Cost-Utility of Omalizumab Compared with Standard of Care for the Treatment of Chronic

Cost-Utility of Omalizumab Compared with Standard of Care for the Treatment of Chronic Spontaneous Urticaria

J. Graham,1 D. McBride,2 D. Stull,1 A. Halliday,3 S.T. Alexopoulos,3 M.M. Balp,4 M. Griffiths,5 I. Agirrezabal,5T. Zuberbier,6A. Brennan7

1RTI Health Solutions, Research Triangle Park, NC, USA, 2RTI Health Solutions, Manchester, United Kingdom, 3Novartis Pharmaceuticals UK Limited, Surrey, United Kingdom, 4Novartis Pharma AG, Basel, Switzerland, 5Costello Medical Consulting Ltd, Cambridge, United Kingdom, 6Department of Dermatology and Allergy, Allergy-Centre-Charité, Charité – University Hospital Berlin, Berlin, Germany, 7University of Sheffield, Sheffield, United Kingdom

Journal: PharmacoEconomics

Correspondence to:

Anna Halliday, Novartis Pharmaceuticals UK Limited, Surrey, United Kingdom. Email:

Phone:+44 1276 698655

Fax: +44 1276 692508

SUPPLEMENTARY MATERIAL

Overview of systematic literature review of the natural history of CSU

In order to understand the natural history of CSU and obtain estimates of disease duration and remission rates, a systematic literature review was conducted.

Online bibliographic databases (MEDLINE, Embase, the Cochrane Library, Web of Science and BIOSIS Previews) were searched for relevant publications, supplemented with horizon scanning and hand-searching of the reference lists of included articles. In order to meet the inclusion criteria for the systematic literature review, articles were required to:

Include patients with CSU aged ≥12 years
Report duration of disease, remission rates, duration of remission or relapse rates following remission
Be primary observational studies which followed up individual patients for ≥1 year, or systematic reviews of observational studies

No restrictions were imposed on publication date. Two reviewers independently applied inclusion and exclusion criteria with disagreements resolved through consensus.

A total of 20 publications were ultimately included in the systematic literature review: 6 RCTs, 7 observational studies and 7 reviews. Three observational studies represented the largest studies in terms of patient populations and had the longest follow-up periods:

Toubi et al. 2004 observed 25%, 57% and 86% of patients being clear of CSU by 1, 3 and 5 years, respectively;[1]
Van der Walk et al. 2002 observed 34% and 49% of patients being clear of CSU by 5 years and 10 years, respectively;[2]
Nebiolo et al. 2009 reported that CSU persisted in 63% and 54% of normotensive patients for up to 24 and 60 months, respectively.[3]

The methods and results of this systematic literature review have been published as a congress abstract and e-poster at the 24th European Academy of Dermatology and Venereology (EADV) Congress, 2015.[4]

Table S 1. Discontinuation, loss to follow-up and relapse proportions

Probability of discontinuation at 24 weeks for omalizumab 300 mg
Variable / Due to adverse events
(SE; 95% CI upper, lower) / Due to physician/patient decision to withdraw
(SE; 95% CI upper, lower) / Due to disease progression
(SE; 95% CI upper, lower) / Source
“Moderate urticaria” at baseline
(UAS7 16–27) / 0.027 (0.019; 0, 0.065) / 0.041 (0.023; 0, 0.086) / 0.000 (0; 0,0) / GLACIAL Study – Patient-Level Analysis
“Severe urticaria” at baseline
(UAS7 28–42) / 0.056 (0.017; 0.022, 0.089) / 0.028 (0.012; 0.004, 0.052) / 0.061 (0.018; 0.026, 0.097) / GLACIAL Study – Patient-Level Analysis
Loss to follow-up at 24 weeks
Variable / Omalizumab 300 mg
(SE; 95% CI upper, lower) / SOC
(SE; 95% CI upper, lower) / Source
“Moderate urticaria” at baseline
(UAS7 16–27) / 0.1096 (0.036; 0.04, 0.18) / 0.1563 (0.063; 0.03, 0.28) / GLACIAL Study – Patient-Level Analysis
“Severe urticaria” at baseline
(UAS7 28–42) / 0.2179 (0.031; 0.16, 0.28) / 0.3333 (0.065; 0.21, 0.46) / GLACIAL Study – Patient-Level Analysis
Cumulative relapse proportions post-treatment by health state and week post-treatment
Health state / Cumulative relapse proportion (distribution parameters) / Source
4 weeks / 8weeks / 12 weeks / 16 weeks
“Mild urticaria” (UAS7 7–15) / 0.3478 (16, 30) / 0.4783 (22, 24) / 0.5000 (23, 23) / 0.5435 (25, 21) / GLACIAL Study – Patient-Level Analysis
“Well-controlled urticaria”
(UAS7 1–6) / 0.2500 (13, 39) / 0.3846 (20, 32) / 0.4423 (23, 29) / 0.4423 (23, 29) / GLACIAL Study – Patient-Level Analysis
“Urticaria-free” (UAS7=0) / 0.1638 (19, 97) / 0.3793 (44, 72) / 0.4828 (55, 60) / 0.5603 (65, 51) / GLACIAL Study – Patient-Level Analysis
CI: confidence interval; SE: standard error; SOC: standard of care; UAS7: Urticaria Activity Score over 7 days.

