TITLE: Influence of subcutaneous specific immunotherapy on drug costs in children suffering
from allergic asthma

  ABSTRACT.BACKGROUND:
Subcutaneous specific immunotherapy (SCIT) is an effective treatment attenuating
the progression of allergic asthma. To date, there is a lack of studies
investigating the economic consequences of SCIT on health care expenditures.

ABSTRACT.METHODS:
A health-economic piggy-back analysis of SCIT was conducted based on a RCT that
enrolled 65 children and adolescents with allergic asthma. Patients were allocated
into two groups: A group receiving SCIT with a high-dose hypoallergenic house dust
mite preparation plus asthma medication and a control group receiving only asthma
medication. For both groups asthma control was achieved before the start of the
SCIT treatment and was maintained during the study. Both, costs and
cost-effectiveness of SCIT with the high-dose hypoallergenic house dust mite
preparation were investigated based on total medication costs, incremental
medication costs and treatment effects (measured as lung function), respectively.
A bootstrap analysis was performed to validate the results.

ABSTRACT.RESULTS:
A steady decline in medication costs could be observed in the SCIT group one year
after treatment start compared to the control group. This cost trend became
statistically significant 3 years after SCIT started. The calculated potential
savings in the SCIT group correlated with an improved lung function. The
distribution of the bootstrap results revealed that the probability of SCIT having
a superior effectiveness compared to the control group is around 90%.

ABSTRACT.CONCLUSION:
SCIT with a high-dose hypoallergenic preparation received by children and
adolescents suffering from mite induced allergic asthma reduces the allergic
medication intake and has cost-saving effects. Additional costs associated with
SCIT may be completely compensated by drug cost savings 4 years after end of SCIT.
Additionally, SCIT is superior compared to routine care as measured by the lung
function that improved in SCIT-treated patients. Trial registration: (EudraCT no.
2004 – 003892 – 35).

BODY.BACKGROUND:
Asthma is one of the most frequent chronic diseases, with about 300 million patients
being affected worldwide [1]. In children, asthma is even the most frequent chronic disease [2]. Considering the age-specific prevalence of asthma, it becomes apparent that
the asthma prevalence peaks in early childhood and then declines steadily. The German
KIGGS study reported the lifetime prevalence of asthma in children and adolescents to be
4.7% [3]. However, this number might overestimate the prevalence, as the answers were
derived from self-responses. Quality of life is reduced in children and adolescents
suffering from asthma [4]. The patients often have a limited ability to participate in physical
activities and are not able to sleep through the night [5]. Asthma therefore poses a significant burden of disease for the affected
patients. The annual mean sick leave days in employed asthma patients are around 23 days [6]. In Germany the total direct costs of asthma were measured to be about 2.35
billion euro; the costs for sick leave days caused by asthma were estimated to be 242
million euro for the year 2006 [7]. This demonstrates that asthma is an important economic factor for the health
system.  Unlike common antiallergic drugs specific immunotherapy (SIT) is the only treatment for
allergic patients that treats the cause of the disease [8]. A specific type of this therapy is the subcutaneous immunotherapy (SCIT).
Here, allergen extracts are injected subcutaneously [9]. Allergen-specific subcutaneous immunotherapy (SCIT) is a well-established
treatment for mild to moderate asthma. A Cochrane review demonstrated that SCIT is an
effective treatment for reducing asthma symptoms as well as medication use [10]. With the decrease in medication use, we hypothesized that the costs in
SCIT-treated children should decrease as well.  To our knowledge the cost-effectiveness of SCIT to date in Germany has primarily been
demonstrated in model-based approaches [11,12], as opposed to actual patient data. This paper therefore aims to analyse the
economic consequences on medication use and the cost-effectiveness of SCIT in children
and adolescents with asthma using data from a randomized controlled trial.

