Cost-effectiveness analysis of abobotulinumtoxinA for the treatment of cervical dystonia in the United Kingdom

Figures & data

Figure 1 Model structure.

Notes: *Level of response is based on average change of TWSTRS from baseline in the three groups from trial reanalysis. TWSTRS and quality of life are tracked for each health state. All patients at any state are at risk of death.
Abbreviations: BSC, best supportive care; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale.

Figure 2 Graphical representation of linkage between utility and TWSTRS estimated from analysis of abobotulinumtoxinA trial. Data extrapolated from a previous study.²⁵

Notes: The line represents the best fit to the available data given by the blue points showing reduced utility with higher TWSTRS total score.
Abbreviation: TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale.

Table 1 Discounted costs and health outcomes in base-case analysis

Costs	AbobotulinumtoxinA (£)	BSC without BoNT-A injections (£)	Incremental (AbobotulinumtoxinA vs BSC) (£)
Drug cost	5,188	0	5,188
Concomitant medications cost	429	488	−59
Drug administration cost	4,600	0	4,600
Disease management cost	6,300	8,869	−2,569
Indirect cost	–	–	–
Total cost	16,517	9,357	7,160
Health outcomes	AbobotulinumtoxinA	BSC without BoNT-A injections	Incremental
Life-years	18.042	18.042	0.000
QALYs	11.970	11.735	0.235
Mean treatment duration with BoNT-A (years)		AbobotulinumtoxinA
Mean treatment duration (years)		10.309
Nonresponders		0.575
Responders		9.734
Cost-effectiveness results		AbobotulinumtoxinA vs BSC without BoNT-A injections
Incremental QALYs gained		0.235
Incremental costs		£7,160
Incremental cost per QALY (ICER)		£30,468

Abbreviations: BoNT-A, botulinum neurotoxin type A; BSC, best supportive care; ICER, incremental cost-effectiveness ratio; QALYs, quality-adjusted life-years.

Table 2 Direct and indirect costs (please refer to Table S1 for further details on the base-case model inputs)

Costs	Details	Source/assumptions
Direct costs
Drug costs	£154 per 500 unit vial at initial dose of BoNT-A, 750 units at subsequent doses; £0 for BSC	Dose varied between first injection and reinjections, as well as among health states with different response levels (nonresponders and responders). Model inputs for drug costs were derived from the BNF,^Citation34 the SmPC of BoNT-A products,^Citation27^–^Citation29 and expert clinical input
Drug administration costs	£146 per neurologist visit for each cycle of BoNT-A; £0 for BSC	Incurred for each injection according to the treating health care professional who administered the BoNT-A injection and the frequency of treatments. Estimated using costs from the PSS,^Citation35 frequency of visits from the US ANCHOR-CD study (Ipsen Pharma, unpublished data, 2012), and UK clinical experts
Disease management costs	£138 per year for BoNT-A; £493 per year for BSC	Hospitalizations, surgery, or health care professional visits that arise in addition to BoNT-A administration visits or costs of not being treated with BoNT-As. Calculated based on costs derived from Unit Costs of Health and Social Care 2011” published by PSS in the UK and “National Schedule of Reference Costs Year 2010–2011” published by Department of Health in the UK.^Citation35 Frequency of disease management interventions was based on consultation with clinical experts in the UK
Indirect costs*
Productivity loss	Average hourly wage was £12.76. Number of hours lost per week: 2 hours for BoNT-A; 5 hours for BSC	Indirect costs per week were estimated by multiplying the lost productivity time by the average hourly income in the UK. Average hourly wage was based on data from the ONS^Citation26 and the number of hours lost derived from published literature^Citation30

Note:

* Indirect costs are only included as part of alternative scenario analysis.

Abbreviations: ANCHOR-CD, AbobotulinumtoxinA Neurotoxin: Clinical and Health Economics Outcomes Registry in Cervical Dystonia; BNF, British National Formulary; BoNT-A, botulinum neurotoxin type A; BSC, best supportive care; ONS, Office for National Statistics; PSS, Personal Social Services; SmPC, summary of product characteristics.

