Cost-effectiveness of Cladribine Tablets and fingolimod in the treatment of relapsing multiple sclerosis with high disease activity in Spain

Figures & data

Figure 1. Markov Model of 11 statuses (Hettle, 2018). Patients with RMS with high disease activity. EDSS: Expanded Disability Status Scale; RMS: relapsing multiple sclerosis; SPMS: Secondary progressive multiple sclerosis.

Table 1. Probabilities (%) per year of transition between EDSS statuses (age of MS onset ≥28 years), adjusted to the RMS with high disease activity [12,16]. EDSS: Expanded Disability Status Scale; RMS: relapsing multiple sclerosis.

EDSS from/to	0	1–1.5	2–2.5	3–3.5	4–4.5	5–5.5	6–6.5	7–7.5	8–8.5	9–9.5
0	58.3	27.8	9.9	3.0	0.6	0.2	0.2	0.0	0.0	0.0
1–1.5	5.8	59.8	22.0	8.5	2.3	0.6	0.9	0.1	0.0	0.0
2–2.5	1.6	12.1	50.9	23.3	6.2	2.6	3.0	0.2	0.1	0.0
3–3.5	0.6	5.0	12.0	43.8	12.6	8.1	16.1	1.4	0.5	0.0
4–4.5	0.2	2.2	6.7	11.5	37.7	14.2	23.0	3.5	0.9	0.1
5–5.5	0.1	0.5	2.9	5.9	8.7	36.8	37.1	5.3	2.6	0.1
6–6.5	0.0	0.1	0.4	2.5	3.1	4.1	67.4	15.5	6.2	0.6
7–7.5	0.0	0.0	0.1	0.2	0.7	0.4	11.7	69.3	16.1	1.6
8–8.5	0.0	0.0	0.0	0.0	0.1	0.1	1.9	5.6	90.3	2.1
9–9.5	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.6	17.4	81.8

Table 2. Premises and values adopted in the economic model.

Item	Cladribine Tablets	Fingolimod	Source
Cohort of patients
Population parameters of the cohort
Mean age Women/men ratio Number of relapses in the previous year Mean weight of the patient Initial distribution of patients EDSS 0 EDSS 1 EDSS 2 EDSS 3 EDSS 4 EDSS 5 EDSS 6 EDSS 7 EDSS 8 EDSS 9	37.1 ± 0.83 years 1.709 2.02 ± 0.4 68,0 2.77% 2.77% 32.53% 21.45% 23.53% 11.07% 5.88% 0.00% 0.00% 0.00%		Giovannoni, 2010[20] “ “ Bártulos, 2015[15];Carreón, 2016[5]; Llaneza, 2016[34]; Giovannoni, 2010[20] “ “ “ “ “ “ “ “ “
Probabilities
Hazard ratio for confirmed progression of disability at 3 months (vs. placebo)	0.281 (95% CrI 0.148–0.532)	0.620 (95% CrI 0.368–1.041)	Siddiqui, 2017[15]
Annualized Relapse Rate (vs. placebo)	0.350 (0.243–0.505)	0.375 (0.269–0.507)	Siddiqui, 2017[15]
Probability of treatment withdrawal 0–1 years 1–2 years Following years	4.9% 0.0% 0.0%	10.3% 10.3% 10.3%	Giovannoni, 2010[20]; Siddiqui, 2017[15]
Likelihood of suffering an AR Progressive multifocal leukoencephalopathy Serious infections Macular oedema Cancer	0.00% 2.82% 0.00% 0.60%	0.01% 2.23% 0.39% 9.60%	Tan, 2009[18]; Cohen, 2010[19]; Kappos, 2010[21]; Saida, 2012[24]; Calabresi, 2014[26]; Pakpoor, 2015[27]; Siddiqui, 2017[15]; Hettle, 2018[12]
Utility
Utility of the patients according to the status
EDSS 0 EDSS 1 EDSS 2 EDSS 3 EDSS 4 EDSS 5 EDSS 6 EDSS 7 EDSS 8 EDSS 9	0.906 0.845 0.804 0.701 0.655 0.565 0.496 0.392 0.025 –0.195		Giovannoni, 2010[20] “ “ “ “ “ Hawton, 2016[29] “ “ Orme, 2007[^Citation17]
Loss of utility of the caregiver EDSS 0 EDSS 1 EDSS 2 EDSS 3 EDSS 4 EDSS 5 EDSS 6 EDSS 7 EDSS 8 EDSS 9	−0.002 –0.002 –0.002 –0.045 –0.142 –0.160 –0.173 –0.030 –0.095 –0.095		Acaster, 2013[25] “ “ “ “ “ “ “ “ “
Loss of utility by AR Progressive multifocal leukoencephalopathy Serious infections Macular oedema Cancer	−0.0510 –0.0073 –0.0092 –0.1160		NICE TA312[33]; Shingler, 2015[28]; NICE TA312[33]; Trogdon, 2016[30]
Healthcare resources
Annual use of healthcare resources per patient Administration Day hospital visit Monitoring Basic analysis (biochemistry) Complete blood count (CBC) MRI Consulting the neurologist Consulting the ophthalmologist QuantiFERON	All years 0 Year 1/Year 2 0/0 3/3 1/0 2/1 0/0 1/0	Year 1/Years 2+ 1/0 Year 1/Years 2+ 6/2 4/2 1/0 3/1 1/0 0/0	Mavenclad, 2018[11]; Gilenya, 2018[10] Mavenclad, 2018[11]; Gilenya, 2018[10]
Costs
Drug acquisition cost ^(1) Annual Four-year	Years 1 and 2 25,197.00 € 50,394.00 €	All years 19,292.86 € 77,171.00 €	BotPlus, 2018[32]; Mavenclad, 2018[11]; Gilenya, 2018[10]
Drug administration costs (2017) Day hospital visit Drug monitoring costs (2017) Basic analysis (biochemistry) Complete blood count (CBC) MRI Consulting the neurologist Consulting the ophthalmologist QuantiFERON* Cost based on disability EDSS 0 to EDSS 3 EDSS 4 to EDSS 7 EDSS 8 and EDSS 9 Adverse events costs Progressive multifocal leukoencephalopathy ^(2) Serious infections ^(3) Macular oedema ^(4) Cancer ^(5)	€ 201 € 90.70 € 4.16 € 291.77 € 84.32 € 84.32 € 8.55 € 2,833.65 € 5,355.25 € 6,487.40 € 7,070 € 4,484 € 2,457 € 6,113		eSalud, 2017[31] eSalud, 2017[31] “ “ “ “ “ Karampampa, 2012[23] e-Salud, 2017[31] Gubieras, 2011[22] e-Salud, 2017[31] “ “ “

