Supplementary Appendix
Supplementary Table 1. Utility gains for different response categories used in sensitivity analysis
<PASI50
PASI response category
≥PASI50 ≥PASI75 ≥PASI90
and
and
<PASI75 <PASI90
0.178
0.178
0.308
EQ-5D utility
values from
adalimumab STA
0.063
Mapped utility
values from
ustekinumab STA
0.04
0.17
0.22
0.25
SF-6D utility
values from
ustekinumab STA
0.00016
0.0424
0.0970
0.1276
Description of methods
Source
The manufacturers pooled EQ5D, PASI and DLQI data from 2
trials and used a mixed model
with repeated measures of
analysis of covariance in order to
assess the relationship between
changes in EQ-5D and clinical
response. The model included
the categorical variables for PASI
response, baseline DLQI and PASI
response by baseline DLQI
interaction and a random effect
for the intercept.
The manufacturers followed the
same methods as Woolacott and
colleagues. Using patient-level
data from 2 ustekinumab trials,
they estimated mean change in
DLQI scores for patients with
different levels of PASI response,
but only included patients with a
baseline DLQI ≥ 10. They then
replicated the ordinary least
squares linear regression analysis
of the DLQI and EQ-5D data
based on information from
Woolacott et al. and used the
regression equation to "map"
changes in DLQI associated with
PASI responses in their studies to
changes in EQ-5D utility.
The manufacturers also used SF36 data collected as part of one
clinical trial and converted values
into SF-6D utility scores.
[1]
[2]
[2]
PASI, Psoriasis Area and Severity Index; PASI50, reduction of at least 50% on PASI score; EQ-5D, EuroQol-5 dimensions; STA,
Single Technology Appraisal; DLQI, Dermatology Life Quality Index; SF-36, Short form-36; SF-6D, Short form-6 dimensions
Supplementary Table 2. Quantity of monitoring tests and outpatient visits per patient - 13.5-week
trial period
FBC
(£2.83) (a)
LFT
(£0.71) (a)
U&E
(£1.31)(a)
Outpatient visits
(£82)(b)
Adalimumab
2
2
2
2
Etanercept
2
2
2
2
Infliximab
3
3
3
1 (a)
Ustekinumab
2
2
2
2
Biologic
(a) Unit costs for monitoring tests from Woolacott and colleauges[3] and inflated to 2013-14 prices using the Hospital and
Community Health Services inflation index[4]
(b) NHS Reference Costs[5] inflated to 2013-14 value
(c) Patients are reviewed during infusion visits and then one additional outpatient appointment.
FBC, Full blood count; LFT, liver function test; U&E, Urea and Electrolytes, including serum creatinine
Supplementary Table 3. Annual monitoring tests and outpatient visits per patient - treatment
period
FBC
(£3.01)
LFT
(£0.76)
U&E
(£1.39)
PIIINP
(£26.93)
Methotrexate
4
4
4
4
Ciclosporin
4
4
4
Adalimumab
4
4
4
4
Etanercept
4
4
4
4
Infliximab
4
4
4
4
Ustekinumab
4
4
4
4
Biologic
GFR
(£251)
1
Liver biopsy
(£596)
Outpatient
visit (£88)
0.04 (a)
4
4
(a) Frequency of liver biopsy with methotrexate with concurrent use of PIIINP test was based on estimates from Chalmers
and colleagues[6]
(b) GFR, Glomerular Filtration Rate
Costs for glomerular filtration rate (GFR) testing and liver biopsy were taken from NHS reference
costs[5] and inflated to 2013-14 values. Liver biopsy was assumed to be performed as a day case
procedure (code GB04Z) and GFR testing was based on a weighted average of the test performed as
a diagnostic imaging outpatient procedure, direct access procedure or other (code RA37Z). The
number of outpatient visits during the trial period for each biologic agent is also presented.
