biosimilars, and official discounts and discounts obtained after negotiated procedures. In addition, to assess specific clinical parameters of disease activity in these patients.

Methods

Retrospective, observational study conducted in a Spanish tertiary hospital. Adult patients diagnosed with RA under treatment from 2009 to 2017 were included.

Results

320, 270 and 389 patients were included in 2009, 2013 and 2017, respectively. The patient/year cost decreased from 10,789€ in 2009, 7491€ in 2013 to 7116€ in 2017. In 2017, due to the established competition, discounts of 14% and 29.5% were achieved on etanercept and its biosimilar; 11.5%, 17.8%, 17.9%, 17.3% on adalimumab, certolizumab, golimumab and tocilizumab IV respectively, and 24.6% and 43.1% on infliximab and its biosimilar. The percentage of patients optimized in 2017 was 35.2%. The annual saving in 2017 was 1,288,535€ (830,000€ due to dose optimization and/or administration regimens, 249,666€ corresponding to 7.5% of the official discount and 208,868€ after negotiated procedures).

Conclusion

The annual cost per patient in RA decreased considerably due to different factors, such as discounts on the purchase of drugs due to official discounts and negotiated procedures, together with the optimization of therapies, the latter being the factor that contributed most to this decrease.

Keywords:
Cost
Arthritis
Rheumatoid
Optimization
Therapy
Resumen
Objetivo

Evaluar la evolución del coste por paciente/año y del coste por paciente/año/medicamento en pacientes en tratamientos con biológicos con artritis reumatoide (AR). Analizar y cuantificar los factores influyentes en dicha evolución tales como la optimización de medicamentos biológicos, el uso de biosimilares y los descuentos oficiales y los obtenidos tras procedimientos negociados. Además, evaluar parámetros clínicos de la actividad propios de la enfermedad en dichos pacientes.

Métodos

Estudio retrospectivo, observacional, realizado en un hospital terciario español. Se incluyeron pacientes adultos diagnosticados de AR en tratamiento con biológicos desde 2009 a 2017.

Resultados

Se incluyeron 320, 270 y 389 pacientes en 2009, 2013 y 2017, respectivamente. El coste paciente/año disminuyó de 10.798€ en 2009, 7.491€ en 2013 a 7.116€ en 2017. En 2017, debido a la competencia establecida, se alcanzaron descuentos del 14 y del 29,5% en etanercept y su biosimilar; 11,5, 17,8, 17,9 y 17,3% en adalimumab, certolizumab, golimumab y tocilizumab IV, respectivamente, así como un 24,6% y 43,1% en infliximab y su biosimilar. El porcentaje de pacientes optimizados en 2017 alcanzó el 35.2%. El ahorro anual en 2017 fue de 1.288.535€ (830.000€ debido a la optimización de dosis y/o pautas de administración, 249.666€ correspondiente al 7,5% del descuento oficial y 208.868€ tras procedimientos negociados).

Conclusión

El coste anual por paciente en AR disminuyó considerablemente debido a diferentes factores, tales como, descuentos en la adquisición de medicamentos debido a descuentos oficiales y procedimientos negociados, junto a la optimización de terapias, siendo este último el factor que más contribuyó en dicho descenso.

Palabras clave:
Coste
Artritis
Reumatoide
Optimización
Terapia
Full Text
Introduction

Rheumatoid arthritis (RA) is a chronic, progressive auto immune disease that causes severe articular damage and functional impotence in the affected joints.1 The prevalence of RA is reported to be 0.5%–1% in developed countries, with a higher prevalence among females (ratio 2:1).1,2 Its prevalence is 0.5% in Spain.3 The therapy of RA aims at early disease control and induction of sustained remission; successful treatment is reflected by sustained quality of live and ability to work.4

Treatment with nonsteroidal anti-inflammatory drugs, conventional disease-modifying antirheumatic drugs and biologic treatment have been assessed in individuals with RA.5 Biologics drugs (BD) approved for use in RA include TNF inhibitors (TNFi), Tocilizumab (Tcz), Rituximab (Rtx), Abatacept (Aba) and Janus kinase inhibitors tofacitinib and baricitinib (Jak).6–8 The TNFi registered for the indication of RA are adalimumab (Ada), certolizumab pegol (Ctz), etanercept (Etn), golimumab (Goli), and infliximab (Ifx)5,7,9; TNFi have improved outcomes for patients who are refractory or intolerant to conventional treatments, inducing long-term remission in some cases.10,11 If TNFi fails, switching to another TNFi or an agent with another mode of action should be considered.6–9 The cost of BD for treating rheumatic diseases has dramatically increased in Spanish hospitals.12 Due to the high cost of BD, it is important to evaluate real costs of use of these agents.13

Aims of the study

The main objective was to calculate the annual cost per patient and the cost of each biological treatment of patients with RA in real practice in a tertiary hospital in Spain for eighteen years (2009–2017). Other secondary objectives were to analyze factors related to treatment costs (the prescription of biosimilars instead of original drugs, discounts and negotiated rebates or biologic regimes optimization according to drug and anti-drug antibodies serum levels.14–16

Methods

We conducted a retrospective observational study between 2009 and 2017 approved by Ethics Committee of La Paz University hospital in April 2017.

