Download Cost-effectiveness of Ikervis® in severe dry eye disease in the UK

4.0%
2.0%
0.0%
8.0%
6.0%
4.0%
2.0%
Table 1 Key model inputs
• Currently available medical treatment options include artificial tear products,
lubricants, topical steroids and ciclosporin A (CsA). Artificial tears (AT) aim to
alleviate mild to moderate symptoms by replacing or retaining moisture on the ocular
surface, providing only short-term relief, and requiring frequent dosing throughout
the day. The preservative in many artificial tear products often causes eye irritation.
• Ikervis® is a sterile, positively charged, oil-in water, unpreserved ophthalmic emulsion
that contains the active ingredient CsA Ph. Eur. at a concentration of 1 mg/mL
(0.1% w/w). CsA has an anti-inflammatory effect on the cornea and the conjunctiva
thereby reducing inflammation in the eye (4). The emulsion formulation is specifically
designed to prolong the residence time of each eye drop on the epithelial layer of the
eye.
• Ikervis® has been shown to be effective in the composite efficacy endpoint (corneal
fluorescein staining (CFS) improvement of at least 3 grades on the modified Oxford
Scale and improvement of at least 30% of the Ocular Surface Disease Index (OSDI))
which measures the effect of ciclosporin on both signs and symptoms (5) (Figure 1).
20.0%
Parameter
Value
£1,200
6 month response rates
Ikervis® + AT + CS
0.214
AT + CS
0.085
£1,000
Incremental costs (£)
• Dry eye disease (DED) (keratoconjunctivitis sicca) is a multifactorial disease of the
tears and ocular surface that results in symptoms of discomfort, visual disturbance,
and tear film instability with potential damage to the ocular surface. It is accompanied
by increased osmolarity of the tear film and inflammation of the ocular surface (1, 2, 3).
£1,400
Treatment continuation probability (cycle)
Ikervis® + AT + CS (cycle 1)
90.0%
Ikervis® + AT + CS (subsequent cycles)
94.2%
AT + CS
94.2%
Responders
30%
Non-responders
10%
£0
0.00
0.9 0.9
AT
£41.01
0.8 0.8
CS
£13.22
Non-responders
£88.63
14.0%
Incremental utility of response
0.10
AT
AT
Ikervis + AT
8.0%
Ikervis + AT
6.0%
4.0%
2.0%
0.0%
Month 3
0.0%
Month 3
Month 6 (baseline)
Month 6 (baseline)
Figure 1 Percentage of CFS-OSDI composite responders over time. AT: artificial tears
• The de novo economic evaluation, a cost utility analysis, utilises a Markov framework
to assess the cost-effectiveness of Ikervis® plus artificial tear substitutes (AT) plus
corticosteroids (CS) as needed compared to AT plus CS in patients with DED and
severe keratitis who responded not adequately to tear substitutes. A 30 year time
horizon and monthly cycles were used. Both costs and benefits were discounted at
3.5% p.a.
• The model captures three frontline therapy states:
1. response (an OSDI improvement from baseline of ≥30%
and a CFS improvement from baseline ≥3),
2. non-response, and
3. death.
• Responders have a higher Health Related Quality of Life (HRQoL) than nonresponders.
• Evidence for the efficacy of Ikervis® and patient utilities were derived from the
SANSIKA (5) and SICCANOVE (6) randomised controlled trials in adult patients with
DED and severe keratitis.
• A visual representation of the model can be seen in Figure 2.
Treatment
Induction
Treatment
Responders
Nonresponders
Post plugs
Permanent
punctal plugs
Temporary
punctal plugs
• Eligible patients enter ‘treatment induction’ where they receive six months of therapy
(Ikervis® + AT + CS or AT + CS).
• Responders to treatment continue on therapy until treatment is no longer efficacious
and active treatment is ceased or, in a small number of patients, temporary punctal
plugs are trialled.
• A small proportion of patients will progress to having the treatment made permanent
if they respond well to the temporary plugs, while the remainder return to using AT +
CS as needed.
• CS were modelled on a response/non-response basis with those who are responsive
to treatment (Ikervis® + AT or AT alone) less likely to require the anti-inflammatory
effects of steroids.