Supplementary Table 4. Distribution parameters for model inputs
Variable Description (HRG code, if applicable)
Mean
utility gain associated with PASI00
0.05
Distribution
type
Gamma
utility gain associated with PASI50 compared to PASI00
0.12
utility gain associated with PASI75 compared to PASI50
alpha
beta
Source
25
0.002
[3]
Gamma
8.47058824
0.0141667
[3]
0.02
Gamma
0.125
0.16
[3]
utility gain associated with PASI90 compared to PASI75
0.02
Gamma
0.09756098
0.205
[3]
utility gain associated with PASI00
0.12
Gamma
16
0.0075
[3]
utility gain associated with PASI50 compared to PASI00
0.17
Gamma
6.42222222
0.0264706
[3]
utility gain associated with PASI75 compared to PASI50
0.09
Gamma
0.81
0.1111111
[3]
utility gain associated with PASI90 compared to PASI75
0.03
Gamma
0.06206897
0.4833333
[3]
cost of consultant led OP follow-up visit
86.01
Gamma
1772.669
0.0485178
[5]
cost of non-consultant led OP follow-up visit
63.64
Gamma
480.438
0.1324679
[5]
cost of regular day/night admission (JD02C)
315.85
Gamma
410.295
0.7698229
[5]
cost of phototherapy session as OP procedure (JC29Z)
cost of phototherapy session as regular day/night
admission (JC29Z)
cost of complex topicals as day case (JD02A)
81.71
Gamma
227.144
0.3597122
[5]
151.24
Gamma
10.133
14.925373
[5]
388.69
Gamma
4185.436
0.0928678
[5]
cost of complex topicals as day case (JD02B)
386.18
Gamma
3682.566
0.1048658
[5]
cost of complex topicals as day case (JD02C)
351.09
Gamma
459.231
0.764526
[5]
cost of elective IP with major CC (JD02A)
4403.77
Gamma
226.354
19.455253
[5]
cost of elective IP with intermediate CC (JD02B)
3720.19
Gamma
134.671
27.624309
[5]
cost of elective IP without CC (JD02C)
3348.11
Gamma
198.9113
16.832183
[5]
cost of excess bed day elective IP stay, major CC (JD02A)
184.56
Gamma
27.131
6.8027211
[5]
cost of excess bed day elective IP stay, intermediate CC
(JD02B)
226.82
Gamma
514.659
0.4407228
[5]
cost of excess bed day elective IP, without CC (JD02C)
302.59
Gamma
1868.792
0.1619171
[5]
cost of non-elective IP stay, with major CC (JD02A)
3873.07
Gamma
210.5789
18.392496
[5]
cost non-elective IP stay, with intermediate CC (JD02B)
3332.04
Gamma
160.6375
20.742585
[5]
cost non-elective IP stay, without CC (JD02C)
3378.98
Gamma
89.8471
37.608123
[5]
197.54
Gamma
6633.504
0.0297787
[5]
185.53
Gamma
26.345
7.0422535
[5]
247.74
Gamma
14.9388
16.583748
[5]
245.61
Gamma
419.995
0.5847953
[5]
cost of GFR other (RA37Z)
301.90
Gamma
1863.938
0.1619695
[5]
cost of GFR direct access (RA37Z)
71.45
Gamma
19.364
3.6900369
[5]
cost of liver biopsy (GB04Z)
553.31
Gamma
1009.794
0.5479452
[5]
cost of excess bed day non-elective IP stay, with major
CC (JD02A)
cost of excess bed day non-elective IP stay , with
intermediate CC (JD02B)
cost excess bed day non-elective IP stay, without CC
(JD02C)
cost of OP GFR (RA37Z)
HRG, health related group; PASI, Psoriasis Area and Severity Index; PASI50, reduction of at least 50% on PASI score; OP,
outpatient; CC, co-morbidity and complication; IP, inpatient; GFR, glomerular filtration rate
Supplementary Table 5. Description of sensitivity and scenario analyses
Sensitivity and scenario analyses
Structural assumptions
Time horizon = 1 year
Time horizon = 2 years
Time horizon = 5 years
Stopping rule: Continue to
'treatment' period if PASI50
Duration of 'trial' period adjusted
for each drug
Gradual loss of efficacy (40%
drop 1 PASI category per year)
Biologic inputs
Infliximab & Ustekinumab only
Infliximab only
Ustekinumab only
Weighted average biologic
(BADBIR data)*
10% annual dropout
50% annual dropout
70% annual dropout
64% reduction in hospitalisations
on biologic therapy
100% reduction in
hospitalisations on biologic
therapy
Best supportive care inputs
BSC pPASI50 = 65%
BSC pPASI50 = 83%
Description
These sensitivity analyses focused on testing structural assumptions in the
model
The time horizon was limited to the 13.5-week trial period followed by 1 year
The time horizon was limited to the 13.5-week trial period followed by 2 years
The time horizon was limited to the 13.5-week trial period followed by 5 years
In the base case, only patients with a PASI75 were considered responders and
allowed to continue on treatment during the 'treatment' period. In this
sensitivity analysis PASI50 is used as the threshold for treatment continuation.
