Volume 12 • Supplement 3 • 2009
V A L (Te I N HIE A L T H
A Time-Cost Augmented Economic Evaluation of Oral
Deferasirox versus Infusional Dereroxmine for Patients with
Iron Overload in South Korea
Jinhyun Kim, PhD,1 Younhee Kim, MPH2
'College of Nursing, Seoul National University, Seoul, South Korea; 2School of Public Health, Seoul National University, Seoul, South Korea
ABSTRACT ______________________________________________________________________________________________________
Objectives: This study aims to conduct an economic evaluation of oral
deferasirox (DSX) compared with infusional deferoxamine (DFO) in
patients with transfusional iron overload.
Methods: Depending on the methods for measuring time-cost and conve­
nience associated with the mode of administration, either cost-utility
analysis or cost-effectiveness analysis was undertaken. The difference in
compliance rate between DSX and DFO was applied.
Results: Although the drug cost of DSX was US$124,070 higher than that
of DFO (US$96,039 vs. US$220,199), all other costs were lower in
Introduction
The majority of patients with p-thalassaemia, sickle cell disease
(SCD), myelodysplastic syndromes (MDS), and other types of
anemia often experience iron overload because of repeated trans­
fusions. Iron overload increases the iron burden of the body,
resulting in impairment of the heart, liver and endocrine func­
tion, and death [1]. Because humans have no physiological
mechanisms to eliminate iron from their bodies, iron chelation
therapy (ICT) has been recommended for transfusion-dependent
patients with iron overload. Infusional deferoxamine (DFO) is
known to be efficacious as a chelating agent [2,3]. Nevertheless,
because of its very poor oral bioavailability and its short half-life,
DFO must be administered in a continuous infusion for 8 to 12
hours, 5 to 7 days a week. Regular infusions are painful and
cumbersome; thus, its effectiveness has been limited mainly by
poor compliance.
Although infusion of DFO using a portable pump at home is
allowed in European countries and the United States, DFO can
be administered via slow subcutaneous or intravenous infusion
only in hospitals in South Korea. Thus, the medical and time
costs of infusion for DFO may be higher and the compliance is
likely to be lower in South Korea than in other countries (for
details, see A Time-cost Augmented Economic Evaluation of
Oral Deferasirox versus Infusional Dereroxmine for Patients
with Iron Overload in South Korea Value in Health Supporting
Information, Part I at: http://www.ispor.org/Publications/value/
ViHsupplementary/ViH12s3_Kim.asp).
Deferasirox (DSX) was recently licensed as an oral ICT in
South Korea. DSX phase II/III clinical trials have shown that
efficacy of DSX is similar to that of DFO [4-9]. In addition, DSX
is expected to have more convenience and lower administration
time [4,10].
Address correspondence to: Younhee Kim, School of Public Health, Seoul
National University, 28 Yungun-Dong, Jongro-Gu, Seoul 110-779, South
Korea. E-mail: jio02@snu.ac.kr
10.1111/j.1524-4733.2009.00633.x
S78 © 2009, International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 1098-3015/09/S78 S78-S8I
patients with DSX than in patients with DFO. In the cost-utility analysis,
DSX resulted in US$3197 savings with a gain of 2.63 quality-adjusted
life-years per patient. The result of the cost-effectiveness analysis also
showed that DSX dominated DFO.
Conclusions: With a considerable improvement in convenience and injec­
tion time rather than efficacy, DSX is considered as a dominant therapy for
patients with iron overload.
Keywords: compliance, cost-effectiveness analysis, cost-utility analysis,
iron chelating agents.
This study aims to conduct an economic evaluation of DSX
compared with DFO in transfusion-dependent patients, focusing
especially on the main differences in medication time and conve­
nience between oral and infusion therapy associated with the
mode of administration.
Methods
Clinical Trials
A comparative phase III clinical trial in regularly-transfused
patients with p-thalassaemia was conducted to demonstrate the
efficacy of DSX versus DFO [4-6,8]. The clinical trial showed
noninferiority of 20-30 mg/kg/day for DSX versus equivalent
doses for DFO in patients with a baseline LIC of ^7 mg Fe/g/dw
(for details, see A Time-cost Augmented Economic Evaluation of
Oral Deferasirox versus Infusional Dereroxmine for Patients
with Iron Overload in South Korea Value in Health Supporting
Information, Part II at: http://www.ispor.org/Publications/value/
ViHsupplementary/ViH12s3_Kim.asp). Phase II clinical trials in
patients with SCD, MDS, and other rare types of anemia have
shown similar results in Phase III clinical trials in patients with
p-thalassaemia [7,9].