• Table 1 summarises the key inputs of the model.
0.20
0.24
0.6 0.6
0.5 0.5
Ikervis
+ AT
Ikervis
+ AT
0.4 0.4
AT AT
0.3 0.3
0.2 0.2
Base case results:
0.1 0.1
• The base case analysis shows that, compared to AT + CS, Ikervis® + AT + CS
results in an incremental lifetime cost to the UK NHS of £709 per patient (£16,530
minus £15,821), but offers an additional 0.05 QALYs (10.09 minus 10.04).
0 0
£0 £0
• The cost-effectiveness plane arising from the probabilistic analysis is presented in
Figure 3 and the associated cost-effectiveness acceptability curve in Figure 4.
• Probabilistic sensitivity analysis confirms that Ikervis® produces a benefit to patients,
generating a utility gain compared with artificial tears in all 1000 cost-effectiveness
simulations (CE sims).
• At a cost-effectiveness threshold of £20,000 per QALY gained, Ikervis® is costeffective in approximately 64% of simulations. This increases to 84% at £30,000 per
QALY. The probabilistic ICER of Ikervis + AT + CS is £15,197 per QALY gained.
Ikervis® + AT + CS
AT + CS
Trial costs
£432
£166
Maintenance costs
£1,182
£171
Non-responder costs
£21,876
£22,413
Total costs (undiscounted)
£24,586
£23,809
Total costs (discounted)
£16,530
£15,821
Difference in total costs
£709
N/A
QALYs
10.09
10.04
QALY difference
0.049
-
ICER
£14,517
-
£10,000
£20,000
£30,000
£40,000
£10,000
£20,000
£30,000
£40,000
Cost-effectiveness
threshold
(per(per
QALY
gained)
Cost-effectiveness
threshold
QALY
gained)
£50,000
£50,000
Figure 4 Cost-effectiveness acceptability curve (CEAC)
• From Table 2 it can be seen that the ICER is therefore £14,517 per QALY gained.
The threshold values used in the UK for reimbursement range from £20,000 to
£30,000 per QALY gained.
• For patients with DED and severe keratitis, different formulations of CsA are used
in clinical practice (7) to treat the condition, although none are licensed for human
use in the UK. These include Restasis (0.05% CsA drops) imported from the USA
and Optimmune (0.2% CsA ointment) ophthalmic ointment – a licensed veterinary
product used to treat dry eye in dogs (8). Ikervis® is available at a significantly lower
monthly cost to the NHS than both unlicensed CsA formulations.
• Univariate deterministic sensitivity analysis (Figure 5) highlighted the parameter that
uncertainty surrounding the absolute utility value for treatment responders has the
greatest impact on the ICER.
Conclusion:
• In summary, there is robust evidence from two clinical trials (SANSIKA and
SICCANOVE (5, 6)) of the efficacy of Ikervis® in patients with DED and severe
keratitis compared to AT without ciclosporin.
• These results demonstrate the improvement in the composite CFS-OSDI endpoint
(an OSDI improvement from baseline of ≥30% and a CFS improvement from
baseline ≥3) with Ikervis®, indicating a clinically relevant therapeutic benefit in
comparison to AT without ciclosporin.
• The base-case ICER of £14,517 per QALY gained is compelling evidence of the
cost-effectiveness of Ikervis® compared with AT at the lowest cost-effectiveness
threshold, of £20,000 per QALY gained.
• At £72 per month, Ikervis® not only has a considerably lower acquisition price than
other available CsAs but also has the additional benefit of a convenient once daily
method of administration.
References:
Sensitivity analysis:
• To test the appropriateness of a 6 month initial trial period, a scenario analysis was
conducted with response assessed after 3 rather than 6 months (Table 4). Due to the
lower proportion of responsive patients at month 3 relative to 6 (Figure 1), a 3 month
stopping rule is less cost-effective, with an ICER of £33,432 per QALY gained.
