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Assessing the cost-effectiveness of using Aclidinium bromide 400 g /formoterol fumarate 12 g compared to Aclidinium bromide 400 g in the management of moderate to severe chronic obstructive pulmonary disease Ramos M, Haughney J, Henry N,

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Assessing the cost-effectiveness of using Aclidinium bromide 400 µg /formoterol fumarate 12 µg compared to Aclidinium bromide 400 µg in the management of moderate to severe chronic obstructive pulmonary disease

Ramos M, Haughney J, Henry N, Lindner L, Lamotte M

IMS Health

CE4 ISPOR Milan 2015 Monday, 9 November 2015

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Disclosure on conflict of interest

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

  • IMS Health, the employer MR, NH and ML received consulting fees from

Almirall/AstraZeneca for the development of the model and the preparation of this presentation.

  • JH received consulting fees for advising on the building of the model and

information on the treatment of COPD in Scotland.

  • LL is a full time employee of AstraZeneca.
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  • Aclidinium bromide/formoterol fumarate combines two effective inhaled

bronchodilators with complementary mechanisms of action

  • Aclidinium bromide 400µg (a long-acting muscarinic antagonist - LAMA)
  • Formoterol fumarate 12µg (a long-acting beta-adrenergic agonist - LABA)
  • 2 phase III studies ACLIFORM and AUGMENT demonstrated that

aclidinium/formoterol compared to aclidinium alone

  • Lung function capacity: increase in peak FEV1 values vs. placebo
  • aclidinium/formoterol: 293.2mL
  • aclidinium alone: 175.0mL
  • COPD-related symptoms

Background

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD FEV1 - mean baseline forced expiratory volume in one second

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Objective

  • To assess the cost-effectiveness of aclidinium/formoterol, against the LAMA,

aclidinium alone in the management of COPD patients

  • Setting: Scotland

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

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The key design elements of this cost-effectiveness analysis

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

Type of model A state-transition (Markov) developed in MS Excel Time horizon 5 years Cycle length 1 month Perspective NHS Scotland Comparator Aclidinium Patients COPD patients in moderate or severe health states Health states Severity levels defined by GOLD 2010 criteria Utility, resource use, cost and risk of exacerbation are health state specific COPD event Exacerbation

  • Mild - treated in community care
  • Severe - treated in hospital

Pneumonia (rates differ by treatment option). Clinical data Published literature including pooled analysis on ACLIFORM and AUGMENT Cost data Year 2014 Published literature and local sources Discounting Costs and effects – 3.5% Outcome Cost per quality of life gained (QALY)

GOLD-Global Initiative for Chronic Obstructive Lung Disease

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  • Initial distribution of patients by health state
  • 59% moderate and 41% severe (ACLIFORM and AUGMENT)
  • To estimate the average FEV1 of a mean patient of both ACLIFORM and AUGMENT trials,

the Langhammer A. et. al. 2001 equations were used

  • average age of patients (ACLIFORM and

AUGMENT)

  • average height of individuals in Scotland (Health

Survey for England, 2009)

To estimate it per health state, the midpoint between the limits of the GOLD criteria was used as multiplicator to determine the severity level (in green/next slide)

Markov Engine: Determining patient’s initial lung function capacity per health state

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

Post- bronchodilator FEV1 % of predicted normal value of the limits, midpoint of GOLD criteria Estimated baseline FEV1 by gender and health state (in Liters) COPD health states Minimum Maximum Midpoint Female Male Moderate 50% 80% 65.0% 1.61 2.30 Severe 30% 50% 40.0% 0.99 1.42 Very severe 0% 30% 15.0% 0.37 0.53

liters Age Height FEV liters Age Age Height FEV

males female

539 . 3 ) 0000685 . ) ln( 342 . 2 556 . 10 exp( 1 476 . 2 ) 007237 . 000163 . ) ln( 004 . 2 091 . 9 exp( 1

2 2

          

FEV1 - mean baseline forced expiratory volume in one second GOLD-Global Initiative for Chronic Obstructive Lung Disease

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  • In the first 24 weeks: a linear improvement of FEV1 due to

treatment effect

  • Transitions will be from:
  • moderate to mild
  • severe to moderate
  • very severe to severe
  • After 24 weeks: only the natural evolution of COPD is

considered

  • lung function capacity declines by 41 ml per year (Tashkin

et al. 2008)

  • Transitions will be from:
  • mild to moderate
  • moderate to severe
  • severe to very severe

Markov engine: simulating the progression of lung function capacity over time and the impact of the different therapies

Key driver of the model: initial improvement in FEV1 due to treatment effect followed by decline over time

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

. . . . . . . . . . . .

