ars.els-cdn.com€¦ · Web viewAssumption. Justification. Transitions between health states. Constant exacerbation rates through time and treatment duration. Exacerbations classified

Table S1 Key model assumptions

Assumption Justification

Transitions

between health

states

Constant exacerbation rates through time and treatment

duration.

Exacerbations classified into clinically significant non-

severe and clinically significant severe.

The available data consisted of the number of exacerbations and number of

patients per treatment group over the follow-up of the RCTs.

The classification of exacerbations corresponded to the classification used in

the RCTs.

Asthma-related

mortality

Patients in the day-to-day state are at increased risk of

asthma-related death.

The literature on asthma supports that patients with severe persistent

allergic asthma are at increased risk of asthma-related death than the

general population.

Cycle lengthFirst cycle is 16 weeks; subsequent cycles have 3 months.

A half-cycle correction was employed.

The length of the first cycle corresponds to the timing of the assessment of

response to omalizumab as specified in its marketing authorisation.

Response to

omalizumab

After the first 16-week cycle, the omalizumab cohort is

divided into omalizumab responders and non-responders.

Omalizumab non-responders revert to standard therapy.

Omalizumab responders are assumed to remain

responders for the duration of treatment.

The marketing authorisation for omalizumab recommends that non-

responders revert to standard therapy.

Responders are assumed to remain on omalizumab based on clinical advice

that patients are mostly adherent to this treatment.

Adverse effects

from

omalizumab

Not considered.

Adverse effects from omalizumab are mostly mild. Serious adverse effects

are rare.

Long-term

effects of OCS

Incorporated in scenario analysis for maintenance OCS

subgroup.

Infrequent OCS bursts due to clinically significant

exacerbations do not increase the risk of OCS-related

adverse effects and have negligible costs.

The excess risk attributable to OCS is based solely on

current exposure to OCS and once patients discontinue

OCS, the excess relative risk becomes negligible.

Patients who discontinue OCS will restart on OCS if

omalizumab treatment is discontinued.

Patients who do not receive omalizumab receive

maintenance OCS for the remainder of their life.

Maintenance use of OCS is associated with adverse effects (ref).

No information was found on the additional risk of infrequent short term

courses of OCS or on the additional risk following discontinuation of

maintenance OCS.

Treatment

duration and

time horizon

Lifetime horizon.

Treatment duration was assumed to be 10 years.

Treatment duration was based on the previous cost-effectiveness analyses

of omalizumab and clinical advice.

Treatment effect The results of INNOVATE and IA-05 EUP are

generalisable to the UK NHS.

Omalizumab reduces exacerbation rates as reported in

INNOVATE for adults and adolescents and IA-05 EUP in

No RCTs conducted solely in the UK NHS were identified.

children.

Health-related

quality of life

Patients on omalizumab experience higher HRQoL in day-

to-day symptoms than patients on standard care only.

Exacerbations are associated with lower HRQoL,

independent of treatment.

The RCTs evaluating omalizumab in the UK/EU licensed population

collected data on the improvement in HRQoL conferred by omalizumab that

is used in the analysis.

Resource use

and costs

Costs of omalizumab estimated using the dose distribution

observed in INNOVATE and IA-05.

Initiation of omalizumab requires one initiation

appointment with respiratory consultant.

Administration by specialist asthma nurse assumed to take

10 minutes.

Monitoring by specialist asthma nurse assumed to take 15

minutes per hour of monitoring. The duration of monitoring

varies as follows: 2 hours for the first 3 administrations, 1

hour up to the 16 assessment, no monitoring thereafter.

Resource use due to exacerbations obtained from the

INNOVATE and IA-05 EUP trials. Unit costs from

published sources (24, 25).

Resource use associated with the administration and monitoring of

omalizumab was based on previous cost-effectiveness assessments and

clinical advice.

Children Children experience the same HRQoL improvement from

omalizumab therapy as adults and adolescents.

There is no reason to believe that the improvement in HRQoL would be

different between patients under and over 12 years of age. The non-

significant increase in the Paediatric Asthma Quality of Life Questionnaire

score observed in IA-05 EUP may be a consequence of under-powering the

study for this secondary outcome.

Table S2 Model inputs for hospitalisation subgroup

Adults and adolescents

(patients ≥ 12 years)

Children

(patients 6-11 years)

Variables

Value

(95% confidence

interval)

Source Value Source

Baseline annual rate of exacerbations

CSNS

exacerbations

0.8706

(0.6308 to 1.2016)

INNOVATE

Hospitalisation

(21)

2.1429

(3.5545 to 1.2918)

IA-05 EUP

hospitalisation

(21)

CSS

exacerbations

1.2235

(0.9323 to 1.6057)

INNOVATE

hospitalisation

(21)

1.2857

(0.6690 to 2.4711)

IA-05 EUP

hospitalisation

(21)

Treatment effectiveness

Proportion of

responders

56.63%

(45.96% to 67.29%)

INNOVATE

hospitalisation

(21)

54.05% (38.00% to

70.11%)

IA-05 EUP

hospitalisation

(21)

Risk ratio for

CSNS

exacerbations

(responders)

0.5902

(0.3137 to 1.1103)

INNOVATE

hospitalisation

(21)

0.2593

(0.1006 to 0.6682)

IA-05 EUP

hospitalisation

(21)

Risk ratio for

CSS

exacerbations

(responders)

0.2907

(0.1433 to 0.5900)

INNOVATE

hospitalisation

(21)

0.1440

(0.0311 to 0.6666)

IA-05 EUP

hospitalisation

(21)

Mortality

All-cause

mortality

UK life-tables

adjusted for

asthma-related

deaths.