(1) Ex-factory price (EFP) with 7.5% deduction; (2) CIE09: 046.3; (3) GRD 79/80; (4) CIE09: 362.83; (5) GRD 694.

95% CrI: 95% credible interval; AR: Adverse reactions; EDSS: Expanded Disability Status Scale; MRI: magnetic resonance imaging; vs.: compared with. *The cost of the tuberculin test was assumed [40].

Table 3. The overall results of the deterministic cost-effectiveness analysis.

Treatment	Total cost per patient	QALYs per patient	Cost difference	Difference of QALYs	Cost of gaining a QALY with Cladribine Tablets^(1)	Net Health Benefit. According to the willingness to pay (€ per QALY gained)^(2)
						20,000 €	25,000 €	30,000 €
Cladribine Tablets	157,856 €	10.39	−86,536 €	1.11	Dominant	4.327	3.461	2.885
Fingolimod	244,392 €	9.28			Dominated

(1) The dominant medication (Cladribine Tablets) is more effective, obtains more QALYs, with lower costs than the medicine dominated (fingolimod). (2) A positive net health benefit indicates that Cladribine Tablets is a cost-effective treatment compared to fingolimod, for willingness to pay 20,000 €, 25,000 € and 30,000 per QALY gained with the most effective treatment (Cladribine Tablets), which will get more QALYs per patient than fingolimod (∆ Effectiveness – ∆ Costs/willingness to pay).

Table 4. Detailed results of the deterministic cost-effectiveness analysis.

Items	Cladribine Tablets	Fingolimod	Cladribine Tablets vs. Fingolimod
Costs (€)
Drug purchase costs	48,264 €	127,247 €	−78,983 €
Administration of Medication	0 €	201 €	−201 €
Medication monitoring	570 €	2,676 €	−2,106 €
Totals for the drug	48,834 €	130,124 €	−81,290 €
Totals by adverse effects	955 €	957 €	−2 €
Totals by relapses	3,693 €	4,336 €	−643 €
Totals based on disability (EDSS)	104,374 €	108,975 €	−4.60.1 €
Total cost	157,856 €	244,392 €	−86,536 €
QALYs
Totals by relapses	−0.11	−0.12	0.01
Totals based on disability (EDSS)	12.24	11.21	1.03
Total losses of caregivers	−1.74	−1.81	0.07
Total QALYs	10.39	9.28	1.11

Figure 2. Deterministic sensitivity analysis (tornado diagram). Net Health Benefit. ARR: annualized relapse rate. A positive net health benefit indicates that Cladribine Tablets is a cost-effective treatment compared to fingolimod.