BODY.METHODS.STUDY DESIGN:
The present health economic piggy back analysis was conducted based on a randomized,
controlled multicenter study (EudraCT-Nr. 2004 – 003892 – 35) including
children and adolescents suffering from allergic asthma (GINA levels II and III).
Before randomization patients' minimal requirement for the inhaled
corticosteroid (ICS) dose to achieve asthma control was determined in the baseline
phase from September 2005 to February 2006 which represents the time of the highest
exposure to house dust mites. Data from patient diaries during the baseline year
build a sound and reliable basis of an individual patient status prior to the start
of treatment. After achieving asthma control, patients were randomized into an
intervention group, receiving a subcutaneous specific immunotherapy with house dust
mite allergoid Acaroid® in addition to standard asthma medication, or into a
control group with standard asthma medication alone. The patients were compared
during a mean follow up period of 3 years. The study including the present health
economic analysis, was approved by an ethics committee in accordance to the ethical
principles that have their origin in the Declaration of Helsinki, and that are
consistent with GCP and the applicable regulatory requirements.  The primary endpoint of the study was the change in the ICS dose steps required to
achieve asthma control (according to GINA [13]) in children treated for two years with SCIT compared with children on ICS
alone. The ICS dosages in both groups during the third treatment year were described
elsewhere [14]. For details on inclusion and exclusion criteria and detailed statistical
methods see the publication of Zielen et al. 2010 [15].

BODY.METHODS.ECONOMIC ASSESSMENT AND OUTCOMES:
The economic evaluation was performed using a longitudinal drug cost-analysis, a
break even analysis and a cost-effectiveness analysis.  During the study, patients were asked to keep a diary about their total medication
use (allergic medication as well as other drugs) and to give information whether a
medication intake was associated with their allergic suffering or whether it was
related to other non-allergic diseases. The drug consumption was monetarily valued in
two ways : If it was applicable to extract the exact quantity of drug intake from
patients diaries, the monetarily valuation was calculated using quantity-based prices
(e.g. price per milligram) of the German Rote Liste 2011 [16]. If patients documentation on the quantity of the active ingredients was
insufficient, we used official DDD-prices (defined daily dose) provided annually by
the German Drug-Prescription report [17]. Unfortunately, further resource consumption, such as outpatient stays or
hospitalizations, could not be included in the analysis. Next, the costs for SCIT
with Acaroid® were considered, and an expected break even-point was calculated.
Therefore, we assumed that potential cost savings, realizable for SCIT patients in
the third treatment year, would be stable over time after the study. Additionally, we
decided to discount the modelled future savings after the third treatment year using
a discount rate of 3% to consider a longer time horizon. The underlying SCIT costs
per patient treated with Acaroid® in 2012 were assumed to be about 1,597 euro
over the 3-years intervention period (perennial therapy, maintenance therapy every 6
weeks, net prices including 19% value added tax, 16% manufacturer sales discount and
a price level of August 1, 2009 due to legal price stop).  The effectiveness measure for the following health economic cost-effectiveness
analysis was the lung function, expressed as the mean annual morning peak flow (in
l/min) after SCIT onset. For cost-effectiveness analysis we hence calculated the mean
annual morning peak flow during the 3 years after SCIT began in relation to the mean
annual total costs (including SCIT costs) associated with treatment arms. To get a
measure of uncertainty we used non-parametric bootstrapping [18]. Therefore, the original sample was bootstrapped 1,000 times to obtain
1,000 means for cost and effect differences that were subsequently plotted in a
cost-effectiveness plane.

BODY.METHODS.STATISTICAL ANALYSIS:
Socioeconomic data at baseline were analysed using Student's t-test for
comparing continuous variables and Chi-Square test for dichotomous variables. Drug
costs in both groups were analysed using Mann–Whitney-U test. For
cost-effectiveness analysis, an analysis of covariance (ANCOVA) was conducted to
adjust all values of costs and effects for age and the respective peak flow baseline
value. The significance level was defined to be 5% (two-sided). For inferential
statistics, we used SPSS© version 20. Finally, we used MS Excel© 2007 to
model bootstrapped cost-effectiveness analyses.