ONS (33);

deterministic

UK life-tables

adjusted for asthma-

related deaths.

ONS (33);

deterministic

Asthma-related

deaths

Asthma-related

mortality rate = 0.4

per 100 person-

years

De Vries et al

(2010) (20)

Asthma-related


per 100 person-years

De Vries et al

(2010) (20)

HRQoL

Omalizumab

effect on HRQoL

HRQoL difference

observed in the trial

0.761 (omalizumab)

versus 0.631

(standard care)

EXALT

hospitalisation

(21)

No HRQoL difference

between treatments

up to age 12.

From age 12, HRQoL

difference as adults

and adolescents.

EXALT

hospitalisation

(21)

HRQoL loss due

to exacerbations

CSNS = -0.10

CSS = -0.20

Lloyd et al (2007)

(23)

CSNS = -0.10

CSS = -0.20

Lloyd et al

(2007) (23)

Duration of

exacerbation4 weeks

Lloyd et al (2007)

(23)4 weeks

Lloyd et al

(2007) (23)

Resource use and costs

Cost of

exacerbations

CSNS = £154.70

CSS = £178.87

INNOVATE

hospitalisation(21)

NHS Reference

costs (24)

PSSRU Unit costs

(25)

CSNS=CSS=£213.89

IA-05

EUP(19)

NHS

Reference

costs (24)

PSSRU Unit

costs (25)

Routine visits2 per year, £160

each

NHS reference

costs (24)

2 per year, £190

each

NHS

reference

Initiation of £245 £247

therapycosts (24)

Standard

therapy costs

(per year)

£1,197 INNOVATE(18) £810IA-05

EUP(19)

Omalizumab

costs

(per year)

£8,056 INNOVATE(18) £8,455IA-05

EUP(19)

Administration

and monitoring

costs

First year: £260

Thereafter: £146

INNOVATE (18)

NHS reference

costs (24)

First year: £268

Thereafter: £151

IA-05 EUP

(19)

NHS

reference

costs (24)

Table S3 Model inputs for maintenance OCS subgroup

Adults and adolescents (patients ≥ 12 years)

Variables Value Source


CSNS exacerbations0.9735

(0.6410 to 1.4784)

INNOVATE

maintenance OCS (21)

CSS exacerbations 1.000 (0.4493 to 2.2259)INNOVATE


Proportion of responders 46.94% (32.97% to 60.91%)INNOVATE


Risk ratio for CSNS exacerbations

(responders)

0.4142

(0.1569 to 1.0938)

INNOVATE


Risk ratio for CSS exacerbations

(responders)

0.2144

(0.0761 to 0.6042)

INNOVATE


Mortality

All-cause mortalityUK life-tables adjusted for asthma-

related deaths.ONS (33)

Asthma-related deathsAsthma-related mortality rate = 0.4

per 100 person-years

De Vries et al (2010)

(20)

HRQoL

Omalizumab effect on HRQoL

HRQoL difference observed in the

trial

0.791 (omalizumab) versus 0.686

(standard care)

EXALT maintenance

OCS(21)

HRQoL loss due to exacerbationsCSNS = -0.10

CSS = -0.20Lloyd et al (2007) (23)

Duration of exacerbation 4 weeks Lloyd et al (2007) (23)


Cost of exacerbationsCSNS = £86.51

CSS = £136.04

INNOVATE

Maintenance OCS (21)

NHS Reference costs

(24)

PSSRU Unit costs (25)

Routine visits 2 per year, £160 each NHS reference costs

(24)Initiation of therapy £245

Standard therapy costs (per year) £1,197 INNOVATE (18)

Omalizumab costs

(per year)£8,056 INNOVATE (18)

Administration and monitoring costsFirst year: £260

Thereafter: £146

INNOVATE (18)

NHS reference costs

(24)

Incorporation of OCS-related adverse effects

Proportion of omalizumab

responders who discontinue OCS41.9%

EXALT maintenance

OCS (21)

Annual acquisition costs of OCS £99.45 per patient EXALT (21)

Costs due to adverse effects of OCS £205.60Manufacturer

submission (21)

Health losses due to adverse effects

of OCS

0.02331 DALYs Manufacturer

submission (21)

1. 95%CI – 95% confidence interval.

2. CSS – clinical significant severe exacerbation; CSNS – clinical significant non-severe

exacerbation.