Table 3 Alternative scenario results: abobotulinumtoxinA compared to BSC

Scenario	AbobotulinumtoxinA		BSC		Incremental (AbobotulinumtoxinA vs BSC)
	Total costs (discounted)	QALYs	Total costs (discounted)	QALYs	Total costs (discounted)	QALYs	ICERs
Base case	£16,517	11.970	£9,357	11.735	£7,160	0.235	£30,468
Considering 5% secondary nonresponders and 25% secondary responders	£19,429	11.982	£9,357	11.735	£10,072	0.247	£40,777
Considering 16 weeks reinjection interval for abobotulinumtoxinA*	£14,728	11.948	£9,332	11.696	£5,396	0.252	£21,413
Considering response as ≥30% improvement in TWSTRS from baseline	£16,222	11.974	£9,357	11.738	£6,865	0.236	£29,089
Considering indirect costs due to productivity loss	£61,971	11.970	£69,282	11.735	−£7,311	0.235	Cost-saving
Considering vial-sharing	£15,591	11.970	£9,357	11.735	£6,234	0.235	£26,526
Time horizon = 5 years	£5,443	2.942	£2,280	2.859	£2,809	0.083	£38,117

Note:

* Same reinjection interval (16 weeks) was assumed for BSC.

Abbreviations: BSC, best supportive care; ICERs, incremental cost-effectiveness ratios; QALYs, quality-adjusted life-years; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale.

Figure 3 Cost-effectiveness planes of incremental costs per QALY of abobotulinumtoxinA versus BSC.

Abbreviation: BSC, best supportive care; QALY, quality-adjusted life-year.

Figure 4 Cost-effectiveness acceptability curves of abobotulinumtoxinA and BSC without toxins injections.

Abbreviation: BSC, best supportive care.

Figure S1 Illustration of QALY gain in first (A) and subsequent cycle (B) when TWSTRS is assumed to have residual benefit at week 12.

Abbreviations: QALYs, quality-adjusted life-years; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale.

Figure S2 Tornado diagram of one-way sensitivity analysis on incremental cost.

Abbreviations: BSC, best supportive care; BoNT-A, botulinum neurotoxin type A.

Figure S3 Tornado diagram of one-way sensitivity analysis on incremental benefit.

Abbreviations: BSC, best supportive care; QALY, quality-adjusted life-year; TWS, Toronto Western Spasmodic.

Figure S4 Tornado diagram of one-way sensitivity analysis on ICER.

Abbreviations: BSC, best supportive care; ICER, incremental cost-effectiveness ratio; TWS, Toronto Western Spasmodic.

Figure S5 Tornado diagram of one-way sensitivity analysis on incremental net benefit with a willingness-to-pay threshold of £20,000/QALY.

Abbreviations: BSC, best supportive care; INB, incremental net benefit; QALY, quality-adjusted life-year; TWS, Toronto Western Spasmodic.