Patients diagnosed of RA who were dispensed BD by the pharmacy department in the study period were included. These dispensations were recorded in a CPOE program (FarmaTools 2.5 Dominion). This software allows pharmacists to register regimes, drugs and unit-drugs used by patient and related them with costs.

Inclusion criteria

Adult patients with RA followed in the rheumatology unit in our hospital were included.

Clinical data were obtained from the La Paz Biological Registry of Rheumatology database, created by the hospital's rheumatology department. Disease activity was measured by the Disease Activity Score 28 (DAS28) and the Simplified Disease Activity Index (SDAI).17 Remission was defined as achieving a DAS28<2.6 and SDAI3; low disease activity were defined as ≥2.6 DAS28<3.2, and >3.3 SDAI11; moderate activity were defined as ≥3.2 DAS28<5.1, and >11 SDAI26; and high activity were defined as DAS28>5.1 and SDAI>26.6,17 These parameters, as well as C-reactive protein (C-RP) and erythrocyte sedimentation rate, were measured every 3–6 months for clinical disease assessment.

Costs were calculated according to direct cost of BD dispensed. Drugs prices used were those set out by the Spanish Medicines Agency.18 Costs associated with concomitant medications, laboratory tests or a switch from initial therapy that affected the overall cost were excluded.

Main variables and secondary variables

To calculate main outcomes such as average-dispensed-patient, the annual cost per average-patient and annual cost per average-patient per drug we applied a standardized methodology used by the public health system of the Community of Madrid. In addition, other variables such the theoretical cost per drug(units) acquired, annual theoretical cost per drug, total cost savings and the cost savings as a result of biological therapy optimization were calculated.15,16

Biological therapy optimization by monitoring drug and ADA serum levels

We also evaluated annual costs per patient and per drug savings due to biologic therapies optimization. Optimized therapies were defined as those in which the dosing interval were extended and/or the dose of biological drug was reduced. Total percentages of patients with optimized therapies and per drug were calculated.

Statistical analysis

The results were expressed as percentage, mean and standard deviation (SD). All tests were performed using IBM SPSS version 19.0. Differences in patients’ characteristics were examined using the analysis of variance (ANOVA) model or a t-test for continuous variables (age, DAS28, SDAI, C-RPC, ESR). Differences in costs were examined using analysis of trends (Joinpoint Regression Program® 4.5.01-June, 2017). Significant values were defined as P<.05.

Results

In 2009, 2013, and 2017 were treated with BD 320, 270, and 389 patients respectively. Patient's characteristics are shown in Table 1. No statistically significant difference was found between study groups except in DAS28.

Table 1.

Characteristics of patients.

  2009  2013  2017  P(*) (between groups) 
Dispensed patient  320  270  389   
Ages (years)  56.94 (14.51)  57.87 (13.25)  58.20 (14.72)  .562 (NS) 
Gender (female)  236 (73.75%)  218 (80.74%)  321 (85.55%)   
DAS28  3.57 (1.35)  3.31 (1.25)  3.21 (1.29)  .012 (S) 
SDAI  11.86 (11.85)  10.93 (11.13)  9.97 (9.55)  .303 (NS) 
CRP-C  5.69 (9.09)  6.51 (13.62)  6.39 (12.89)  .366 (NS) 
ESR  22.09 (15.92)  18.93 (13.28)  21.18 (16.17)  .086 (NS) 

Data are expressed as mean (SD) for continuous variables and frequencies (percentage) for categorical variables

DAS28: Disease Activity Score28; SDAI: Simplified Disease Activity Index.

CRP-C: C-Reactive Protein; ESR Erythrocite Sedimentation Rate.

Statistical signification P<.05; (*) ANOVA test.

Fig. 1 shows the evolution of the results for RA per average-dispensed-patient, annual cost, and annual cost per average-dispensed-patient. “We observed an average-dispensed-patient decrease from 2009 to 2013, and an upward trend from 2014 to 2017 (Fig. 1a)”. The same tendency in terms of annual cost of RA was observed, with a minimum data in 2013 (Fig. 1b)”. However, the annual cost per patient decreased (P<.001 from 2009 to 2013) (Fig. 1c).