Time difference

  • The most efficacious treatments will have a higher initial increase in FEV1 and a delayed progression compared to

less effective treatments

  • The best therapy will require more time to reach the next health state

FEV1 - mean baseline forced expiratory volume in one second

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  • ACLIFORM and AUGMENT (= pooled analysis)
  • FDC 400/12µg statistically significantly improved lung function and breathlessness over

24 weeks compared with monotherapies

  • Lung function improvement was given by the increase of mean baseline forced expiratory volume

in one second (FEV1) at 24 weeks and taken in the morning one-hour post-dose (as peak value)

Initial increase in FEV1 in the two treatment arms

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

Mean difference in peak FEV1 by treatment at 24 weeks (in ml) 24 weeks 4 weeks Type of bronchodilator Mean 95 CI Mean 95%CI LAMA+ LABA Aclidinium/formoterol 293.20 (265.00;321,00) 53.1 (48.0;58.2) LAMA alone Aclidinium 175.00 (147.00;203.00) 31.7 (26.6;36.8)

FEV1 - mean baseline forced expiratory volume in one second

OWSA: CI; PSA: Normal distributions.

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  • Risk of pneumonia was taken from pooled analysis (ACLIFORM and AUGMENT)
  • No statistical significant difference was observed between the treatment arms
  • The same weighted average was applied in both arms (0.0097=21/2158 cases per year/0.0008 per

month).

  • Risk of an exacerbation (Karabis et al. 2014 Oostenbrink et al. 2005)
  • Risk of dying (Boutou A. K. et.al. 2013)
  • Kaplan–Meier survival curves of four population groups categorized by GOLD stages
  • A linear extrapolation was used to obtain the probability of dying per month

Clinical data on adverse events

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

Mean (SD) Mild Moderate Severe Very severe

  • Prob. of having an exacerbation

19% (1.5%) 19% (1.5%) 24% (1.8%) 30% (2.3%) Proportion of exacerbations treated in hospital 68.40% (5.2%) 68.40% (5.2%) 62.50%(4.8%) 66.70% (5.1%) Mild Moderate Severe Very severe Probability of death per cycle per health state 0.00508 0.00596 0.00665 0.00812

OWSA: 15% variability; PSA: Beta distribution OWSA: 30% variability; PSA: Beta distribution

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  • Drug acquisition costs (British National Formulary, 2014)
  • Management cost and resource use per health state (Personal Social Services Research Unit, 2013; National Schedule of

Reference Cost, 2012/13; British National Formulary. 2014; Oostenbrink et al. 2005)

Cost & utility data

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

Treatment Price/pack # Dose DDD Cost/DDD Cost/month Aclidinium £28.60 60 2 £0.95 £29.02 Aclidinium/formoterol £32.50 60 2 £1.08 £32.97 COPD event Cost (Mean=SD) Utility reduction Mean (SD) Exacerbation treated in hospital care £1,423 0.85 (0.077) Exacerbation treated in community care £68 0.5 (0.051) Treating pneumonia £2,267

  • Event costs (Samyshkin et al. 2014)
  • exacerbation treated in community
  • exacerbation treated in hospital
  • pneumonia treated in hospital
  • Year 2014
  • Utilities per health state (Rutten-van Mölken et al. 2006)
  • Utility reductions for exacerbation and

pneumonia (Oostenbrink et al. 2005)

Health state Cost of managing COPD (Mean=SD) Utility Mean (CI) Mild £7.53 0.787 (0.771;0.802) Moderate £22.41 Severe £55.16 0.750 (0.731;0.768) Very Severe £164.75 0.647 (0.598;0.695)