Table 5. Results of the deterministic analysis of scenarios.

Item	Cost difference	Difference of QALYs	Cost per AVAC gained ^(1)
Base case	−86,536 €	1.12	Cladribine Tablets is dominant
Time horizon
40 years (10 years less)	−83,108 €	1.03	Cladribine Tablets is dominant
30 years (20 years less)	−84,525 €	0.78	Cladribine Tablets is dominant
20 years (30 years less)	−79,172 €	0.38	Cladribine Tablets is dominant
10 years (40 years less)	−56,823 €	0.01	Cladribine Tablets is dominant
Discount costs and QALYs
0%	−117,023 €	2.43	Cladribine Tablets is dominant
6%	−67,064 €	0.56	Cladribine Tablets is dominant
Exclusion from loss of utility on caregivers	−86,536 €	1.05	Cladribine Tablets is dominant

(1) The dominant medication (Cladribine Tablets) is more effective, obtains more QALYs, with lower costs than the medicine dominated (fingolimod).

Table 6. Detailed results of the deterministic cost-effectiveness analysis.

Treatment	Costs mean (CI 95%)	Mean QALYs (CI 95%)	Mean cost difference	Difference of mean QALYs	Cost of gaining 1 QALY^(1)	Probability of cost-effectiveness according to the willingness to pay (€ per QALY gained)^(2)
						20,000	25,000	30,000
Cladribine Tablets	158,149 € (146,420–170,985 €)	10.57 (7.39–13.18)	−86,328 €	1.13	Dominant	94.6%	96.1%	94.8%
Fingolimod	244,477 € (232,998–257,097 €)	9.44 (7.15–11.77)			Dominated	5.4%	3.9%	5.2%

(1) The dominant medication (Cladribine Tablets) is more effective, you get more QALYs, with lower costs than the medicine dominated (fingolimod). (2) Probability that Cladribine Tablets is a cost-effective treatment compared to fingolimod, for the willingness to pay 20,000 €, 25,000 € and 30,000 € for each QALY gained with the most effective treatment (Cladribine Tablets), which achieves more QALYs per patient than fingolimod (∆ Effectiveness – ∆ Costs/willingness to pay).

Figure 3. Probabilistic analysis. QALY: quality-adjusted life year. The likelihood that Cladribine Tablets is cost-effective compared to fingolimod ranged between 94.6% and 96.1% for willingness to pay between € 20,000 and € 30,000 per QALY gained.

Hettle R, Harty G, Wong SL. Cost-effectiveness of cladribine tablets, alemtuzumab and natalizumab in the treatment of relapsing-remitting multiple sclerosis with high disease activity in England. J Med Econ. 2018;21(7):676–686.

 PubMed Web of Science ®Google Scholar

Palace J, Bregenzer T, Tremlett H, et al. UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model. BMJ Open. 2014;4(1):e004073.

 PubMed Web of Science ®Google Scholar

Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416–426.

 PubMed Web of Science ®Google Scholar

Siddiqui MK, Khurana IS, Budhia S, et al. Systematic literature review and network meta-analysis of cladribine tablets versus alternative disease-modifying treatments for relapsing-remitting multiple sclerosis. Curr Med Res Opin. 2017;34(8):1361–1371.

 PubMed Web of Science ®Google Scholar

Carreón-Guarnizo E, Andreu-Reinón E, Cerdán-Sánchez M, et al. Prevalencia de la esclerosis múltiple en la Región de Murcia. Rev Neurol. 2016;62(9):396–402.

 PubMed Web of Science ®Google Scholar

Llaneza MA Epidemiología de la esclerosis múltiple en el Área sanitaria de Ferrol. Tesis doctoral Universidad de la Coruña, 2016[cited 2017 Sep 14] . Available from: http://hdl.handle.net/2183/17565

 Google Scholar

Tan K, Roda R, Ostrow L, et al. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology. 2009;72(17):1458–1464.