Fig. 1.

Data evolution in rheumatoid arthritis from 2009 to 2017. (a) Average dispended patient from 2009 to 2017. (b) Annual cost for rheumatoid arthritis 2009–2017. (c) Annual cost 2017 per average dispensed patient 2009–2017.

(0.27MB).

When evaluating costs according to each drug used a similar trend was observed (Table 2). Annual cost per patient from 2009 to 2017 decreased significantly for Ifx and Eta (P<.001), Ctz and Aba IV (P<.05), and from 2009 to 2013 for Ada (<.001) and Toci IV (P<.05).

Table 2.

Economic data evolution per drug from 2009 to 2017 in rheumatoid arthritis.

  2009  2010  2011  2012  2013  2014  2015  2016  2017 
Adalimumab
Average dispensed patient  62.12  59.91  59  52.7  41.54  35.52  35.17  34.24  30.73 
Annual cost (€)  781.698  722.026  596.887  488.699  301.058  239.691  245.295  233.874  215.512 
Annual cost per average patient (€)  12.584  12.052  10.117  9.273  7.247  6.748  6.975  6.830  7.013 
Incremental difference annual cost    −4.2%  −16.1%  −8.3%  −21.8%  −6.9%  3.4%  −2.1%  2.7% 
Etanercept
Average dispensed patient  73.58  68.58  66.53  70.44  73.48  69.92  70.46  78.91  86.16 
Annual cost (€)  802.414  737.450  660.645  633.196  543.150  556.287  554.835  549.650  579.680 
Annual cost per average patient (€)  10.905  10.753  9.930  8.989  7.392  7.956  7.874  6.966  6.728 
Incremental difference annual cost    −1.4%  −7.7%  −9.5%  −17.8%  7.6%  −1.0%  −11.5%  −3.4% 
Certolizumab
Average dispensed patient  –  0.5  8.6  17.95  22.23  24.75  33  37.53  44.48 
Annual cost (€)  –  4.260  87.869  172.010  178.747  194.765  246.084  281.660  335.283 
Annual cost per average patient (€)  –  8.520  10.217  9.583  8.041  7.869  7.457  7.505  7.538 
Incremental difference annual cost        −6.2%  −16.1%  −2.1%  −5.2%  0.6%  0.4% 
Golimumab
Average dispensed patient  –  –  1.83  1.41  3.9  4.6  9.16  11.38 
Annual cost (€)  –  –  14.521  9.564  14.573  33.965  37.326  85.081  96.171 
Annual cost per average patient (€)  –  –  7.935  9.564  10.335  8.709  8.114  9.288  8.451 
Incremental difference annual cost          8.1%  −15.7%  −6.8%  14.5%  −9.0% 
Infliximab
Average dispensed patient  64.54  47.83  37.72  31.6  22.78  25.29  29.98  24.09  27.68 
Annual cost (€)  628.903  439.037  283.243  187.865  123.575  142.822  188.394  103.430  92.414 
Annual cost per average patient (€)  9.744  9.179  7.509  5.945  5.425  5.647  6.284  4.293  3.339 
Incremental difference annual cost    −5.8%  −18.2%  −20.8%  −8.7%  4.1%  11.3%  −31.7%  −22.2% 
Tocilizumab IV
Average dispensed patient  –  3.87  10.66  16.2  23.79  27.17  25.35  17.52  20.92 
Annual cost (€)  –  46.437  118.381  167.048  199.503  210.997  185.996  121.669  158.076 
Annual cost per average patient (€)  –  11.999  11.105  10.312  8.386  7.766  7.337  6.945  7.556 
Incremental difference annual cost      −7.5%  −7.1%  −18.7%  −7.4%  −5.5%  −5.3%  8.8% 
Tocilizumab SC
Average dispensed patient  –  –  –  –  –  –  9.38  20.91  28.9 
Annual cost (€)  –  –  –  –  –  –  68.410  154.759  240.921 
Annual cost per average patient (€)  –  –  –  –  –  –  7.293  7.401  8.336 
Incremental difference annual cost                1.5%  12.6% 
Abatacept IV
Average dispensed patient  7.16  4.6  7.08  8.93  7.95  7.81  8.5  8.46  10.21 
Annual cost (€)  81.131  53.252  81.497  89.371  66.972  67.728  82.066  69.025  90.261 
Annual cost per average patient (€)  11.331  11.577  11.511  10.008  8.424  8.672  9.655  8.159  8.840 
Incremental difference annual cost    2.2%  −0.6%  −13.1%  −15.8%  2.9%  11.3%  −15.5%  8.3% 
Abatacept SC
Average dispensed patient  –  –  –  –  –  –  8.52  12.26  12.86 
Annual cost (€)  –  –  –  –  –  –  80.151  99.619  102.692 
Annual cost per average patient (€)  –  –  –  –  –  –  9.407  8.126  7.985 
Incremental difference annual cost                −13.6%  −1.7% 
Rituximab
Average dispensed patient  24.4  21.99  15.67  15.43  14.98  23.58  21.54  29.71  29.51 
Annual cost (€)  210.095  169.293  134.357  115.163  128.359  135.331  177.886  202.985  242.484 
Annual cost per average patient (€)  8.610  7.699  8.574  7.464  8.569  5.739  8.258  6.833  8.217 
Incremental difference annual cost    −10.6%  11.4%  −12.9%  14.8%  −33.0%  43.9%  −17.3%  20.3% 
Baricitinib VO
Average dispensed patient  –  –  –  –  –  –  –  –  0.33 
Annual cost (€)  –  –  –  –  –  –  –  –  2.508 
Annual cost per average patient (€)  –  –  –  –  –  –  –  –  7.600 
Tofacitinib VO
Average dispensed patient  –  –  –  –  –  –  –  –  0.42 
Annual cost (€)  –  –  –  –  –  –  –  –  3.266 
Annual cost per average patient (€)  –  –  –  –  –  –  –  –  7.776 