Table S1 Model inputs

Parameters	Base case				Source/assumptions
	AbobotulinumtoxinA	OnabotulinumtoxinA	IncobotulinumtoxinA	BSC
Clinical inputs
Change from baseline of TWSTRS at weeks 4, 8, 12 (mean (SE))
TWSTRS change from baseline at 4 weeks				−5.0 (2.0)	AbobotulinumtoxinA trial^Citation1
No response	−0.6 (0.0)	−0.6 (0.0)	−0.6 (0.0)	–	AbobotulinumtoxinA trial ^Citation1
Response	−20.3 (2.0)	−20.3 (2.0)	−20.3 (2.0)	–	OnabotulinumtoxinA and incobotulinumtoxinA are assumed to have same response as abobotulinumtoxinA
TWSTRS change from baseline at 8 weeks				−4.2(2.0)	AbobotulinumtoxinA trial^Citation1
No response	−0.1 (0.0)	−0.1 (0.0)	−0.1 (0.0)	–	AbobotulinumtoxinA trial^Citation1
Response	−18.3 (2.0)	−18.3 (2.0)	−18.3 (2.0)	–	OnabotulinumtoxinA and incobotulinumtoxinA are assumed to have same response as abobotulinumtoxinA
TWSTRS change from baseline at 12 weeks				−3.3 (2.0)	AbobotulinumtoxinA trial^Citation1
No response	−0.2 (0.1)	−0.2 (0.1)	−0.2 (0.1)	–	AbobotulinumtoxinA trial^Citation1
Response	−9.4 (2.0)	−9.4 (2.0)	−9.4 (2.0)	–	OnabotulinumtoxinA and incobotulinumtoxinA are assumed to have same response as abobotulinumtoxinA
Response rate of first injection for BoNT-A therapies (%)
Response rate of first injection
No response	37.0	37.0	37.0		AbobotulinumtoxinA trial^Citation1
Response	63.0	63.0	63.0		OnabotulinumtoxinA and incobotulinumtoxinA are assumed to have same response as abobotulinumtoxinA
Response rate of subsequent injection for BoNT-A therapies (%)
Annual rate of response after initial nonresponse (rate per year)	0.0	0.0	0.0		Patients who do not respond at the initial injection do not achieve response in subsequent injection cycles
Annual rate of secondary nonresponse after initial response (rate per year)	0.0	0.0	0.0		Similarly, patients who achieve response at the initial injection do not develop secondary nonresponse
Reinjection interval for BoNT-A therapies (weeks)
Duration of treatment cycle (weeks)	12.0#	12.0##	12.0###		Assumed to be in line with abobotulinumtoxinA SmPC^Citation2 and experts clinical opinion
Annual rate of all-cause treatment discontinuation (%)
Discontinuation rate per year
No response	1.1	1.1	1.1	–	Kessler et al (1999)^Citation3
Response	1.1	1.1	1.1	–
Adverse events by BoNT-A therapies (%)
Dysphagia rate per injection	15	19	13	–	Inferred from SmPCs of BoNT-A products^Citation2,Citation4,Citation5
Utility inputs
Baseline utility and utility gains (mean)
	BoNT-A			BSC 0.6368	Calculated from estimated utility-TWSTRS relationship and TWSTRS data at weeks 0, 4, 8, and 12
Baseline utility
No response	0.6398
Response	0.6349
QALYs gain per person for				0.0026
first cycle
No response	0	0	0
Response	0.0117	0.0117	0.0117
QALY gain per person for subsequent cycles				0.0035
No response	0	0	0
Response	0.0130	0.0130	0.0130
Resource use and cost inputs
Drug costs
Cost per vial	£154.00 per 500 unit vial, £92.40 per 500 unit vial	£276.40 per 200 unit vial, £138.20 per 100 unit vial	£129.90 per 100 unit vial, £72.00 per 50 unit vial	–	BNF^Citation6
Average dose per cycle: first injection
Mean dose (units)	500	200	200	–	SmPC of BoNT-A products^Citation2,Citation4,Citation5
Average dose per cycle: subsequent injections
Mean dose (units) – no response	750	300	300		Expert clinical input
Mean dose (units) – response	400	133	160
Drug administration costs and frequency of use of BoNT-A therapies
	Cost per injection (per visit) for BoNT-A therapies	Frequency of use (for 1 visit per injection) for BoNT-A		Frequency of use (for 1 visit per injection)for BSC	Administration costs were derived from PSS^Citation7 Frequency of visits was collected from Ipsen US ANCHOR-CD study (Ipsen Pharma, unpublished data, 2012) and verified with clinical experts in the UK
Neurologist visit	£146.00	73.5%		NA
Neurophysiologist visit	£146.00	26.5%		NA
Nurse visit	£42.00	0.0%		NA
Concomitant medication costs and frequency of use
	Unit costs (per mg)	Dose per day (mg)			Unit drug costs and dosing schedule for concomitant medications were obtained from BNF^Citation6
Anticholinergics	£0.0070	1
Benzodiazepines	£0.0720	1
Analgesics	£0.0003	1,000
Dopamine antagonist	£0.0990	2.5
Beta blockers	£0.0011	40
Baclofen	£0.0020	60
Antiepileptics	£0.0006	600
Other muscle relaxants	£0.0094	7.5
Frequency of use (for BoNT-As and BSC)	BoNT-A (%)			BSC (%)	Distribution of frequency of use among different drugs were collected from Ipsen US ANCHOR-CD study (Ipsen Pharma, unpublished data, 2012) and verified with clinical experts in UK
% of patients taking concomitant medications	35			50
Anticholinergics	0.6			0.6
Benzodiazepines	23.5			26.5
Analgesics	33.5			33.5
Dopamine antagonist	0.6			0.6
Beta blockers	0.6			0.6
Baclofen	3.2			3.2
Antiepileptics	5.8			5.8
Other muscle relaxants	29.2			29.2
Disease management costs and frequency of disease management interventions
	Unit costs	Frequency per year (for BoNT-A)	Frequency per year (for BSC)		The disease management costs were derived from “Unit Costs of Health and Social Care 2011” published by (PSS) in the UK and “National Schedule of Reference Costs Year 2010–2011” published by Department of Health in the UK^Citation7 The frequency of disease management interventions was based on consultation with clinical experts in UK
Neurologist visit (excluding BoNT-A injection per visit)	£146.00	0	2
GP visit (per visit)	£53.00	2	2
Hospitalization (per day)	£428.00	1.5%	1.5%
Average length of stay	–	5	5
Deep brain stimulation (per surgery)	£4,384.89	NA	1%
Selective peripheral denervation (per surgery)	£1,867.00	NA	1%
Indirect costs*
Median hourly wage in the UK (per hour)	£12.76				Median hourly wage reported by Office for National Statistics Survey for 2013^Citation8
LPT due to patients with CD and carers combined (number of hours per week)
Productivity loss	2			5	The model uses LPT due to absenteeism and presenteeismfrom Stacy et al (2012)^Citation9 Indirect costs due to time to doctor office visit and caregiver time are not considered, since no data was available
Time to doctor office visit	–			–
Caregiver time	–			–
Total	2			5

Notes:

* Indirect costs are not included in the base case analysis.