(1) 2007 Report of the International Dry Eye Work Shop (DEWS). The Ocular Surface. 2007;5(2)
(2) Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. ArchOphthalmol. [10.1001/ archophthalmol.2011.364]. 2012;130(1):90-100
(3) Lemp MA. Advances in understanding and managing dry eye disease. American Journal of Ophthalmology. [10.1016/j. ajo.2008.05.016]. 2008;146(3):350-6.
Table 3 Cost minimization analysis results
Ciclosporin formulation
Monthly cost
Restasis eye drops (0.05%) 0.4ml
£454
Ciclosporin eye ointment (0.2%)
£109
Ikervis®
£72
(4) Donnenfeld E., and Pflugfelder S.C.. Topical ophthalmic cyclosporine: Pharmacoloy and clinical uses. Surv Ophthalmol 54. 2009. 0039-6257/09
(5) Santen. A multicenter, randomized, double-masked, 2 parallel arm, vehicle-controlled, 6-month phase III trial with a 6 month open label treatment safety follow-up period to
evaluate the efficacy and safety of Cyclokat 1mg/ml (ciclosporin/cyclosporine) eye drops,
emulsion administered once daily in adult patients with Severe dry eye disease (DED)
[NVG10E117]. SANSIKA 2013.
(6) Santen. A phase III, multicentre, randomized, controlled, doublemasked trial of nova22007 Table 4 Three month trial period cost-effectiveness results
(ciclosporin 0.1%) ophthalmic cationic emulsion versus vehicle in patients with moderate to
severe dry eye syndrome [NVG06C103]. SICCANOVE2013.
Intervention
Discounted cost
Discounted QALYs
Ikervis + AT + CS
£16,205
9.95
AT + CS
£15,780
9.94
+cost+analysis&sort=Relevance&size=10&page=1&area=both#top [ 2015 Available from: Difference
£425
0.01
+cost+analysis&sort=Relevance&size=10&page=1&area=both#top
ICER per QALY gained
£33,432
-
®
Figure 2 Treatment schematic (excluding death)
0.12
0.16
Incremental QALYs
0.7 0.7
Table 2 Base case results
Methods:
0.08
1 1
£113.01
0.66
0.04
Figure 3 Cost-effectiveness plane
Utilities
10.0%
£400
Ikervis®+ AT
Non-responders
ICER
£200
Treatment cost (per month)
16.0%
CE sims
£600
Corticosteroid usage (per cycle)
18.0%
12.0%
£800
Probability cost-effective
Probability cost-effective
6.0%
Background:
Percentage of CFS ≥ 3, OSDI ≥ 30% responder
3 and OSDI 30% responder patients
patients
8.0%
Morton T1, Ernst F2, Mealing S1, Eaton J1, Hawkins N1, Thompson J1. 1ICON Health Economics and Epidemiology, Oxford, United Kingdom, 2Santen GmbH, Munich, Germany.
Contact: [email protected], [email protected].
Percentage of CFS
0.0%
Cost-effectiveness of Ikervis in severe dry eye disease in the UK [UPDATE]
®
(7) Health & Social Care Information Centre. Prescription Cost Analysis, England - 2014
[NS]. http://www.hscic.gov.uk/article/2021 WebsiteSearch?productid=17711&q=prescription
URL:http://www.hscic.gov.uk/article/2021/Website-Search?productid=17711&q=prescription
(8) Merck Animal Health. Optimmune Opthalmic Ointment. http://www merck-animal-health-usa com/products/130_163354/productdetails_130_163712 aspx [ 2015
ICER per QALY gained
£0
£5,000
£10,000
£15,000
£20,000
£25,000
£30,000
Response Utility set to 0.72/0.8
Ikervis acquisition cost set to 50/100
Ikervis total cost set to 90.4/135.61
6 month response probability (Ikervis) set to 0.17/0.26
6 month response probability (AT) set to 0.07/0.1
Number of treated eyes set to 1/2
Background AT cost (Ikervis) set to 32.8/49.21
Ikervis drops per day set to 10.78/16.17
Non-responders AT cost set to 69.52/104.28
Non-responders drops per day set to 23.35/35.02
Upper
Lower
Figure 5 Deterministic sensitivity analysis - Tornado diagram
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