Biologics acquired by our center (units) as well as the data for BD dispensed (units) to patients with RA are shown in Table 3. We detected that there was an increase in the number of marketed BD and total savings per drug. In order of appearance, official discounts and negotiated rebates in 2017 were 11.5% for Ada, 15.5% for Eta, 30.9% for Ifx, 17.9% for Goli, 17.8 for Ctz and 17.4% for Rtx, and 19.8% for Aba SC, 15.9% for Tcz, 10.3% for Bari and 7.5% for Tofa, the latest released biological. We checked that the release of a biosimilar infliximab increased the rebates up to 43.1% in 2017, with a gradual increase in bonus units over time while original Ifx rebate reached a 24.6%.

Table 3.

Official discounts and negotiated rebates from 2009 to 2017.

    2009  2010  2011  2012  2013  2014  2015  2016  2017 
Adalimumab  Total acquired                   
Rebates (€)    3.161  183,172  374,030  301,885  306,498  322,854  305,937  531,078  360,828 
Rebates (% Unit)    0.2%  6.7%  12.8%  11.1%  11.5%  12.1%  11.6%  16.7%  11.5% 
Bonus (U)    314  200  202  128  166  606  282 
Dispensed units (U) in RA    1.489  1.438  1.260  1.023  635  501  487  551  508 
Rebates in RA (€)    1.198  5.415  87,209  61,100  40,038  33,454  26,629  46,500  27,326 
Etanercept  Total acquired                   
Rebates (€)    37,680  152,295  202,444  240,499  209,525  228,183  262,751  260,054  297,629 
Rebates (% Unit)    1.5%  6.1%  8.8%  10.3%  10.3%  10.6%  12.6%  12.4%  15.5% 
Bonus (U)    2.400  23,500  26,600 
Dispensed units (U) in RA    165,425  160,050  146,925  143,075  122,960  128,700  132,775  141,500  160,750 
Rebates in RA (€)    15,061  59,908  79,207  74,039  61,421  67,608  79,733  80,189  104,404 
Infliximab  Total acquired                   
Rebates (€)    3.313  114,842  269,141  413,595  391,423  340,626  561,199  286,529  746,340 
Rebates (% Unit)    0.1%  4.8%  10.0%  13.4%  15.1%  12.7%  19.6%  11.7%  30.90% 
Bonus (U)    65  112  134  118  84  34 
Dispensed units (U) in RA    1.131  821  561  390  262  265  109  271  323 
Rebates in RA (€)    935  22,206  32,831  33.115  21.908  20.880  35.927  18.502  43.842 
Golimumab  Total acquired                   
Rebates (€)      10,455  71,370  60,224  134,736  197,754  83,426  91,867  142,098 
Rebates (% Unit)      100.0%  37.0%  30.3%  25.8%  30.2%  17.7%  13.7%  17.90% 
Bonus (U)      50  14  13  43 
Dispensed units (U) in RA      25  12  21  39  47  107  127 
Rebates in RA (€)      10,455  13,024  3.950  6.373  14,662  7.953  14,205  20,119 
Certolizumab  Total acquired                   
Rebates (€)      13,064  25,783  61,679  72,288  92,400  87,027  77,024.6  88,822 
Rebates (% Unit)      32.3%  22.9%  24.6%  26%  25.5%  21%  17.7%  17.80% 
Bonus (U)      10  40 
Dispensed units (U) in RA      14  240  462  490  552  701  777  929 
Rebates in RA (€)      13,064  22,742  55,874  62,803  69,489  65,387  61,769  73,741 
Rituximab  Total acquired                   
Rebates (€)    48,633  82,676  89,485  95,321  161,332  197,217  217,623  256,074 
Rebates (% Unit)    4.20%  7.50%  7.50%  7.50%  13.20%  15.10%  15.0%  17.40% 