# For AbobotulinumtoxinA, it is 16 weeks as per AbobotulinumtoxinA SmPC – this is tested as part of scenario analyses,

## For OnabotulinumtoxinA, it is 10 weeks as per OnabotulinumtoxinA SmPC – this is also tested as part of scenario analyses,

### For IncobotulinumtoxinA, it is 10 weeks as per IncobotulinumtoxinA SmPC – this is also tested as part of scenario analyses.

Abbreviations: ANCHOR-CD, AbobotulinumtoxinA Neurotoxin: Clinical and Health Economics Outcomes Registry in Cervical Dystonia; BNF, British National Formulary; BoNT-A, botulinum neurotoxin type A; BSC, best supportive care; GP, general practitioner; LPT, lost productive time; PSS, Personal Social Services; QALYs, quality-adjusted life-years; SE, standard error; SmPC, summary of product characteristics; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale; NA, not available.

Table S2 Estimates of statistical model linking utility and TWSTRS based on analysis of abobotulinumtoxinA trial

Parameter	Parameter estimate	Parameter
Intercept	1.255
Coefficient for TWSTRS	−0.0159
	Covariance matrix Intercept	Coefficient for TWSTRS
Intercept	0.01157
Coefficient for TWSTRS	−0.000234	5.437E-06

Abbreviations: TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale.

Table S3 Parameters included in one-way sensitivity analysis

Parameter/variable name	Description	Base-case input	Low value	High value
discH	Discount rate for health (%)	0.035	0.028	0.042
discC	Discount rate for cost (%)	0.035	0.028	0.042
iAge	Age (years)	53.00	42.400	63.600
pMale	Gender (% male)	0.37	0.296	0.444
TWSBline_NonResp	Mean baseline TWSTRS – nonresponders: abobotulinumtoxinA	42.79	34.232	51.348
TWSBline_Resp	Mean baseline TWSTRS – responders: abobotulinumtoxinA	44.12	35.296	52.944
TWSBline_BSC	Mean baseline TWSTRS – BSC	43.63	34.902	52.353
Coeff_TWS	Coefficient for TWSTRS	−0.02	−0.019	−0.013
Coeff_Inter	Intercept	1.26	1.004	1.506
iReinj_PriNonResp	Number of reinjection attempts for primary nonresponders before abandoning treatment	6.00	4.800	7.200
iReinj_SecNonResp	Number of reinjection attempts for secondary nonresponders before abandoning treatment	4.00	3.200	4.800
TWSChangeAt4Wks_Abo_nonresponder	AbobotulinumtoxinA_TWSTRS change from baseline at 4 weeks – nonresponders	−0.61	−0.643	−0.583
TWSChangeAt4Wks_Abo_fullresponder	AbobotulinumtoxinA _TWSTRS change from baseline at 4 weeks – responders	−20.29	−22.290	−18.290
TWSChangeAt8Wks_Abo_nonresponder	AbobotulinumtoxinA _TWSTRS change from baseline at 8 weeks – nonresponders	−0.14	−0.140	−0.136
TWSChangeAt8Wks_Abo_responder	AbobotulinumtoxinA _TWSTRS change from baseline at 8 weeks – responders	−18.30	−20.300	−16.300
TWSChangeAt12Wks_Abo_nonresponder	AbobotulinumtoxinA _TWSTRS change from baseline at 12 weeks – nonresponders	−0.21	−0.283	−0.143
TWSChangeAt12Wks_Abo_fullresponder	AbobotulinumtoxinA _TWSTRS change from baseline at 12 weeks – responders	−9.35	−11.350	−7.350
TWSChangeAt4Wks_BSC	BSC_TWSTRS change from baseline at 4 weeks	−4.97	−6.970	−2.970
TWSChangeAt8Wks_BSC	BSC_TWSTRS change from baseline at 8 weeks	−4.22	−6.220	−2.220
TWSChangeAt12Wks_BSC	BSC_TWSTRS change from baseline at 12 weeks	−3.32	−5.320	−1.320
distriFirstInj_Abo_nonresponder	Probability of nonresponse at first injection	0.37	0.296	0.444
distriFirstInj_Abo_responder	Probability of response at first injection	0.63	0.504	0.756
pAE_Abo	AE rate per injection: abobotulinumtoxinA (%)	15%	12%	18%
dFirstInj_Abo	AbobotulinumtoxinA _first injection dosage: mean dose (unit)	500.00	400.000	600.000
dFirstInj_Ona	OnabotulinumtoxinA _first injection dosage: mean dose (unit)	200.00	160.000	240.000
dFirstInj_Inco	IncobotulinumtoxinA _first injection dosage: Mean dose (unit)	200.00	160.000	240.000
dReinj_Abo_nonresponder	Average abobotulinumtoxinA reinjection dosage: nonresponder (unit)	750.00	600.000	900.000
dReinj_Abo_responder	Average abobotulinumtoxinA reinjection dosage: responder (unit)	400.00	320.000	480.000
cDrugFirstInj_Abo	AbobotulinumtoxinA _first injection cost (£)	154.00	123.200	184.800
cDrugReinj_Abo_nonresponder	AbobotulinumtoxinA _reinjections cost – nonresponder (£)	246.40	197.120	295.680
cDrugReinj_Abo_fullresponder	AbobotulinumtoxinA _reinjections cost – responder (£)	154.00	123.200	184.800
cConMed_BoNTA	Concomitant Meds Cost_BoNTA (£)	0.05	0.042	0.062
cConMed_BSC	Concomitant Meds Cost _BSC (£)	0.07	0.059	0.089
cDrugAdmin	Cost Drug Admin (£)	146.00	116.800	175.200
cDisMgt_Abo	Cost Disease Management_AbobotulinumtoxinA (£)	31.77	25.419	38.129
cDisMgt_BSC	Cost Disease Management _BSC (£)	113.31	90.645	135.967
cAE	Cost AEs_BoNTA (£)	–	–	–
cIndirect_BoNTA	Cost Indirect_Abo (£)	306.24	244.992	367.488
cIndirect_BSC	Cost Indirect_BSC (£)	765.60	612.480	918.720
timeYearsInCycle_Abo	Reinjection Interval (years)	0.23	0.184	0.276