Cost: OWSA-30% variability, PSA-Gama distribution and Briggs assumption; Utility: OWSA-CI, PSA-Beta distributions; Utility reduction OWSA-20% variability, PSA-Normal distribution

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Results: aclidinium/formoterol vs. aclidinium is a cost- effective therapy in the management of COPD in Scotland

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD Treatment Total Costs (£) Total QALYs Incr. Cost (£) Incr. QALYs ICER (£) Aclidinium/formoterol 13,730 2.902 41 0.014 2,976 Aclidinium 13,679 2.888 N/A N/A N/A

Cost-effectiveness results FEV1 at the baseline

  • £2,000

£0 £2,000 £4,000 £6,000 £8,000 £10,000 £12,000 Mean baseline FEV1 (very severe) Mean baseline FEV1 (severe) % of exacerbation (mod) % of exacerbation (severe) FEV1 improv. (24W/peak)FDC 400/12 μg COPD Lung Volume Decline (in L) % female Age (years) Monthly maintenance cost (sev) Incidence of pneumonia of LABA+LAMA Net Monetary Benefit (£)

One Way Sensitivity Analysis Tornado diagram

Lower bound Upper bound

  • £2,000
  • £1,500
  • £1,000
  • £500

£0 £500 £1,000

  • 0.02
  • 0.01

0.00 0.01 0.02 0.03 0.04 0.05 0.06

Incremental Costs (£)

QALYG

Probabilistic Sensitivity Analysis Cost-effectiveness scatter-plot

Baseline lung function capacity, determined using the Langhammer A. et. al. 2001[

  • Aclidinium/formoterol provides QALY gains, of 0.014, with a cost increase of £41,

resulting in an ICER of £2,976

  • Aclidinium/formoterol provides less maintenance costs and in treating exacerbation

Main 5 drivers: baseline FEV1 values and rates of exacerbation (severe and very severe health states) and also the lung function improvement of aclidinium/formoterol . In 79% of Monte Carlo simulations, aclidinium/formoterol is cost-effective

  • Willingness to pay of £20,000/QALY

Impact of variation in key inputs within plausible fixed limits Distributions were assigned, based on parameter’s applicability fixed limits

Moderate Severe Male 2,3L 1.42L Female 1,61L 0.99L Total 59% 41%

NMB=∆QALY*WTP-∆Cost

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Conclusion

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

  • Aclidinium/formoterol compared to aclidinium is a cost-effective therapy in the

management of COPD in Scotland (willingness to pay of £20,000/QALY)

  • Yet, the clinical benefits of aclidinium/formoterol as a bronchodilator could be

underestimated

1. The CE model only measures improvements when patient changes health state 2. Sustained increase in bronchodilation was modeled but improvement on COPD-symptoms and its impact on the quality of life was not.

  • COPD-symptoms endpoints were available from ACLIFORM and AUGMENT (Transition Dyspnoea Index focal

score and St. George's Respiratory Questionnaire total score)

  • Starkie et al. 2011 explains that the translation of COPD-symptoms outcomes into indicators of relevance for the

health authorities (e.g. cost/QALYG) would introduce uncertainty and raise discussion

Why?

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Limitations

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

Issue/decision needed Solution Baseline FEV1

  • Not available per health state in the pooled

analysis

  • Use of predictive equations to estimate the lung function

Natural decline of lung function

  • Different studies available, what is the best?
  • 41 ml per year after bronchodilator from UPLIFT study (lower

values than in others studies but most recent and taking into account latest treatments). Head to head comparison

  • Step-up therapy would mimic the real clinical

practice, however the programming high number of possible treatment pathways would be technically difficult to model

  • To limit the impact of head to head comparison, a short time

horizon was considered - 5 years COPD severity level at start

  • Ideally stochastic simulation could be done, to

represent patients with different severity levels within each GOLD severity level.