Bonus (U)   
Dispensed units (U) in RA    163  136  112  96  107  148  165  186  237 
Rebates in RA (€)    6.916  8.760  8.893  9.817  24,616  30,271  34,245  47,876 
Abatacept  Total acquired  2009  2010  2011  2012  2013  20142015
    IV(mg)  IV(mg)  IV(mg)  IV(mg)  IV(mg)  IV(mg)  SC (units)  IV(mg)  SC (units) 
Rebates (€)    1.567  7.861  22,331  9.399  8.792  984  10,238  9.640 
Rebates (% Unit)    0.00%  2.80%  7.50%  16.40%  11.40%  7.50%  7.50%  7.50%  10.00% 
Bonus (U)    4.500  4.500  2.500  12 
Dispensed units (U) in RA    58,250  39,250  63,250  76,000  56,750  72,250  60  62,500  416 
Rebates in RA (€)    1.567  7.078  19,908  8.603  5.105  984  6.630  9.348 
Tocilizumab  Total acquired                   
Rebates (€)    –  6.680  13,971  28,766  73,108  74,536  –  54,698  20,045 
Rebates (% Unit)    –  5.60%  7.50%  9.30%  21.20%  20.90%  –  16.10%  22.10% 
Bonus (U)    –  – 
Dispensed units (U) in RA    –  27,200  70,520  101,480  135,040  152,680  –  122,840  368 
Rebates in RA (€)    –  4.285  9.498  17,778  56,081  55,211  –  37,081  20,049 
Abatacept  Total acquired  20162017Oral drugs  Total acquired  2017
    IV(mg)  SC (units)  IV(mg)  SC (units)      Baricitinib  Tofacitinib 
Rebates (€)    9.027  27,504  18,736  31,083  Rebates (€)580 €  152.203 € 
Rebates (% Unit)    7.50%  19.40%  14.20%  19.20%  Rebates (% Unit)10.30%  19.80% 
Bonus (U)    76  80  Bonus (U)
Dispensed units (U) in RA    54,500  562  75,750  601  Dispensed units (U) in RA
Rebates in RA (€)    5.704  24,228  14,979  25,486  Rebates in RA (€)
Tocilizumab  Total acquired                 
Rebates (€)    51,188  46,757  60,088  49,436         
Rebates (% Unit)    14.50%  21.30%  17.30%  15.90%         
Bonus (U)    72         
Dispensed units (U) in RA    80,960  843  110,760  1177         
Rebates in RA (€)    23,080  44,040  33,984  47,191         

U: Dispensed or Bonus Units.

RA: Rheumatoid arthritis.

Disease activity decreased annually in patients with optimized regimes when compared with patients without optimized regimes (P<.001) (Table 4a).

Table 4a.

Clinical characteristics of patients according to the optimizations of their treatments.

  2013  P(*)  2017  P(*) 
DAS28 optimized group  2.77(0.97)  <.001  2.64(0.96)  <.001 
DAS28 not optimized group  4.00(1.25)    3.61(1.34)   
SDAI optimized group  6.11(6.02)  <.001  5.42(4.93)  <.001 
SDAI not optimized group  16.96(12.38)    13.06(10.64)   
CRP-C optimized group  3.38 (5.5)  .004  4.70(7.93)  .244 
CRP-C not optimized group  9.44 (17.39)    7.65(15.54)   
ESR optimized group  17.62 (11.93)  .553  19.31(14.22)  .197 
ESR not optimized group  19.68 (13.93)    22.63(17.47)   

As Fig. 2 shows, active patients and percentage using optimized regimes from 2009 to 2017, reached 51.5% and 35.2% of patients with optimization by 2013 and 2017 respectively. The optimized therapies per drug and annually was analyzed (Table 4b).

Fig. 2.

Proportion of active patients with optimized regimes.

(0.14MB).
Table 4b.

Number of active patients and % patients with optimized therapies per drug.