In the base case, the trial duration is 13.5 weeks for all drugs regardless of
national guidance. In this sensitivity analysis, the trial period is adjusted for
each drug (i.e. trial period is 12 weeks for etanercept, 16 weeks for
ustekinumab and adalimumab and 10 weeks for infliximab)
In the base case, level of treatment response achieved in the trial period was
assumed to be maintained for the duration of the treatment period or until the
patient dropped out. In this sensitivity analysis, it was assumed that loss of
efficacy and drop out was more gradual. Before dropping out and switching to
BSC, patients cycled first through lower levels of PASI response (i.e. PASI90
moved to PASI75, PASI75 to PASI50 and PASI50 to discontinuation). The rate
tested was 40% per year would drop one PASI response category.
These sensitivity analyses focused on testing inputs that specifically related to
biologic, including their cost, persistence rates and effect on resource
utilisation.
In the base case, an average cost was assumed across all biologics. In this
sensitivity analysis, an average of only infliximab and ustekinumab was used,
reflecting the fact that the clinical trial data in the model was based only on
these two drugs.
In this sensitivity analysis, only infliximab cost data was used
In this sensitivity analysis, only ustekinumab cost data was used, reflecting the
fact that the majority of clinical trial data in the model was from trials of
ustekinumab.
In this sensitivity analysis, a weighted average of drugs was used, with weights
informed by a distribution obtained from the British Association of
Dermatologists Biologic Interventions Register (BADBIR) (cut-off 31st March
2012): Adalimumab= 1225, Etanercept = 665, Infliximab =143, Ustekinumab=
451 (Personal communication Dr Nicola Lawes 18th April 2012).
In the base case, 20% of patients on biologic were assumed to drop out each
year. In this sensitivity analysis, the drop-out rate was decreased to 10% per
year.
In this sensitivity analysis, the drop-out rate was increased to 50% per year.
In this sensitivity analysis, the drop-out rate was increased to 70% per year.
In the base case, biologic therapy was assumed to reduce hospitalisations by
76%. In this sensitivity analysis, biologic therapy was assumed to reduce
hospitalisations by just 64% (data from Driessen and colleagues[7].
In this sensitivity analysis, biologic therapy was assumed to eliminate
hospitalisations.
These sensitivity analyses focused on testing inputs that specifically related to
best supportive care, particularly its efficacy and cost.
In the base case, the efficacy of best supportive care was based on effects
observed in the placebo arms of included RCTs. In this sensitivity analysis,
efficacy of best supportive care was based on the proportion of patients with a
baseline PASI score of 10-20 who achieved a PASI50 following an inpatient
hospitalisation of approximately 20.8 days[8]
In this sensitivity analysis, efficacy of best supportive care was based on the
MTX and Ciclosporin excluded
from BSC
BSC assumed as 1 annual
hospitalisation and 5 outpatient
visits
Hospitalisations and other
resource use inputs
Longer mean LOS (23.7 days) if
hospitalised
Greater proportion very high
need patients (30%)
Lower very high need patients
(5%)
Fewer annual hospitalisations for
high need patients (0.25)
Fewer annual hospitalisations for
high and very high need patients
(0.5 and 2 respectively)
1 annual hospitalisation all
patients
0.312 annual hospitalisations for
all
0 annual hospitalisations
BSC assumed as 1 annual
hospitalisation and 5 outpatient
visits; Biologics reduce number
of hospitalisations 100%
Utility inputs
No utility gain for <PASI50
Utility gain values from patients
with worst DLQI at baseline (4th
quartile)
Utility values from adalimumab
STA
Utility values from ustekinumab
STA
Utility values from ustekinumab
STA using SF-6D
BSC assumed as 1 annual
proportion of patients with a baseline PASI score of >20 who achieved a PASI50
following an inpatient hospitalisation of approximately 23.7 days[8].