Patient Population
In this study, the patients were transfusion-dependent patients
requiring ICT because of iron overload. The patients with
p-thalassaemia, SCD, MDS, and other rare types of anemia were
included. The standard patient was assumed to weigh 50 kg and
this patient started chelation therapy at 50 years old (for details,
see A Time-cost Augmented Economic Evaluation of Oral
Deferasirox versus Infusional Dereroxmine for Patients with
Iron Overload in South Korea Value in Health Supporting
Information, Part III at: http://www.ispor.org/Publications/value/
ViHsupplementary/ViH12s3_Kim.asp).
Model Overview
DFO must be infused over 8-12 hours per day for 5-7 days a
week, while DSX is a once-daily oral chelation agent. There may
A Time-Cost Augmented Economic Evaluation S79

be significant differences between DFO and DSX in terms of was considered as the utility weights of the patients who were not
convenience and time-saving. There is no guideline regarding treated with ICT, 0.61 (95% CI: 0.55-0.67) for DFO, and 0.85
whether the outcome should be life-years gained (LYG) or (95% CI: 0.81-0.89) for DSX were reported [16]. Clinical trials
quality-adjusted life-years (QALYs) when differences in conve­ of DSX compared with DFO reported symptoms of side effects
nience and time-saving are evaluated. Thus, depending on the with two ICTs were temporary and negligible and did not affect
method measuring this convenience associated with the mode patients’ quality of life [5,6]. Thus, this study did not consider
of administration, either a cost-utility analysis or a cost­ these side effects.
effectiveness analysis was undertaken. In addition, the results of
these analyses were compared. Costs
In the cost-effectiveness analysis, the administration and
When convenience and time-saving were considered as indirect
travel time cost were calculated as indirect costs and the outcome
costs, the list of costs included productivity loss associated with
was presented in terms of LYG. When the convenience due to the
medical utilization. Drug treatment, physician fees, medical
use of DSX compared with DFO was considered as a utility, a
devices, and travel costs were included as the direct costs of DFO.
cost-utility analysis was conducted. Indirect costs—productivity
In the list of the costs of oral DSX, medical devices for infusion
loss due to the injections and visits to the hospital—were
and productivity loss due to injections were excluded.
excluded in the lists of costs in the cost-utility analysis to avoid
Although common costs including the monitoring costs of the
double counting.
two drugs were excluded because of limited data, a creatinine
A Markov model was used to estimate the incremental cost­
clearance test cost was added to the list of DSX costs based on
utility ratio (ICUR) and the incremental cost-effectiveness ratio
clinical trials in which DSX increased serum creatinine levels.
(ICER) of DSX versus DFO. The Markov health states were
Patients with DSX who received additional monitoring of crea­
survival with ICT, survival without ICT, and death (see Fig. SI at
tinine levels were assumed to be able to control the creatinine
A Time-cost Augmented Economic Evaluation of Oral Defera-
levels and experience no advanced event because of the increased
sirox versus Infusional Dereroxmine for Patients with Iron Over­
serum creatinine levels. Commonly occurring costs with different
load in South Korea Value in Health Supporting Information at:
frequencies, such as physician fees and travel costs, were also
http://www.ispor.org/Publications/value/ViHsupplementary/
considered in this study.
ViH12s3_Kim.asp). Although natural death depended on age,
Table SI (see Table SI at A Time-cost Augmented Economic
disease-specific death was allowed to vary with the compliance of
Evaluation of Oral Deferasirox versus Infusional Dereroxmine
ICT.
for Patients with Iron Overload in South Korea Value in Health
Future costs and QALYs were evaluated over a 50-year time­
Supporting Information at: http://www.ispor.org/Publications/
frame and discounted to their present value using an annual
value/ViHsupplementary/ViH12s3_Kim.asp) shows the unit
discount rate of 5%. A societal perspective was adopted.
costs associated with DFO and DSX. The recommended doses of
DFO and DSX depend on the level of transfusion, liver iron
Health Outcome and Compliance in an concentration, and on the weight of the patient. In this study, the
Economic Evaluation daily dose for a patient weighing 50 kg was assumed to be
2000 mg for DFO and 1000 mg for DSX based on the directions
The health outcomes of this study were LYG in a cost­
of 40 mg/kg/day for DFO and 20 mg/kg/day for DSX [7]. The
effectiveness analysis and QALYs in a cost-utility analysis. The
resource use of other medical costs of DFO was based on a
impact on survival of ICT was reported to depend on the com­
hospital survey of ICT patients in South Korea.