  200920102011201220132014201520162017
  Active pat  Opt (%)  Active pat  Opt (%)  Active pat  Opt (%)  Active pat  Opt (%)  Active pat  Opt (%)  Active pat  Opt (%)  Active pat  Opt (%)  Active pat  Opt (%)  Active pat  Opt (%) 
Etn  87  2.3%  85  3.5%  81  18.5%  83  28.9%  78  59.0%  76  51.3%  78  50.0%  83  57.8%  93  39.8% 
Ada  71  0.0%  69  2.9%  64  21.9%  56  37.5%  39  76.9%  36  69.4%  38  52.6%  36  41.7%  27  55.6% 
Ctz      0.0%  14  0.0%  18  11.1%  26  34.6%  31  29.0%  33  36.4%  43  34.9%  44  29.5% 
Goli          0.0%  0.0%  0.0%  50.0%  14.3%  11  36.4%  13  30.8% 
Tcz SC                      0.0%  16  31.3%  27  25.9%  29  31.0% 
Aba SC                      0.0%  14  0.0%  14  14.3%  13  7.7% 
Ifx  63  12.7%  47  14.9%  38  44.7%  32  59.4%  25  60.0%  25  52.0%  20  55.0%  15  73.3%  14  57.1% 
Bios Ifx                      0.0%  0.0%  11  0.0%  10  20.0% 
Rtx  32  0.0%  36  0.0%  24  0.0%  20  0.0%  22  13.6%  31  9.7%  37  24.3%  42  19.0%  43  34.9% 
Tcz IV      10  0.0%  18  0.0%  26  0.0%  33  42.4%  33  54.5%  27  66.7%  18  55.6%  25  32.0% 
Aba IV  10  20.0%  66.7%  11  9.1%  12  8.3%  33.3%  11  18.2%  11  45.5%  10  40.0%  14  28.6% 
Oral drugs                                  0.0% 
Total  263  4.6%  253  5.5%  252  18.7%  248  27.0%  231  51.5%  251  44.2%  285  42.1%  310  40.0%  330  35.2% 

Data are expressed as mean (SD) for continuous variables and frequencies (percentage) for categorical variables.

DAS28: Disease Activity Score 28; SDAI: Simplified Disease Activity Index.

CRP-C: C-Reactive Protein; ESR Erithrocite Sedimentation Rate.

Statistical signification P<.05; (*) T-Test Mann–Whitney U.

Active pat: number of active patients per drug.

Opt (%): Percentage of patients with optimized therapies per drug.

Etn: Etanercept; Ada: Adalimumab; Ctz: Certolizumab; Goli: Golimumab; Tcz: Tocilizumab; Aba: Abatacept; Ifx: Infliximab; Bios Ifx: Biosimilar Ifx; Rtx: Rituximab; Oral drugs: Bariticinib and Tofacitinib.

Costs evolution according to the factors studied (results in 2017 are shown in Table 5). Thus, costs savings related to therapy optimization (830,000€), costs savings by monitoring drug and anti-drug antibody (ADA) serum levels in 2017 represented a 73.87% (613,101€).

Table 5.

Calculation of different factors that have an impact on costs in 2017.

Annus  Theoretical  Theoretical cost  Average  Theoretical  Annual  Saved  Rebates,  Saved Optimized 
Drugs  Unit per annus  (Unit or mg)  Dispensed pat  Annual cost € (A)  Cost (€)(B)  Cost (€)(A-B)  Discount €(C)  Regimes €(A-B-C) 
RA 2017
Certolizumab  30  442  44.48  589.804,80  335.283  254.521,80  73.441,00  181.080,80 
Etanercept  2.600,00  4.28  86.16  958.788,48  579.680  379.108,48  104.113,00  274.995,48 
Adalimumab  26  480.54  30.73  383.941,85  215.512  168.429,85  46.500,00  121.929,85 
Rituximab  1.261,77  29.51  297.878,66  242.484  55.394,66  47.876,00  7.518,66 
Abatacept SC  52  218.59  12.86  146.175,50  102.692  43.483,50  25.486,00  17.997,50 
Abatacept IV  9.100,00  1.37  10.21  127.288,07  90.261  37.027,07  14.979,00  22.048,07 
Infliximab+BIOSIM  1.499,40  4.18  27.68  173.484,18  92.414  81.070,18  43.842,00  37.228,18 
Tocilizumab IV  7.280,00  1.74  20.92  264.997,82  158.076  106.921,82  33.984,00  72.937,82 
Tocilizumab SC  52  243.91  28.9  366.547,95  240.921  125.626,95  47.191,00  78.435,95 
Golimumab  13  921.63  11.38  136.345,94  96.171  40.174,94  20.119,00  20.055,94 
Baricitinib (envase)  13  706.06  0.33  3.029,00  2.508  521  580  −59 
Tofacitinib (envase)  13  706.06  0.42  3.855,09  7.600  −3.744,91  424  −4.168,91 
Total 2017      303.58  3.452.137,34  2.163.602  1.288.535,34  458.535,00  830.000,34 

Theoretical annual cost: Theoretical unit per annus×Theoretical cost (unit or mg)×Average-dispensed-patient.