In the base case, MTX and ciclosporin are included among the best supportive
care components. In this sensitivity analysis they are excluded.
In the base case, best supportive care includes drug, monitoring, outpatient
visits, phototherapy and day centre costs along with 1.28 hospitalisations per
patient for a total cost of £11,435 per year. In this sensitivity analysis, only 1
hospitalisation and 5 outpatient visits are included per patient, costing just
£6,512 per year.
These sensitivity analyses focused on testing inputs that specifically related
hospitalisation assumptions.
In the base case, the mean length of stay (LOS) per hospital admission was 20.8
days based on the mean LOS for patients with PASI 10-20 at baseline in Woods
and colleagues[8]. In this sensitivity analysis, this value was increased to 23.7
days, based on the LOS data for patients with PASI >20 at baseline.
In the base case, 18% of patients were assumed to be very high need[7]. In
this sensitivity analysis, the proportion of very high need patients was
increased to 30%.
In this sensitivity analysis, the proportion of very high need patients was
decreased to 5%.
In the base case, high need patients were assumed to require 1 hospitalisation
each year. In this sensitivity analysis, only 25% of patients were assumed to
require hospitalisation each year.
In the base case, high need patients were assumed to require 1 hospitalisation
and very high need, 2.55, each year. In this sensitivity analysis, only 50% of
high need patients were assumed to require a hospitalisation each year and
very high need patients were assumed to only require 2 per year.
In this sensitivity analysis, high and very high need patients were assumed to
require only 1 hospitalisation each year.
In this sensitivity analysis, only 31.2% of patients were assumed to require a
hospitalisation each year.
In this sensitivity analysis, no one required a hospitalisation
In this sensitivity analysis, patients on best supportive care are assumed to
require only 5 outpatient visits and 1 hospitalisation per year, whilst patients
on biologic therapy are assumed to require no hospitalisations. This scenario
most closely matches the base case assumptions in economic evaluations of
biologics for biologic-naive patients[3;9] .
These sensitivity analyses focused on testing inputs that specifically related to
utility data.
The base case assumed that treatment non-responders (patients achieving
<PASI50) gained 0.05 QALYs. In this sensitivity analysis, these patients are
assumed to experience no benefits.
In this sensitivity analysis, estimates of utility gain are sourced from an analysis
undertaken in patients with the worst quality of life at baseline.
The base case used utility data from Woolacott and colleagues[3] which was
derived using data from etanercept trials. In this sensitivity analysis, EQ-5D
data from the manufacturer's submission on the NICE STA for adalimumab was
used. For details of the methods used, see Supplementary Table 1.
In this sensitivity analysis, mapped EQ-5D data from the manufacturer's
submission on the NICE STA for ustekinumab was used. For details of the
methods used, see Supplementary Table 1.
In this sensitivity analysis, mapped SF-6D data from the manufacturer's
submission on the NICE STA for ustekinumab was used. For details of the
methods used, see Supplementary Table 1.
In this sensitivity analysis, other scenarios are combined to assess the impact
hospitalisation and 5 outpatient
visits and utility values from
patients with worst DLQI at
baseline
of reduced resource use for BSC and worse baseline quality of life.
PASI, Psoriasis Area and Severity Index; PASI50, reduction of at least 50% on PASI score; BSC, best supportive care; RCT,
randomised controlled trial; MTX, methotrexate; LOS, length of stay; QALY, quality-adjusted life years; DLQI, Dermatology
Quality Life Index; EQ-5D, EuroQol-5 dimensions; STA, single technology appraisal; NICE, National Institute for Health and
Care Excellence; SF-6D, Short form-6 dimensions.
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