BODY.RESULTS.BASELINE CHARACTERISTICS:
A total of 65 patients were initially recruited and randomized into two groups (33
SCIT, 32 controls). The mean age of these patients was 10.0±SD 3.1 years in the
SCIT group and 10.6±SD 2, 9 years in the control group. In both groups, about
30% of patients were female. We found no significant differences in the average
severity of asthma (GINA) or the peak flow measurements before the SCIT. Differences,
however, were detectable with regard to the allergic-drug costs (434 euro per year
for SCIT, 296 euro per year in controls, p = 0.130) as well as the resulting total
drug costs before the SCIT intervention started (485 euro per year for SCIT, 345 euro
per year in controls, p = 0.083). These differences were due to the fact that before
the intervention started a total of 6 patients (5 SCIT, 1 control) were identified as
outliers with calculated annual total drug costs of more than 1,000 euro per year.
These patients were excluded from the following analyses (see Figure  1). The important baseline characteristics before and after
outlier exclusion are presented more detailed in Table  1.  Figure 1Total baseline drug costs per year and outlier analysis (each dot represents
one patient).   Table 1 Baseline characteristics of study participants Item SCIT Control p-value Baseline characteristics including outliers (all randomized
patients) n 33 32   Female proportion [n (%)] 11 (33.3%) 10 (31.2%) 0.534 Mean age in years [mean (SD)] 10.0 (3.1) 10.6 (2.9) 0.403 GINA level 2 [n (%)] 26 (78.8%) 26 (81.2%) 0.525 GINA level 3 [n (%)] 7 (21.2%) 6 (18.8%) Mean peak flow in l/min [mean (SD)] 296 (101) 315 (91) 0.444 Mean annual costs for allergic-drugs before intervention onset in euro
[mean (SD)] 434 (332) 296 (220) 0.130 Mean annual costs for non-allergic-drugs before intervention onset in
euro [mean (SD)] 51 (87) 50 (98) 0.571 Mean total annual drug costs before intervention onset in euro [mean
(SD)] 485 (377) 345 (245) 0.083 Baseline characteristics without outliers (all analysed
patients) n 28 31   Female proportion [n (%)] 8 (28.6%) 10 (32.3%) 0.785 Mean age in years [mean (SD)] 10.4 (3.2) 10.8 (2.8) 0.628 GINA level 2 [n (%)] 21 (75.0%) 25 (80.6%) 0.417 GINA level 3 [n (%)] 7 (25.0%) 6 (19.4%) Mean asthma level GINA [mean (SD)] 2.25 (0.441) 2.19 (0.402) 0.755 Mean peak flow in l/min [mean (SD)] 308 (105) 317 (91) 0.727 Mean annual costs for allergic-drugs before intervention onset in euro
[mean (SD)] 315 (180) 273 (183) 0.443 Mean annual costs for non-allergic-drugs before intervention onset in
euro [mean (SD)] 33 (54) 48 (99) 0.974 Mean total annual drug costs before intervention onset in euro [mean
(SD)] 349 (192) 322 (209) 0.627 

BODY.RESULTS.DRUG COSTS ANALYSIS:
The descriptive longitudinal total drug cost analysis (see Figure  2) shows a comparable cost trend in the first year after SCIT was
started. During the further course of time an increasing cost difference trend was
observable favouring patients in the SCIT group. The total drug costs (see
Table  2) reach a significant difference in year 3 after
the intervention began (193 euro 95% CI [114 to 273] for SCIT, 498 euro 95% CI [293
to 702] for controls, p=0.001). This decreasing course of total drug costs for
SCIT-patients was mainly driven by a decrease in costs of allergic medication intake.
A significant group difference was already reached after the second treatment year.
Expectedly, no intervention effect was detectable with regard to non-allergic drug
costs.  Figure 2Course of total drug costs during the study on daily basis (descriptive)
– not involving SCIT intervention costs.   Table 2 Results on total and allergic/non-allergic drug costs by year after SCIT
onset (analytic) – not involving SCIT intervention costs Years after SCIT onset SCIT Control p-value Total drug costs in euro [mean (95% CI)] 1. year 319 (236 to 402) 364 (262 to 466) 0.716 2. year 250 (168 to 333) 389 (272 to 506) 0.077 3. year 193 (114 to 273) 498 (293 to 702) 0.001 Allergic drug costs in euro [mean (95% CI)] 1. year 270 (197 to 343) 306 (219 to 393) 0.716 2. year 206 (135 to 277) 341 (232 to 451) 0.021 3. year 168 (94 to 242) 453 (249 to 656) 0.002 Non-Allergic drug costs in euro [mean (95% CI)] 1. year 49 (24 to 75) 58 (16 to 100) 0.233 2. year 44 (13 to 75) 47 (7 to 88) 0.262 3. year 25 (2 to 48) 45 (0 to 92) 0.373 