Table S4 Model inputs for ≥ 3 exacerbations subgroup

Adults and adolescents

(patients ≥ 12 years)

Children

(patients 6-11 years)

Variables Value Source Value Source


CSNS

exacerbations

2.2143

(1.8070 to 2.7133)

INNOVATE≥3

exacerbations

(34)

2.7651

(2.1763 to 3.5132)

IA-05 EUP ≥3

exacerbations

(34)

CSS

exacerbations

1.2619

(0.9618 to 1.6518)

INNOVATE≥3

exacerbations

(34)

0.6190

(0.3732 to 1.0269)

IA-05 EUP ≥3

exacerbations

(34)

Treatment effectiveness

Proportion of

responders

46.51%

(35.97% to

57.05%)

INNOVATE≥3

exacerbations

(34)

77.08%

(68.68% to 85.45%)

IA-05 EUP ≥3

exacerbations

(34)

Risk ratio for

CSNS

exacerbations

(responders)

0.3565

(0.2126 to 0.5978)

INNOVATE≥3

exacerbations

(34)

0.2269

(0.1433 to 0.3592)

IA-05 EUP ≥3

exacerbations

(34)

Risk ratio for

CSS

exacerbations

(responders)

0.1840

(0.0735 to 0.4602)

INNOVATE≥3

exacerbations

(34)

0.2838

(0.1157 to 0.6960)

IA-05 EUP ≥3

exacerbations

(34)

Mortality

All-cause

mortality

UK life-tables

adjusted for

asthma-related

deaths.

ONS(33)

UK life-tables

adjusted for asthma-

related deaths.

ONS(33)

Asthma-

related deaths

Asthma-related


De Vries et al Asthma-related


De Vries et al

per 100 person-

years(2010) (20) per 100 person-years (2010) (20)

HRQoL

Omalizumab

effect on

HRQoL

HRQoL difference

observed in the

trial

0.740

(omalizumab)

versus 0.698

(standard care).

INNOVATE: 0.787

vs. 0.651

EXALT ≥3

exacerbations

(34)

INNOVATE≥3

exacerbations

(34)

No HRQoL difference

between treatments

up to age 12.

From age 12, HRQoL

difference as adults

and adolescents.

EXALT ≥3

exacerbations

(34)

INNOVATE≥3

exacerbations

(34)

HRQoL loss

due to

exacerbations

CSNS = -0.10

CSS = -0.20

Lloyd et al

(2007) (23)

CSNS = -0.10

CSS = -0.20

Lloyd et al

(2007) (23)

Duration of

exacerbation4 weeks

Lloyd et al

(2007) (23)4 weeks

Lloyd et al

(2007) (23)


Cost of

exacerbations

CSNS = £154.70

CSS = £178.87

INNOVATE

(18)

NHS Reference

costs (24)

PSSRU Unit

costs (25)

CSNS=CSS=£213.89

IA-05 EUP (19)

NHS Reference

costs (24)

PSSRU Unit

costs (25)

Routine visits2 per year, £160

each NHS reference

costs (24)

2 per year, £190

each NHS reference

costs (24)Initiation of

therapy£245 £247

Standard £1,197 INNOVATE £810 IA-05 EUP (19)

therapy costs

(per year)(18)

Omalizumab

costs

(per year)

£8,056INNOVATE

(18) £8,455 IA-05 EUP (19)

Administration

and

monitoring

costs

First year: £260

Thereafter: £146

INNOVATE

(18)

NHS reference

costs (24)

First year: £268

Thereafter: £151

IA-05 EUP (19)

NHS reference

costs (24)

1. 95%CI – 95% confidence interval.

2. CSS – clinical significant severe exacerbation; CSNS – clinical significant non-severe

exacerbation.

Table S5 Full cost-effectiveness results for overall and subgroup populations under the PAS

price

Population Intervention Mean costs (£) Mean QALYs ICER (£/QALY)

Overall

patient

population

Adults and adolescents (≥ 12 years of age) – age at model entry: 43 years

Standard care 33,153 13.66

Omalizumab 60,406 14.14 57,557

Children (6-11 years of age) – age at model entry: 9 years


Omalizumab 76,386 17.39 53,348

Hospitalisation



Omalizumab 63,410 12.68 31,782



Omalizumab 70,967 15.32 30,109

Maintenance OCS



Omalizumab 58,287 13.45 34,386

≥ 3 exacerbations



Omalizumab 58,884 13.34 £53,087



Omalizumab 80,797 16.58 48,537

Table S6 Full cost-effectiveness results for overall and subgroup populations under the list price

Population Intervention Mean costs (£) Mean QALYs ICER (£/QALY)

Overall

patient

population



Omalizumab 72,938 14.13 83,822



Omalizumab 92,497 17.39 78,009

Hospitalisation



Omalizumab 75,826 12.68 46,431



Omalizumab 83,145 15.32 44,142

Maintenance OCS



Omalizumab 68,995 13.44 50,181

≥ 3 exacerbations



Omalizumab 69,317 13.34 77,868



Omalizumab 96,611 16.74 76,149

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ars.els-cdn.com€¦ · Web viewAssumption. Justification. Transitions between health states. Constant exacerbation rates through time and treatment duration. Exacerbations classified