Table S 2. Drop-out data from the GLACIAL study

n at baseline / Missing UAS7 score at 24 weeks / Proportion of drop-outs at 24 weeks
Omalizumab arm
Moderate at baseline / 73 / 8 / 11.0%
Severe at baseline / 179 / 39 / 21.8%
SOC arm
Moderate at baseline / 32 / 5 / 15.6%
Severe at baseline / 51 / 17 / 33.3%

SOC: Standard of care; UAS7: Urticaria Activity Score over 7 days.

Calculation of four-week risk of adverse events

The 4-week risk of each adverse event included in the model was calculated from reported risk values at a given length of follow-up from the GLACIAL study using the rate-probability conversion equation reports in Fleurence et al. (2007).[5]

Equation (1) generates the annual rate of a given adverse event:

(1) r = -(1/t)ln(1-p)

Where r = rate, t = time and p = probability

In the form of a rate, this can then be divided arithmetically to computetherate per 4-week unit of time for the adverse event.

Equation (2) converts this rate back to a probability:

(2) p = 1-exp(-rt)

Where r = rate, t = time and p = probability

The four-week risks of adverse events using the above method are provided in Table S 3.

Table S 3. Four-week risk of adverse events within the economic model

Adverse event / 4-week risk of adverse event (omalizumab arm) / 4-week risk of adverse event (SOC)
Sinusitis / 1.65% / 0.69%
Headache / 2.07% / 0.97%
Arthralgia / 0.98% / 0.14%
Injection site reaction / 0.90% / 0.28%
Upper respiratory infection / 0.97% / 0.52%
SOC: standard of care

Mixed-effects regression model for estimation of health state utilities

In the absence of any published information on the relationship between health states and utility values in patients with CSU, a study was performed to investigate the relationship between UAS7-defined health states and EQ-5Dutility values in order to inform the economic model.

Mean utilities were calculated for each of the 5 UAS7-defined health states based on patient-level utility data from each of the three trials of omalizumab in CSU (GLACIAL, ASTERIA I and ASTERIA II). The utility data reported in each of the trials was in the form of EQ-5D-3L, valued using UK preferences from Kind et al. 1998.[6] Data was collected at baseline, week 12 and week 40 in the GLACIAL and ASTERIA I trials, and at baseline, week 12 and week 28 in the ASTERIA II trial. Individual trial analyses by treatment arm and time-point produced inconsistent utilities across health states due to small sample sizes and therefore data was pooled across all treatment arms and all time points of the three studies for the analysis; thereby representing data across a total of 2,030 observations.

A linear mixed-effects model was therefore established based on this pooled patient-level trial data, with EQ-5D as the dependent variable and UAS7 health states as the predictor. A number of covariates including presence of angioedema at baseline, duration of CSU and gender were included in the model, as were interaction terms. Sensitivity analyses confirmed the robustness of the results.

Further details of this mixed-effects regression model have previously been published in a congress poster: “Hawe E, Stull DE, McBride D, Balp M. Estimating utility data for patient symptom severity in chronic spontaneous urticaria. Poster presented at the 17th Annual European Congress of the International Society for Pharmacoeconomics and Outcomes Research; November 2014. Amsterdam, the Netherlands.”[7]

In addition, this research is, at the current time, in-press at PharmacoEconomics, with the following citation: “Hawe E, McBride D, Balp M-M, Tian H, Halliday A, Stull DE. EQ-5D Utilities in Chronic Spontaneous/Idiopathic Urticaria. PharmacoEconomics 2016 (in print).”[8]