BODY.RESULTS.BREAK EVEN CALCULATION:
The results of the drug cost analysis indicate cost savings for patients treated with
Acaroid®. If these potential drug cost-savings will be extrapolated for a longer
time horizon, as it was described in the methods section, the additional costs of
1,597 euro over the 3-years intervention period that are necessary for realizing
SCIT, will be expected to be compensated by the drug costs savings about 7 years
after SCIT onset or 4 years after the end of triannual SCIT (see Figure  3).  Figure 3Break-even calculation.

BODY.RESULTS.COST-EFFECTIVENESS ANALYSIS:
For cost-effectiveness measurement, the SCIT costs were additionally included and the
resulting total costs were evaluated in relation to the observable treatment effects.
After consideration of SCIT costs, the adjusted total mean costs per patient over the
3 years treatment duration differed significantly between the groups (770 euro 95% CI
[701 to 839] for SCIT, 383 euro 95% CI [317 to 449] for controls, p<0.001). On the
other hand, the use of SCIT with Acaroid® seems to be associated with superior
effectiveness, measured by changes in peak flow results. The mean annual adjusted
morning peak flow over the 3 years of SCIT intervention shows higher values for
patients receiving SCIT (369 l/min 95% CI [354 to 385] for SCIT, 334 l/min 95% CI
[319 to 348] for controls, p=0.001). The bootstrapped cost-effectiveness results are
shown in Figure  4. Most of the dots (900 of 1,000) are
located in the upper right hand quadrant of the cost-effectiveness plane, indicating
that SCIT is associated with additional costs over the 3-years treatment period, but
also with better effectiveness. The probability, that SCIT leads to superior
effectiveness compared to controls can be directly derived from the
cost-effectiveness plane and is about 90%.  Figure 4Cost-effectiveness results including SCIT costs.