pliance rate of ICT patients [2,11,12]. The study examined
The fee schedule of the Korean National Health Insurance in
patients initiating ICT at 5 years old showed that life expectancy
2007 was used to calculate the drug costs, the physician fees,
was 12.5 years with compliance under 75 times, 28.4 years with
monitoring costs, and the material costs. Travel costs were estab­
compliance between 75 and 225 times, 47.3 years with compli­
lished to be US$10.07 per round trip according to the Natio­
ance between 225 and 300 times, and 57 years with compliance
nal Health and Nutritional Examination Survey (for details,
over 300 times per year [2,13]. Using this data, the continuous
see Supporting Information, Part V at: http://www.ispor.org/
relationship with the mortality rate and the compliance rate
Publications/value/ViHsupplementary/ViH12s3_Kim.asp). The
was derived (for details, see A Time-cost Augmented Economic
average wage rate of each age group in 2007 was calculated.
Evaluation of Oral Deferasirox versus Infusional Dererox­
Productivity loss due to utilization was estimated considering the
mine for Patients with Iron Overload in South Korea Value in
labor participation rate and ages of the patients. Only half of the
Health Supporting Information, Part IV at: http://www.ispor.org/
patients requiring ICT assumed to have an intention to work in
Publications/value/ViHsupplementary/ViH12s3_Kim.asp). The
this study.
compliance for oral deferiprone was reported to be 16% higher
than that of DFO in clinical trials [14]. There was no clinical data
regarding compliance of DFO in South Korea. Thus, compliance Results
with DFO and DSX was assumed to be 64%, the reported
average compliance rate and 74.24%, the estimated compliance Base-Case Analysis
rate of deferiprone, respectively, in the base case analysis of this Although the discounted drug cost of DSX was US$124,070
study. To explore the impact of compliance with DFO on the higher than that of DFO (US$96,039 vs. US$220,199), all other
results, a sensitivity analysis was performed. costs including health service costs and time costs were lower in
The ICT patient-reported outcome showed DSX had a much patients with DSX than in patients with DFO. These lower costs
higher score than DFO in terms of convenience, satisfaction, and offset the higher drug cost of DSX. In the cost-utility analysis,
preference [4,10]. Patients’ quality of life was improved with oral DSX resulted in lower direct costs and higher QALYs gained
ICT [15]. The utility outcomes associated with the mode of (US$3197 savings with a gain of 2.63 QALYs per patient). The
administration based on a community survey using the time results of the cost-effectiveness analysis also showed that DSX
trade-off method were employed. In this survey, mean utility dominated DFO in these measures (see Table S2 at A Time-cost
weights of 0.75 (95% CI: 0.70-0.80) for the anchor state, which Augmented Economic Evaluation of Oral Deferasirox versus
S80
Infusional Dereroxmine for Patients with Iron Overload in South
Korea Value in Health Supporting Information at: http://
www.ispor.org/Publications/value/ViHsupplementary/ViH12s3_
Kim.asp).
Sensitivity Analysis
Given the compliance of DSX of 74.24%, for a sensitivity analy­
sis, the compliance of DFO was varied from 1% to 74.24%
(equivalent compliance of DSX). A decrease in the compliance of
DFO indicates a relative increase in the compliance of DSX. The
result of the sensitivity analysis showed that the relative improve­
ment in the compliance rate for ICT leads not only to higher
effects but also to higher costs, resulting in an increase in the
ICUR or ICER (see Figs. S2-S5 at A Time-cost Augmented Eco­
nomic Evaluation of Oral Deferasirox versus Infusional Der­
eroxmine for Patients with Iron Overload in South Korea Value
in Health Supporting Information at: http://www.ispor.org/
Publications/value/ViHsupplementary/ViH12s3_Kim.asp). After
the difference between the compliance rates of the two drugs
exceeded 58.24%, however, the ICUR decreased. The result of
the sensitivity analysis of the cost-effectiveness analysis was
similar. The relationship between the net cost and the net effect
had a convex curve as the compliance rate of DFO decreased.
When the difference in the compliance rate was 49.24% (25%
for DFO, 74.24 for DSX), ICER was highest.
Trade-Off between QALY and Productivity Loss Costs
Let the incremental QALY (AQALY) be comprised of the incre­
mental LYG (ALYG) and the incremental quality of life (AQOL).
Because the incremental total costs (ATC) is sum of the incre­
mental direct costs (ADC) and indirect costs (AIDC), ICUR
f ADC A k , « ATC-AIDC „
=----------- can be expressed as ---------------------------.