Table S 4. Disutilities associated with adverse events applied in the model

Variable / Value (SD; distribution) / Source
Sinusitis / -0.0022 (-0.0004; Beta) / Sullivan et al. (2006)[9]
Headache / -0.0297 (-0.0059; Beta) / Sullivan et al. (2006)[9]
Arthralgia / -0.0402 (-0.0080; Beta) / Sullivan et al. (2006)[9]
Injection site reaction / -0.0040 (-0.0008; Beta) / Matza et al. (2013)[10]
Upper respiratory infection / -0.0022 (-0.0004; Beta) / Sullivan et al. (2006)[9]
SD: standard deviation

Table S 5. Breakdown of unit costs and resource use assumptions informing the model

Category / Resource / Unit cost / Frequency
“Severe urticaria”
(UAS7
28–42) / “Moderate urticaria” (UAS7
16–27) / “Mild urticaria”
(UAS7
7–15) / “Well-controlled urticaria” (UAS7 1–6) / “Urticaria-free”
(UAS7=0)
Number of patients per health state / 17 / 28 / 21 / 6
A&E/
hospital visits / Emergency room / £107.60 / 0 / 1 / 0 / 2 / 0
Emergency consultant visit / £143.46 / 1 / 1 / 2 / 0 / 0
Emergency non-consultant visit / £63.91 / 1 / 0 / 0 / 0 / 0
Total mean (SD) weighted emergency cost / £12.20 (£37.20) / £8.97
(£33.28) / £13.66 (£43.15) / £35.87 (£55.56) / 0
Op visits / General dermatology / £95.98 / 33 / 42 / 26 / 5 / 0
Consultant allergist / £132.41 / 13 / 33 / 18 / 3 / 0
Consultant immunologist / £198.01 / 0 / 1 / 0 / 0 / 0
Other consultant / £147.44 / 0 / 0 / 0 / 3 / 0
Non-consultant doctor / £103.96 / 4 / 7 / 6 / 2 / 0
Hospital nurse / £61.13 / 15 / 4 / 14 / 0 / 0
Mental health professional / £26.62 / 0 / 0 / 0 / 0 / 0
Total mean (SD) weighted routine cost / £365.97 (£282.83) / £341.82 (£183.60) / £302.79 (£260.12) / £254.57 (£172.69) / 0
Lab testsresource / Full blood count / £10.49 / 40 / 45 / 39 / 7 / 0
Sedimentation rate / £10.49 / 7 / 14 / 10 / 4 / 0
C-reactive protein / £9.83 / 10 / 33 / 18 / 4 / 0
Thyroid-stimulating hormone / £13.95 / 9 / 16 / 13 / 3 / 0
Liver function / £10.49 / 42 / 40 / 27 / 8 / 0
Thyroid antibodies, renal profile and C4 / £10.49 / 8 / 15 / 10 / 3 / 0
Other tests / £10.96 / 32 / 19 / 22 / 5 / 0
Total mean (SD) weighted laboratory cost / £93.64 (£93.74) / £69.69 (£68.27) / £71.49 (£68.85) / £61.12 (£75.38) / 0
Lab; Laboratory; Op: outpatient; SD: standard deviation; UAS7: Urticaria Activity Score over 7 days. No patients with UAS7=0 were enrolled in the ASSURE-CSU study and values for the “urticaria-free” health state therefore represent an assumption. All values represent the units of resource used across all patients in each health state (n numbers provided in the first row of the table).

Table S 6. Four-week cost of adverse events applied in the model

Adverse event / Value / SD (distribution) / Source
Sinusitis / £7.84 / 1.57 (Normal) / PSSRU 2013 (inflated to 2014) & BNF July 2014
Headache / £6.26 / 1.25 (Normal)
Arthralgia / £6.26 / 1.25 (Normal)
Injection site reaction / £0.00 / N/A
Upper respiratory infection / £7.84 / 1.57 (Normal)
BNF: British National Formulary; N/A: Not applicable; PSSRU: Personal Social Services Research Unit; SD: standard deviation

Inputs for one-way sensitivity analysis

For the OWSA parameters were varied by ±20%, with the exception of the following:

Discount rates for costs and outcomes:upper value 6%, lower value 0%
Spontaneous remission hazard ratio:±10%
Disutility of all adverse events: ±15%
Utility values per health state:upper and lower bounds of the 95% confidence intervals
Relapse probabilities: altered based on the 95% confidence intervals of the cumulative relapse at 16 weeks post-treatment. From these confidence intervals a percentage variation is estimated and applied to all data points (i.e. week 4, week 8, week 12, week 16 post-treatment)
Dropouts:upper and lower bounds of the 95% confidence intervals
Discontinuations: upper and lower bounds of the 95% confidence intervals
Health state costs: upper and lower bounds of the 95% confidence intervals
Productivity (percentage employed, absenteeism and presenteeism): Upper and lower bounds of the 95% confidence intervals
Patient distribution across health states: based on the 95% confidence intervals of the proportion of patients in the “well-controlled urticaria” state. The “urticaria-free” proportion was held constant and the remaining patients distributed across the “mild urticaria”, “moderate urticaria” and “severe urticaria” health states as per the original proportions in those states. This was done separately for the omalizumab arm and the SOC arm of the model. Separately, the process was repeated based on changing the proportion of patients in the “urticaria-free” state according to the 95% confidence intervals, with patients then redistributed across the four remaining states according to the original proportions in those states

Methods for model validation

The model was assessed for clinical validity, validity of the modelling approachand technical accuracy, as outlined below.

Clinical validity

Expert feedback on the clinical validity of the model structure and inputs was gathered through three approaches:

Iterative discussions with clinical experts in the CSU disease area from the UK and from Germany, one of whom is a co-author on this paper.
Gathering of feedback from UK clinical experts at an Advisory Board held in July 2013.
A series of one-to-one discussions with UK clinical experts during model development throughout 2014.

Validity of the modelling approach

Validity of the technical approach to modelling was ascertained through iterative discussions with a UK professor of health economics, who is a co-author on this paper.

Technical accuracy

The model underwent two forms of full quality control reviews for technical accuracy:

Internal quality control procedures by the agency responsible for model development. This included an independent researcher not involved in the original model design conducting a series of diagnostic tests to assess the correctness of the model code, calculations and mechanics, as well as a check of input values against source documents.
An independent quality control review of the economic model submitted to NICE in 2014 (on which the model presented in this publication is based) was performed by Dr Oliver Rivero-Arias, a health economist with extensive experience in cost-effectiveness analysis of health care technologies.

References

1. Toubi E, Kessel A, Avshovich N, Bamberger E, Sabo E, Nusem D et al. Clinical and laboratory parameters in predicting chronic urticaria duration: a prospective study of 139 patients. Allergy. 2004;59(8):869-73. doi:10.1111/j.1398-9995.2004.00473.x.

2. van der Valk PG, Moret G, Kiemeney LA. The natural history of chronic urticaria and angioedema in patients visiting a tertiary referral centre. The British journal of dermatology. 2002;146(1):110-3.

3. Nebiolo F, Bergia R, Bommarito L, Bugiani M, Heffler E, Carosso A et al. Effect of arterial hypertension on chronic urticaria duration. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2009;103(5):407-10. doi:10.1016/s1081-1206(10)60360-2.

4. Marsland A, Balp MM, Halliday A, Alexopoulos ST, Allen F, Buchanan-Hughes A et al. The natural course of chronic spontaneous urticaria: A systematic review. 24th European Academy of Dermatology and Venereology Congress; 7–11th October 2015; Copenhagen, Denmark. Abstract no. COP15-1728

5. Fleurence R, Hollenbeak C. Rates and Probabilities in Economic Modelling. Pharmacoeconomics. 2007;25(1):3-6. doi:10.2165/00019053-200725010-00002.

6. Kind P, Dolan P, Gudex C, Williams A. Variations in population health status: results from a United Kingdom national questionnaire survey. BMJ : British Medical Journal. 1998;316(7133):736-41.

7. Hawe E, Stull DE, McBride D, Balp M. Estimating utility data for patient symptom severity in chronic spontaneous urticaria. Poster presented at the 17th Annual European Congress of the International Society for Pharmacoeconomics and Outcomes Research; November 2014. Amsterdam, the Netherlands.

8. Hawe E, McBride D, Balp M-M, Tian H, Halliday A, Stull DE. EQ-5D Utilities in Chronic Spontaneous/Idiopathic Urticaria. PharmacoEconomics 2016 (in print).

9. Sullivan PW, Ghushchyan V. Preference-Based EQ-5D index scores for chronic conditions in the United States. Medical decision making : an international journal of the Society for Medical Decision Making. 2006;26(4):410-20. doi:10.1177/0272989x06290495.

10. Matza LS, Cong Z, Chung K, Stopeck A, Tonkin K, Brown J et al. Utilities associated with subcutaneous injections and intravenous infusions for treatment of patients with bone metastases. Patient preference and adherence. 2013;7:855-65. doi:10.2147/ppa.s44947.