Average dispensed pat: average-dispensed-patient.

Saved cost (€): Theoretical annual costAnnual cost.

Saved optimized regimes: Theoretical annual costAnnual costRebates and discounts.

Moreover, costs savings by drugs monitoring were 88.08% (322,882€) in 2011, 75.38% (797,906€) in 2013 and a 79.19% (730,810€) in 2015.

Moreover, we found that from 2009 to 2017 the total savings increased (Table 6). The greatest contribution to economic savings was therapy optimization (24.93%). Savings associated with official discounts and negotiated rebates (13.77%) in 2017 (Table 6).

Table 6.

Quantification of influential factor that affect on treatment costs in rheumatoid arthritis.

Rheumatoid arthritis  2009  2011  2013  2015  2017 
Annual cost (€) (AC)  10.798,00 €  95.00%  9.547,00  77.51%  7.491,00  59.55%  7.242,00  61.23%  7.116,00  61.29% 
Theoretical annual cost (€)(TAC)  11.367 €  100.00%  12.317 €  100.00%  12.579 €  100.00%  11.828 €  100.00%  11.610 €  100.00% 
Difference (€): (TAC) – (AC)  568.51 €  5.00%  2.769,78 €  22.49%  5.087,96 €  40.45%  4.585,65 €  38.77%  4.493,95 €  38.71% 
Total saved cost (€):  132.268,16 €  0.58%  574.193,00  22.49%  1.062.529,00  40.45%  1.049.073,00  38.77%  1.288.535,34  38.71% 
* Rebates+bonus+offitial discount (€)  17.193,50 €  0.08%  254.837,19  9.98%  264.622,48  10.07%  318.262,83  11.76%  458.535,00  13.77% 
- Royal Decret Law (€)  0.00 €  0.00%  191.500,79  7.50%  197.016,76  7.50%  202.938,51  7.50%  249.666,02  7.50% 
- Negotiated Rebates and Bonus (€)  17.193,50  0.08%  63.336,40  2.48%  67.605,72  2.57%  115.324,32  4.26%  208.868,98  6.27% 
* Saved by optimized regimes (€)  115.074,00 €  0.50%  322.882,00  12.51%  797.907,00  30.37%  730.810,00  27.01%  830.000,34  24.93% 
Discussion

The results obtained are in line with an article that we recently published in patient with Spondyloarthritis.16 Over the study period there was a marked decrease in annual cost per-average-patient diagnosed with RA (incremental difference: −34.9%), however average-dispensed-patient trend increased. Also annual cost per drug decreased during 2009–2017.

In Spain, the Royal Decree Law 4/2010 implementation in June 2010 lead to decreased the prices of all medications by 7.5%19 this fact was associated with cost reduction from 2010 to 2011. Therapy optimization, use of biosimilar TNFi, and official discounts or negotiated rebates that lowered prices in some biologics were other factors associated to the cost reduction for 2011–2017.16

Different published studies have analyzed the economic impact of biological therapies in RA. Gómez-DeRueda et al.,20 in a study conducted from 2013 to 2015, concluded that Ifx (€10,717) had the lowest cost per patient per year under the established practice, followed by Etn (€11,015) and Ada (€11,977). Our study differs in that the costs of Ifx, Etn, and Ada were lower (41.3%, 28.5%, and 41.7%, respectively), compared with the aforementioned study in 2015. Mariatena et al.,21 in a study conducted in 2013, concluded that Ifx (€10,073) had the lowest cost per patient per year under the established practice, followed by Toci (€10,798), Eta (€11,056), and Ada (€11,512). Our study differs in that the costs of Ifx, Toci, Etn, and Ada were lower (46.1%, 22.3%, 33.1% and 37.0%, respectively), compared with the aforementioned study in 2013. Toci, Eta and Ada doses in the first study were optimized empirically and they were reduced a 13.3%, 6.9% and 10.7% for Toci, Eta and Ada, respectively. Ramírez-Herraiz et al.22 concluded that mean doses used were significantly lower with Eta than with Ada and Ifx and they used 81.0%, 93.02% and 135.73% of recommended dose for Eta, Ada and Ifx, respectively. In this study, BD were optimized empirically, controlling for disease activity. Thus patient-year cost in 2011 were €9594, €11,962 and €10,094 for Eta, Ada and Ifx, respectively. Our study differs in that the costs of Ada and Ifx were lower (15.4%, 25.6% respectively), and costs of Eta was higher (3.4%). Finally, Ivorra et al.23 published annual costs per patient and per drug referred to 2013 and our data for the same period showed that these therapies were cheaper 54.3% for Ifx, 43.6% in Ada, 40.1% in Tcz, 37.6% in Eta, 36.0% in Aba IV, 32.1% in Ctz and 19.8% in Goli, that reported in the aforementioned study.