I AQALY J ALYG + AQOL
As indirect cost of DSX is lower than that of DFO, the
incremental indirect cost of DSX versus DFO is negative
(-AIDC >0). In addition, QOL of DSX is higher than that of
DFO, thus the incremental QOL of DSX versus DFO is positive
(AQOL >0). Therefore, theoretically, both net effects and net
costs are higher in the cost-utility analysis than in the cost-utility
analysis.
An additional analysis was conducted to identify the relation­
ship between increased effects of the QOL and decreased pro­
ductivity loss | L AIDC y The absolute ratios of the incremental
II AQOL|J
QOL to productivity loss were likely to be maintained at
US$20,000, the implicit threshold of QALY in South Korea (see
Fig. S6 at A Time-cost Augmented Economic Evaluation of
Oral Deferasirox versus Infusional Dereroxmine for Patients
with Iron Overload in South Korea Value in Health Sup­
porting Information at: http://www.ispor.org/Publications/value/
ViHsupplementary/ViH12s3_Kim.asp).
Discussion
Cost-utility analysis and cost-effectiveness analysis were con­
ducted to present methods measuring convenience and time­
saving associated with the mode of administration. Impact of an
improvement in the compliance on the economic evaluation was
also examined.
The results of the cost-utility analysis and cost-effectiveness
analysis showed that a different conclusion could be derived.
Nevertheless, knowing which is the more suitable model remains
controversial.
Kim and Kim
The two base-case analyses showed that DSX saved on costs
and gained effectiveness compared with DFO. When the gap
between the compliance rates of the two ICTs exceeded 14.24%
in the cost-utility analysis and 21.24% in the cost-effectiveness
analysis, however, the costs of DSX became higher than those of
DFO. Both ICUR and ICER increased until the compliance dif­
ference reached 58.24% (16% for DFO vs. 74.24% for DSX) in
the cost-utility analysis and 49.24% (25% for DFO vs. 74.24%
for DSX) in the cost-effectiveness analysis. This result showed
that the relative improvement in compliance increased the treat­
ment cost as well as clinical outcome.
In South Korea where a portable pump at home is not per­
mitted, the introduction of DSX is likely to bring an improve­
ment in the compliance rate of ICT and will improve its outcome.
Nevertheless, ICER or ICUR will increase if the incremental costs
due to the increased utilization overwhelm the incremental effec­
tiveness (for details, see A Time-cost Augmented Economic
Evaluation of Oral Deferasirox versus Infusional Dereroxmine
for Patients with Iron Overload in South Korea Value in
Health Supporting Information, Part VI at: http://www.ispor.org/
Publications/value/ViHsupplementary/ViH12s3_Kim.asp).
This situation was mentioned in a study conducted in the UK
[17]. The ICUR in a US study [13], reflecting the difference in the
compliance rate, was higher than the ICUR in the UK study
assuming compliance of the two ICTs to be 100%. The author of
the UK study argued that the benefit associated with compliance
should be excluded in the main analysis because the compliance
benefit had not been proven. Nevertheless, to identify the benefits
associated with the mode of administration, the compliance dif­
ference must be considered. Especially in South Korea, where the
compliance of DFO is likely to be lower than in other countries,
it will be meaningful to consider the compliance [18].
There are several limitations in this study. First, in South
Korea, most patients who receive transfusions are MDS patients.
Nevertheless, because of limited data, the data from patients with
p-thalassaemia were used to apply the utilities for QALYs and to
estimate the relationship between the compliance rate and the
mortality rate. Other clinical trials reported that the efficacies of
ICT were likely related to transfusional iron loading rate rather
than to a disease [7]. In addition, the investigation of the utility
values of MDS patients was also found to be 0.55 for DFO and
0.78 for DSX showing a difference of 0.23, which is similar to
those pertaining to p-thalassaemia patients (0.24) [19]. Thus, the
problem may be minor.
An exponential formula for the compliance rate and mortal­
ity rate was derived using limited data to identify the impact of
compliance rate on the survival rate. Nevertheless, the goodness-
of-fit was 0.999. Thus, this second limitation is likely to be
minor.
Conclusion
With a considerable improvement in the convenience and saving
in injection time of DSX, the results of the cost-utility analysis
and the cost-effectiveness analysis of DSX versus DFO showed
that DSX is a dominant therapy for patients with iron overload
in South Korea. Nevertheless, a relative improvement in the
compliance rate for DSX would rather have a negative effect on
the economic evaluation.
Source of financial support: This study was sponsored by a research grant
from the Novartis Pharmaceuticals Corporation.
Jinhyun Kim and Younhee Kim have no conflicts to declare.
A Time-Cost Augmented Economic Evaluation
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