A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in four European countries: Austria, Belgium, Greece, and Italy

Figures & data

Figure 1. Schematic representation of the cost-effectiveness model structure. Abbreviations. Dmab, denosumab; MM, multiple myeloma; Tx, treatment; ZA, zoledronic acid.

Table 1. Model economic inputs by country.

Economic parameter	Austria	Belgium	Greece	Italy
Annual discount rates, %
Costs	5.0	3.0	3.5	3.0
Health outcomes	5.0	1.5	3.5	3.0
Parameter source	Walter and Zehetmayr 2006^43	Cleemput et al. 2012^44	NICE 2013^45^,^a	Capri et al. 2001^46
Drug acquisition and administration costs per administration, €
Dmab acquisition	333.45	287.15	205.68	282.00
ZA acquisition	86.75	100.28	39.62	73.54
Dmab administration	10.98	9.34	0.0	12.91
ZA administration^b	27.46	24.93	89.05	26.48
Parameter source	Warenverzeichnis 2018^47	INAMI–RIZIV 2018^48^,^c	Ministry of Health 2018^49; Ministry of Health Decree, 2011^50^,^d	Codifa 2018^51; Official Gazette of the Italian Republic, 2013^52^,^e
SRE management cost per SRE episode, €
Pathologic fracture	10,305	6,780	4,478	3,565
Radiation to bone	14,603	2,998	9,734	1,961
Surgery to bone	21,496	14,559	7,943	3,075
Spinal cord compression	22,191	17,249	7,538	12,755
Parameter source	Pereira et al. 2016 (Austrian data)^53	Body et al. 2013^54^,^f	Pereira et al. 2016 (Greek data)^53	Ashcroft et al. 2018^10; Official Gazette of the Italian Republic, 2013^52^,^g
SAE management cost per SAE episode, €
ONJ	4,100	1,790	1,144	1,651
Hypocalcemia	2,100	14,272	319	1,758
Renal toxicity	3,459	12,003	283	3,734
Parameter source	Data on file (Amgen)^h	Data on file (Amgen)^f^,^i	Ministry of Health Decree, 2011^50	Official Gazette of the Italian Republic, 2013^52^,^j

^aThere are no official guidelines in Greece; therefore, we considered NICE recommendations, which is common practice in the Greek setting⁴⁵.

^bIncludes renal function laboratory testing costs.

^cDmab administration cost was a weighted average of administration costs according to administration setting (nurse at home, during a GP visit, or in hospital). ZA administration cost was calculated as (2 × Dmab administration cost) + serum creatinine laboratory testing cost.

^dNo cost incurred to payer for Dmab administration.

^eOfficial Gazette of the Italian Republic no. 23, January 28, 2013—general series (supplemento ordinario 8, allegato 3).

^fCosts inflated using the health consumer index (+13%)⁵⁵.

^gMicro-costing approach using HRU reported by Ashcroft et al.¹⁰ and published unit costs (Official Gazette of the Italian Republic no. 23, January 28, 2013—general series [supplemento ordinario 8, allegato 1 e 3]).

^hMicro-costing approach.

ⁱCalculated using the same method as Body et al.⁵⁴ for SREs.

^jMicro-costing approach using unit costs (Official Gazette of the Italian Republic no. 23, January 28, 2013—general series [supplemento ordinario 8, allegato 1 e 3]).

Abbreviations. Dmab, denosumab; GP, General Practice; HRU, healthcare resource use; INAMI–RIZIV, Institut National d’Assurance Maladie-Invalidité–Rijksinstituut voor Ziekte- en Invaliditeitsverzekering (National Institute for Health and Disability Insurance [Belgium]); NICE, National Institute for Health and Care Excellence (UK); ONJ, osteonecrosis of the jaw; SAE, serious adverse event; SRE, skeletal-related event; ZA, zoledronic acid.

Table 2. Base case cost-effectiveness analysis (discounted) by country.