BODY.DISCUSSION:
The present investigation indicates SCIT with Acaroid® as a treatment option for
children and adolescents suffering from allergic asthma. Thus, allergic medication
intake and related drug costs can be reduced, and asthma symptoms improved. After SCIT
onset, a cost reduction trend was observable, showing that allergic medication costs
decrease from year to year. With regard to SCIT intervention costs, the present analysis
indicates, that these costs will be completely compensated by drug cost savings about 7
years after SCIT began resp. 4 years after the end of triannual SCIT.  An important strength of the present analysis is its embedding in a randomized
controlled trial, thus reducing the risk for selection bias and increasing the internal
validity [19]. As yet, there is a lack of comparable studies on allergic treatment
strategies that focus on economic consequences especially in children. A study,
published by us in 2008, investigated the economic effects of SCIT using a
Markov-model-based approach in age-stratified patients suffering from allergic rhinitis
and allergic asthma, and reached similar conclusions [12]. In that study, we calculated a possible break even 10 years post
intervention from a society's perspective.  An important point of discussion in the present analysis is the coverage of costs that
could be included for economic assessment. Since the health economic analysis was not
initially considered in the planning of the study design, we were not able to get
retrospective information on resource consumption outside the medication use. It could
be that besides the drug costs savings we detected in the present analysis, further
costs will be caused in further health care areas. On the other hand, it seems also
plausible, that a reduced need for allergic medication will have a positive effect on
other medical claims. To get clearness on other cost effects, it would be desirable to
anchorage health economic questions during the planning phase of future studies.  In the present study asthma in all children had to be controlled and the study
preparation (Acaroid®) helped to maintain this asthma control. Therefore no
emergency visits were observed during the study. Consistently very poorly controlled
asthma increases the risk for future severe asthma exacerbations [20,21] and it is well described in literature that patients with uncontrolled asthma
have a higher risk for emergency visits [22-24]. Emergency visits are associated with higher total and asthma-related health
care costs compared to patients without exacerbations [25]. Our calculation therefore might be considered as very conservative taking
only medication costs into account.  Our bootstrapped cost effectiveness results showed that a mean increase of 35 L/min in
morning peak flow ( 10% of total peak flow) in SCIT-treated children can be
achieved for additional annual costs of about 385 euro. This better peak flow is
combined with a fluticasone propionate reduction for asthma control. This is of
importance because the use of inhaled corticosteroids in children is often seen
critical. In a recent study by Kelly et al. [26] it was shown that the corticosteroid-induced growth retardation in
prepubertal children persisted in adulthood although it was not progressive or
cumulative. The anti-inflammatory effect of the allergoid preparation demonstrated by an
increased lung function is comparable to the effect of inhaled corticosteroids used for
asthma control [27].  For break even calculation we assumed the cost savings observed in year 3 to be stable
over the following years. This could be criticized as the limited study duration of 3
years did not allow proving this assumption. Yet, a longer treatment effect is not
unlikely. For instance, a systematic review published in 2011 found some evidence for
beneficial long-term effects of SCIT in allergic children after SCIT termination [28]. Due to the adjusting for differential timing of costs, using a mean annual
discounting-rate of 3% after the third year, the future cost savings were valued lower
than the present. Although the process of discounting is basically accepted in health
economic research [29] it is consistently a subject of discussion, particularly for long-term health
care programs where benefits mainly appear in the future [28].  Another limitation could arise from the way we measured the SCIT's
cost-effectiveness. This calculation focused only on the 3 years study duration. During
that time, the SCIT took place and caused additional intervention costs while future
potential cost savings after year 3 were ignored. Considering a longer time horizon
would lead to less additional costs for SCIT and would improve the intervention's
cost-effectiveness.

BODY.CONCLUSION:
SCIT with a hypoallergenic high-dose mite preparation received by children and
adolescents suffering from mite-allergic asthma reduces the anti-allergic medication
intake of ICS and has cost-saving effects. Additional costs associated with SCIT may be
completely compensated by drug cost savings 4 years after the end of triannual SCIT.
Additional SCIT is superior compared to only routine care and leads to an improved lung
function while asthma control is maintained.

BODY.COMPETING INTERESTS:
The study was financially supported by ALLERGOPHARMA GmbH & Co. KG, Germany. The
design and implementation of the analysis was solely the responsibility of the
authors.

BODY.AUTHORS’ CONTRIBUTIONS:
TR: substantial contributions to conception and design of, or acquisition of data or
analysis and interpretation of data, drafting the article or revising it critically for
important intellectual content. JKO: drafting the article and revising it critically for
important intellectual content. STO: substantial contributions to the discussion,
revising the manuscript critically for important intellectual content. BB: final
approval of the version to be published. All authors read and approved the final
manuscript.

Question: Compared to Control what was the result of Subcutaneous specific immunotherapy on Total medication costs after 3 years?
Evidence: The total drug costs (see
Table  2) reach a significant difference in year 3 after
the intervention began (193 euro 95% CI [114 to 273] for SCIT, 498 euro 95% CI [293
to 702] for controls, p=0.001). This decreasing course of total drug costs for
SCIT-patients was mainly driven by a decrease in costs of allergic medication intake.
A significant group difference was already reached after the second treatment year.
Answer: significantly decreased