Abbreviations: AE, adverse event; BoNTA, botulinum neurotoxin type A; BSC, best supportive care; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale.

Table S4 Parameters included in probabilistic sensitivity analysis

Parameter	Distribution
Utility at each TWSTRS score (based on mapping)	Multivariate normal (Cholesky)
Mean baseline TWSTRS distribution, nonresponders and responders at 0, 4, 8, 12 weeks	Gamma
Transition probability: response to secondary nonresponse	Beta
Duration of treatment cycle: abobotulinumtoxinA	Gamma
Treatment discontinuation rate per year	Gamma
AbobotulinumtoxinA_first injection dosage	Gamma
AbobotulinumtoxinA_reinjection dosage: nonresponder	Gamma
AbobotulinumtoxinA_reinjection dosage: responder	Gamma
Setting where drug is administered (distribution)
Neurologist visit	Beta
Physiotherapist visit	Beta
Nurse visit	Beta
Disease management
Neurologist visit (excluding BoNT-A injection) per year	Gamma
GP visit per year	Gamma
Hospitalization rate per year: BoNT-A	Beta
Hospitalization rate per year: BSC	Beta
Length of stay for hospitalization: BoNT-A	Gamma
Length of stay for hospitalization: BSC	Gamma

Abbreviations: BSC, best supportive care; BoNT-A, botulinum neurotoxin type A; GP, general practitioner; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale.

Table S5 Alternative scenario results: other comparisons

Scenario	OnabotulinumtoxinA		BSC		Incremental (onabotulinumtoxinA vs BSC)
	Total costs (discounted)	QALYs	Total costs (discounted)	QALYs	Total costs (discounted)	QALYs	ICERs
Base case	£20,573	11.964	£9,357	11.735	£11,216	0.229	£48,978
Considering 10 weeks reinjection interval for onabotulinumtoxinA*	£21,968	11.954	£9,277	11.693	£12,691	0.261	£48,625
Scenario	IncobotulinumtoxinA		BSC		Incremental (IncobotulinumtoxinA vs BSC)
	Total costs (discounted)	QALYs	Total costs (discounted)	QALYs	Total costs (discounted)	QALYs	ICERs
Base case	£22,473	11.959	£9,357	11.735	£13,116	0.224	£58,554
Considering 10 weeks reinjection interval for incobotulinumtoxinA*	£21,364	11.962	£9,277	11.693	£12,087	0.269	£44,933

Note:

* Same reinjection interval (10 weeks) was assumed for BSC.

Abbreviations: BSC, best supportive care; ICERs, incremental cost-effectiveness ratios; QALYs, quality-adjusted life-years.

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