	Austria			Belgium			Greece			Italy
	Dmab	ZA	Δ	Dmab	ZA	Δ	Dmab	ZA	Δ	Dmab	ZA	Δ
Costs, €
Total	191,687	186,808	4,879	134,092	129,778	4,314	97,910	96,465	1,445	70,804	64,946	5,858
Drug acquisition	10,730	2,706	8,024	9,696	3,282	6,414	6,860	1,281	5,579	9,522	2,407	7,115
Drug administration	353	857	−503	315	816	−501	0.0	2,879	−2,879	436	867	−431
SRE management	180,351	183,019	−2,668	123,202	124,878	−1,676	91,016	92,282	−1,266	60,606	61,430	−824
SAE management	253	227	26	878	802	76	35	23	11	240	242	−3
Health outcomes
Life-years	6.27	6.27	0.0	7.75	7.75	0.0	6.83	6.83	0.0	7.04	7.04	0.00
QALYs	3.24	3.06	0.19	3.92	3.67	0.24	3.50	3.29	0.21	3.60	3.38	0.22
Cost-effectiveness
ICER (cost [€] per QALY gained)	26,294			17,737			6,982			27,228
1–3 × GDP per capita^a, €	42,100–126,300			38,700–116,100			16,700–50,100^b			28,500–85,500

^a GDP at market prices (2017)⁵⁷. The European Union GDP per capita (2017) was €30,000⁵⁷.

^b Provisional value.

Abbreviations. Δ, increment/decrement (Dmab vs ZA); Dmab, denosumab; GDP, gross domestic product; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year; SAE, serious adverse event; SRE, skeletal-related event; ZA, zoledronic acid.

Table 3. Alternative scenario cost-effectiveness analyses (discounted) by country.

Base case	Austria			Belgium			Greece			Italy
	ΔCosts	ΔQALYs	ICER	ΔCosts	ΔQALYs	ICER	ΔCosts	ΔQALYs	ICER	ΔCosts	ΔQALYs	ICER
	4,879	0.19	26,294	4,314	0.24	17,737	1,445	0.21	6,982	5,858	0.22	27,228
Anti-MM treatment costs included	−15,402	0.186	Dominant	−29,661	0.243	Dominant	−20,457	0.207	Dominant	−11,836	0.215	Dominant
Dmab vs no treatment	−34,207	0.456	Dominant	−17,713	0.538	Dominant	−14,715	0.487	Dominant	−3,863	0.499	Dominant
15-month landmark analysis for SREs	3,537	0.196	18,038	3,425	0.256	13,392	783	0.218	3,586	5,421	0.227	23,905
Shorter time horizon
10 years	4,810	0.136	35,372	4,241	0.158	26,763	1,422	0.145	9,811	5,759	0.148	38,874
20 years	4,878	0.178	27,451	4,313	0.225	19,178	1,445	0.196	7,384	5,857	0.202	28,936
0% discount rates	5,537	0.278	19,903	4,666	0.278	16,760	1,583	0.279	5,681	6,336	0.279	22,744
PFS modeled with Weibull distribution^a	4,879	0.130	37,601	4,314	0.155	27,837	1,445	0.140	10,359	5,858	0.143	40,929

Costs are €. ICERs are cost (€) per QALY gained. Dominant = Dmab was associated with more QALYs and fewer overall costs than ZA. The model input parameters are provided in Supplementary Table S3.

^a Proportional hazards assumption.

Abbreviations. Δ, increment (Dmab vs ZA); Dmab, denosumab; ICER, incremental cost-effectiveness ratio; MM, multiple myeloma; PFS, progression-free survival; QALY, quality-adjusted life-year; SRE, skeletal-related event; ZA, zoledronic acid.

Figure 2. Main drivers of uncertainty in cost-effectiveness analysis by country. The ICER is the cost (€) per QALY gained derived from univariate analyses employing the lower and upper bounds of top five key model inputs. Cross-hatching represents situations in which Dmab is dominant vs ZA (Dmab is associated with more QALYs and fewer overall costs than ZA). The ranges for the model parameters are provided in Supplementary Table S4. Abbreviations. Dmab, denosumab; ICER, incremental cost-effectiveness ratio; i.v., intravenous; MM, multiple myeloma; QALY, quality-adjusted life-year; SRE, skeletal-related event; ZA, zoledronic acid.