Although in most of these studies the treatments were empirically optimized, our results showed marked differences in RA. This could be explained by the fact that the monitoring of drugs (Etn, Ifx, Ada, Toci) helps the clinician to optimize treatments earlier, with greater safety, and lower doses and wider dosing intervals regarding empirical optimization.

According to the EULAR recommendations,7 tapering of a biological drug can be considered in patients that achieve persistent remission. REDOSER project established criteria for reducing doses of biological therapies for RA, both extending the dosing interval and/or reducing the dose. In addition, serum drug levels and ADAs in serum, when available, can help to clinicians to optimize biological therapy and the clinical monitoring.24

We observed that patients with optimized regimes increased from 12 (4.6%) to 116 (35.2%) patients (2009–2017). Monitoring of Ifx, Etn and Ada using serum levels is used by clinicians in clinical practice in our center from 201114–16; serum levels for monitoring Toci began in 2014 and Goli and Rtx began in 2015, and were available in usual practice in 2017, and for their optimization, rheumatologists have stablished clinical protocols.

Our results show that optimization of biological therapies leads to a marked costs reduction. Moreover, other authors proved that dosing regimen optimization of biologicals does not mean an increase in disease activity parameters, no differences with patients under full dose regimens were found.16,25

In parallel with the beginning of the optimization of treatments, costs decreased. Ada and Ifx annual costs decreased mainly in 2011 and 2012 and Etn in 2013.

When analyzing savings related to therapy optimizations, we detected that the main factor contributing to these savings was optimization by drug serum levels monitorization that were around 80%, respect saving related to empirically optimizations, for analyzed years as we described in result section.

The majority of drugs that contributed to cost savings by optimization were Ada, Etn, Ifx and Tcz group over Goli and Ctz, coinciding with the percentage of optimized regimes for these drugs, in which Goli and Ctz were optimized in a lower percentage than first group probably they joined later.

The presence in the market of many drugs for a pathology produces an economic competition.26 However, bonus units and discounts can then reduce the expenditure on medicines. In our hospital, we have observed that introduction of Goli, Ctz, and Aba or Tcz SC was accompanied by significant invoice discounts of between 15.9% and 37% in different years; and bonus units gradually rose during the study period.

It is known that when a biosimilar is released there is an increased access and a lower health cost burden. According to the law in Spain, when a biosimilar is marketed the original have to decrease its price to the same level of the biosimilar.27,28 Over the study period the European Medicines Agency approved biosimilars of Ifx and Etn in 2013 and 2015 respectively, which led to an increase in discounts for Ifx and Eta.

Original Ifx rebate in our study (24.6%) are in line with the reduction in the price of infliximab published articles,29 however biosimilar Ifx retabe obtained (43.1%) exceed published data.30

Taking together all factors influencing annual RA cost per patient we observed that when the annual cost decreased slightly, increased the number of treated patients and the total saved costs. Our results show that the greatest saving contributions were biological therapy were optimizations, followed by official discounts and negotiated rebates.

Taking into account our results future strategies leading toward the implementation of therapeutic drug monitoring based on scientific evidence31 should be promoted in order to reduce costs and maintaining disease control at the same time.

There were several study limitations. Farmatools does not provide definitive reports of economic and clinical results in order to make a posterior statistical analysis. We have to do a data treatment before use them. Moreover, the annual theoretical cost of Ifx could be overestimated because we considered an estimated average weight of 70kg for all patients treated. Moreover, the saved by optimized regimes could be overestimated because units not dispensed by the possible lack of adherence to treatment are not included. Finally, costs from 2009 to 2017 were not adjusted.

The most important strength of our study is the very long analysis period and the large sample size, which allowed us to analyze and to quantify influential factors in decreasing cost per patient and to prove that optimization was the strategy that most influenced this decline.

Also, annual cost per average-dispensed-patient allows us to compare our data with other hospitals in Spain.

Conclusion

Our study proves that the greatest contribution to economic savings in biological therapy in rheumatoid arthritis was biological therapy optimization by monitoring drug and ADA serum levels when comparing with official discounts, negotiated rebates.

Financial disclosure

No financial support.

Conflict of interest

No conflicts of interest have been declared.

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