 PubMed Web of Science ®Google Scholar

Cohen JA, Barkhof F, Comii G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–415.

 PubMed Web of Science ®Google Scholar

Kappos L, Radue EW, Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New Engl J Med. 2010;362(5):387–401.

 PubMed Web of Science ®Google Scholar

Saida T, Kikuchi S, Itoyama Y, et al. A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis. Mult Scler. 2012;18(9):1269–1277.

 PubMed Web of Science ®Google Scholar

Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of in patients with relapsing-remittingmultiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(6):545–556.

 PubMed Web of Science ®Google Scholar

Pakpoor J, Disanto G, Altmann DR, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm. 2015;2(6):e158.

 PubMed Web of Science ®Google Scholar

Hawton A, Green C. Health utilities for multiple sclerosis. Value Health. 2016;19(4):460–468.

 PubMed Web of Science ®Google Scholar

Orme M, Kerrigan J, Tyas D, et al. The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK. Value Health. 2007;10(1):54–60.

 PubMed Web of Science ®Google Scholar

Acaster S, Perard R, Chauhan D, et al. A forgotten aspect of the NICE reference case: an observational study of the health related quality of life impact on caregivers of people with multiple sclerosis. BMC Health Serv Res. 2013;13:346.

 PubMed Web of Science ®Google Scholar

NICE TA312. National Institute for Health and Clinical Excellence (NICE). Alemtuzumab for treating relapsing-remitting multiple sclerosis. NICE technology appraisal guidance 312; 2014 [cited 2016 Nov]. Available from: https://www.nice.org.uk/guidance/ta312?unlid=106213045220161014202829

 Google Scholar

Shingler S, Fordham B, Evans M, et al. Utilities for treatment-related adverse events in type 2 diabetes. J Med Econ. 2015;18(1):45–55.

 PubMed Web of Science ®Google Scholar

Trogdon JG, Ekwueme DU, Chamiec-Case L, et al. Breast cancer in young women: health State utility impacts by race/ethnicity. Am J Prev Med. 2016;50(2):262–269.

 PubMed Web of Science ®Google Scholar

Mavenclad 10 mg comprimidos. Ficha técnica o Resumen de características del producto; [cited 2018 Apr 13]. Available from: https://cima.aemps.es/cima/pdfs/es/ft/1171212001/FT_1171212001.pdf

 Google Scholar

Gilenya 0,5 mg cápsulas duras. Ficha técnica o Resumen de características del producto; [cited 2018 Apr 13]. Available from: https://cima.aemps.es/cima/dochtml/ft/11677005/FT_11677005.html

 Google Scholar

BotPlus 2.0. Consejo General de Colegios Oficiales de Farmacéuticos (CGCOF); 2018 [cited 2018 Jan 11]. Available from: www.portalfarma.com

 Google Scholar

MSSSI: Ministerio de Sanidad, Servicios Sociales e Igualdad. Estrategia en Enfermedades Neurodegenerativas del Sistema Nacional de Salud; 2016 [cited 2018 Jun]. Available from: http://www.msps.es/organizacion/sns/planCalidadSNS/pdf/Est_Neurodegenerativas_APROBADA_C_INTERTERRITORIAL.pdf

 Google Scholar

e-salud. Base de datos de costes sanitarios en España; 2017 [cited 2017 Nov]. Available from: http://www.oblikue.com/bddcostes

 Google Scholar

Karampampa K, Gustavsson A, Miltenburger C, et al. Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from Spain. Mult Scler. 2012;18(2 Suppl):35–39.

 PubMed Web of Science ®Google Scholar

Gubieras L, Casado V, Romero-Pinel L, et al. Cost of the relapse of multiple sclerosis in Spain. Value Health. 2011;14(5):A320.

 Web of Science ®Google Scholar

Resolución de adjudicación. Suministro de productos y equipos necesarios para la realización de pruebas mediante Enzimoinmunoanálisis en el Laboratorio Central de la OSI Araba; [cited 2018 Sep 5]. Available from: http://www.contratacion.euskadi.eus/w32-1084/en/v79aWar/comunJSP/v79aObtenerFichero.do;jsessionid=fSLO1l59MGryeVEuGZ4GUYTIAj3qlo8pipVaKmOlpQOCubFtKA-E!-2033055975!-1619630890?identificador=140721&idTabla=007&R01HNoPortal=true

 Google Scholar