Figure 3. Cost-effectiveness acceptability curves by country. The model input parameters are provided in Supplementary Table S5. Abbreviations. Dmab, denosumab; QALY, quality-adjusted life-year; WTP, willingness to pay; ZA, zoledronic acid.

Walter E, Zehetmayr S. Guidelines zur gesundheitsökonomischen evaluation konsensuspapier [Guidelines for health-economic evaluation consensus paper]. Wien Med Wochenschr. 2006;156:628–632. [German].

 PubMedGoogle Scholar

Cleemput I, Neyt M, Van de Sande S, et al. Belgian guidelines for economic evaluations and budget impact analyses. 2nd ed. Health Technology Assessment. Brussels (Belgium): Belgian Healthcare Knowledge Centre (KCE). 2012. KCE Report 183C. D/2012/10.273/54.

 Google Scholar

National Institute for Health and Care Excellence (United Kingdom). Processing and methods guidance [PMG9]. Guide to the methods of technology appraisal. 2013. [cited 2018 Nov 20]. Available from: https://www.nice.org.uk/process/pmg9/resources/guide-to-the-methods-of-technology-appraisal-2013-pdf-2007975843781

 Google Scholar

Capri S, Ceci A, Terranova L, et al. Guidelines for economic evaluations in Italy: recommendations from the Italian Group for Pharmacoeconomic Studies. Drug Info J. 2001;35:189–201.

 Web of Science ®Google Scholar

Warenverzeichnis (Austria). Official list price of drugs. 2018. [cited 2018 Nov 20]. Available from: https://warenverzeichnis.apoverlag.at/

 Google Scholar

National Institute for Health and Disability Insurance – INAMI–RIZIV (Belgium). Reimbursed pharmaceutical drugs: list and reference files. 2018. [cited 2018 Nov 20]. Available from: https://www.inami.fgov.be/fr/themes/cout-remboursement/par-mutualite/medicament-produits-sante/remboursement/specialites/Pages/specialites-pharmaceutiques-remboursables-listes-fichiers-reference.aspx#.WRA3UlWLS70

 Google Scholar

Ministry of Health (Greece). Corrected price list for medicines for human use, November 2017. 2018. [cited 2018 Nov 20]. Available from: http://www.moh.gov.gr/articles/times-farmakwn/deltia-timwn/5313-laquo-diorthwtiko-deltio-timwn-farmakwn-anthrwpinhs-xrhshs-noembrioy-2017-raquo

 Google Scholar

Ministry of Health (Greece). Decree 1702/B/01.08. 2011. [cited 2018 Nov 20]. Available from: http://www.moh.gov.gr/articles/ken-eswteriko/710-ypoyrgikes-apofaseis-egkyklioi-g-g?fdl=2431

 Google Scholar

Codifa (Italy). 2018. [cited 2018 Nov 28]. Available from: https://www.codifa.it/

 Google Scholar

Official Gazette of the Italian Republic. General series. Ordinary supplement. 2013. [cited 2018 Nov 30]. Available from: http://www.gazzettaufficiale.it/

 Google Scholar

Pereira J, Body JJ, Gunther O, et al. Cost of skeletal complications from bone metastases in six European countries. J Med Econ. 2016;19:611–618.

 PubMed Web of Science ®Google Scholar

Body JJ, Chevalier P, Gunther O, et al. The economic burden associated with skeletal-related events in patients with bone metastases secondary to solid tumors in Belgium. J Med Econ. 2013;16:539–546.

 PubMedGoogle Scholar

Ashcroft J, Duran I, Hoefeler H, et al. Healthcare resource utilisation associated with skeletal-related events in European patients with multiple myeloma: results from a prospective, multinational, observational study. Eur J Haematol. 2018;100:479–487.

 PubMed Web of Science ®Google Scholar

Statistics Belgium (STATBEL). Consumer price index and health index. 2017. [cited 2018 Nov 20]. Available from: https://statbel.fgov.be/en/open-data/consumer-price-index-and-health-index

 Google Scholar

European Commission. Eurostat. Gross domestic product at market prices. 2017. [cited 2018 Nov 2]. Available from: https://ec.europa.eu/eurostat/tgm/table.do?tab=table&init=1&language=en&pcode=tec00001&plugin=0&tableSelection=1

 Google Scholar