  • However, this would bring extra complexity to the

model and the need of using software with higher numeric and algorithm capabilities

  • Numeric algorithm simplification was the rationale
  • The midpoint of the limits of each of the 4 severity states

defined by the GOLD criteria Risk of dying

  • Choice of the best mortality data and methodology.
  • Hoogendoorn M et.al. 2014[44] explains that

mortality is the most important factor determining the differences of CE outcomes in the COPD studies

  • Overall mortality per health state (incl. other causes of death

and death due to exacerbation)

  • Additional risk of death due to pneumonia

Cost data

  • Cost information was not all available from national

databases and sources

  • Data from published studies was used
  • Equal assumptions between countries were used
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References

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

  • Information Services Division Scotland. Chronic Obstructive Pulmonary Disease (COPD). 2013.
  • Global Initiative for Chronic Obstructive Lung Disease, Global Strategy for the Diagnosis, Management and Prevention of COPD. 2014.

Clinical Study Report: M/40464/30R. 2013.

  • Clinical Study Report: LAC-MD-31. 2013.
  • Bateman, E.D., et al., Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from

two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respiratory Research, 2015.

  • Gruffydd-Jones, K. and M.M. Jones, NICE guidelines for chronic obstructive pulmonary disease: implications for primary care. Br J Gen Pract, 2011. 61(583): p.

91-2.

  • Karabis, A., et al., Economic evaluation of aclidinium bromide in the management of moderate to severe COPD: an analysis over 5 years. Clinicoecon Outcomes

Res, 2014. 6: p. 175-85.

  • Samyshkin, Y., et al., Cost-effectiveness of roflumilast as an add-on treatment to long-acting bronchodilators in the treatment of COPD associated with chronic

bronchitis in the United Kingdom. Eur J Health Econ, 2014. 15(1): p. 69-82.

  • Rutten-van Mölken, M.P., et al., Modelling the 5-year cost effectiveness of tiotropium, salmeterol and ipratropium for the treatment of chronic obstructive

pulmonary disease in Spain. Eur J Health Econ, 2007. 8(2): p. 123-35.

  • Langhammer, A., et al., Forced spirometry reference values for Norwegian adults: the Bronchial Obstruction in Nord-Trøndelag Study. Eur Respir J, 2001. 18(5):
  • p. 770-9.
  • Health and Social Care Information Center, Health Survey for England2009, Trend tables. Table 2 - Mean height, by survey year, age and sex.
  • Tashkin, D.P., et al., A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med, 2008. 359(15): p. 1543-54.
  • Oostenbrink, J.B., et al., Probabilistic Markov model to assess the cost-effectiveness of bronchodilator therapy in COPD patients in different countries. Value

Health, 2005. 8(1): p. 32-46.

  • Boutou, A.K., et al., Lung function indices for predicting mortality in COPD. Eur Respir J, 2013. 42(3): p. 616-25.
  • BNF Publications, British National Formulary. 2014
  • Personal Social Services Research Unit, Unit Costs of Health& Social Care 2013. 2013: University of Kent, Canterbury.

. NHS-Department of Health, National Schedule of Reference Cost 2012/13. UK Government. NHS: England.

  • Scotland, NHS., 2013/14 Scottish National Tariffs for Cross Boundary Flow Costing (Based on 1Spells within Specialty).
  • NHS, National Schedule of Reference Cost 2012/13. UK Government. NHS: England.
  • Rutten-van Mölken, M.P., et al., Does quality of life of COPD patients as measured by the generic EuroQol five-dimension questionnaire differentiate between

COPD severity stages? Chest, 2006. 130(4): p. 1117-28.

  • Briggs, A., M. Sculpher, and K. Claxton, Decision Modelling for Health Economic Evaluation. Handbooks in Health Economic Evaluation. Vol. 1. 2006.
  • Starkie, H.J., et al., Predicting EQ-5D values using the SGRQ. Value Health, 2011. 14(2): p. 354-60.
  • Hoogendoorn, M., et al., Comparing the cost-effectiveness of a wide range of COPD interventions using a stochastic, dynamic, population model for COPD. 2010.
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Thank you!

Assessing the cost-effectiveness of using aclidinium 400µg / formoterol 12µg compared to aclidinium 400µg in the management of COPD

  • For further information contact:
  • mafalda.ramos@be.imshealth.com
  • mlamotte@be.imshealth.com