Pharmacoeconomics 2012; 30 (9): 763-777

ORIGINAL RESEARCH ARTICLE 1170-7690/12/0009-0763/$49.95/0

Adis ª 2012 Springer International Publishing AG. All rights reserved.

Cost of Illness of Cystic Fibrosis

in Germany
Results from a Large Cystic Fibrosis Centre
Mareike Heimeshoff,1 Helge Hollmeyer,2 Jonas Schreyögg,1,3 Oliver Tiemann1,3 and Doris Staab2
1 Institute for Health Care Management and Health Economics, Faculty of Economics and Business
Administration, University of Hamburg, Hamburg, Germany
2 Department of Paediatric Pneumology and Immunology, Charité University Medicine Berlin, Berlin,
Germany
3 Institute of Health Economics and Health Care Management, Helmholtz Zentrum München, German
Research Center for Environmental Health, Munich, Germany

Abstract Background: Cystic fibrosis (CF) is the most common life-shortening genetic
disorder among Whites worldwide. Because many of these patients experi-
ence chronic endobronchial colonization and have to take antibiotics and be
treated as inpatients, societal costs of CF may be high. As the disease severity
varies considerably among patients, costs may differ between patients.
Objectives: Our objectives were to calculate the average total costs of CF per
patient and per year from a societal perspective; to include all direct medical
and non-medical costs as well as indirect costs; to identify the main cost
drivers; to investigate whether patients with CF can be grouped into ho-
mogenous cost groups; and to determine the influence of specific factors on
different cost categories.
Methods: Resource utilization data were collected for 87 patients admitted to
an inpatient unit at a CF treatment centre during the first 6 months of 2004
and 125 patients who visited the centre’s CF outpatient unit during the entire
year. Fifty-four patients were admitted to the hospital and also visited the
outpatient unit. Since all patients were exclusively treated at the centre, data
could be aggregated. Costs that varied greatly between patients were mea-
sured per patient. The remaining costs were summarized as overhead costs
and allocated on the basis of days of treatment or contacts per patient. Costs
of the outpatient and inpatient units and costs for drugs patients received at
the outpatient pharmacy were summarized as direct medical costs. Direct
non-medical costs (i.e. travel expenses), as well as indirect costs (i. e. absence
from work, productivity losses), were also included in the analysis. Main cost
drivers were detected by the analysis of different cost categories. Patients were
classified according to a diagnosis-related severity model, and median com-
parison tests (Wilcoxon-Mann-Whitney tests) were performed to investigate
differences between the severity groups. Generalized least squares (GLS)
764 Heimeshoff et al.

regressions were used to identify variables influencing different cost cate-

gories. A sensitivity analysis using Monte Carlo simulation was performed.
Results: The mean total cost per patient per year was h41 468 (year 2004
values). Direct medical costs accounted for more than 90% of total costs and
averaged h38 869 (h3876 to h88 096), whereas direct non-medical costs were
minimal. Indirect costs amounted to h2491 (6% of total costs). Costs for
drugs patients received at the outpatient pharmacy were the main cost driver.
Costs rose with the degree of severity. Patients with moderate and severe
disease had significantly higher direct costs than the relatively milder group.
Regression analysis revealed that direct costs were mainly affected by the
diagnosis-related severity level and the expiratory volume; the coefficient
indicating the relationship between costs for mild CF patients and other pa-
tients rose with the degree of severity. A similar result was obtained for drug
costs per patient as the dependent variable. Monte Carlo simulation suggests
that there is a 90% probability that annual costs will be lower than h37 300.
Conclusions: The share of indirect costs as a percentage of total costs for CF
was rather low in this study. However, the relevance of indirect costs is likely
to increase in the future as the life expectancy of CF patients increases, which
is likely to lead to a rising work disability rate and thus increase indirect costs.
Moreover we found that infection with Pseudomonas aeruginosa increases
costs substantially. Thus, a decrease of the prevalence of P. aeruginosa would
lead to substantial savings for society.

Key points for decision makers

 The cost of cystic fibrosis rises with the degree of severity
 Costs for drugs patients receive at outpatient pharmacies are the main cost driver
 A decrease of the prevalence of infection rates with Pseudomonas aeruginosa would lead to
substantial savings for society

Introduction therapy, CF is no longer simply a paediatric dis-

Cystic fibrosis (CF) is the most common life-
shortening genetic disorder among Whites world-
wide. The number of newborns with CF among
all births varies between 1 in 2500 and 1 in 3500
depending on the ancestry of the population and
on the intensity of screening performed.[1-4] In
recent decades, life expectancy of patients with
CF has improved considerably.[5] Due to the in-
troduction of a number of therapeutic measures,
including inhaled antibiotics and inhaled enzyme
ease.[6] Today, more than half of the patients
are aged 18 years and older[5] and the mean life
expectancy has increased from approximately
20 years in 1980 to nearly 40 years today.[7]
CF is an autosomal recessive disease in which
the modified protein product of a defective gene
causes abnormal chloride ion transport, resulting
in increased viscosity of mucus. The unusually thick,
sticky mucus clogs the lungs and leads to lung
infections, disturbances of the digestive tract, and
high sodium concentration in sweat as well as

Adis ª 2012 Springer International Publishing AG. All rights reserved. Pharmacoeconomics 2012; 30 (9)
Cost of Illness of Cystic Fibrosis
obstructions of the pancreas and inhibition of
natural enzymes that would help the body over-
come pancreatic insufficiency.[7]
Therapy for CF is still restricted to treat-
ing symptoms, and the patient’s health worsens
over time. Pulmonary disease is the primary
cause of morbidity and mortality among patients
with CF, and more than 70% of all patients aged
18 years and older test positive for Pseudomonas
aeruginosa.[8] Many of these patients experience
chronic endobronchial colonization and have
to take antibiotics and be treated as inpatients.
Therefore, societal costs of CF, including direct
medical costs as well as direct non-medical and
indirect costs (resulting from work disability of
CF patients), may be high. As the disease severity
varies considerably among patients, costs may be
quite unequal between patients. Furthermore,
previous studies have identified demographic and
especially clinical variables, such as lung function
and level of disease severity, as influencing total
costs per patient.[9-12]
Depending on the perspective, an economic
evaluation should also include indirect costs. There
are a number of arguments from an economic
point of view to follow the societal perspective,
which Jönsson[13] summarized. For instance, it is
often argued that, particularly in healthcare
systems with highly fragmented healthcare fi-
nancing, e.g. Germany and other social health
insurance countries, the societal perspective is
very important, because in these countries the
statutory health insurance only covers one part of
the total healthcare costs while other payers and
private households cover the remaining part.
Moreover, in a review on pharmacoeconomic guide-
lines required by official evaluation agencies in
different countries, Zentner et al.[14] found that
the majority of these (e.g. Canada, the Nether-
lands, Norway) prefer and require the societal
perspective. There are only a few exceptions, e.g.
Britain, that require the payer perspective. In this
article, we took the societal perspective including
indirect costs following the German recommen-
dations on health economic evaluation.[15] The
societal perspective requires the inclusion of in-
direct costs. So far, there is only one cost-of-
illness study on CF that includes some indirect
Adis ª 2012 Springer International Publishing AG. All rights reserved.
765
costs. DeWitt et al.[16] calculate cost of illness of
patients with CF with mild impairment in lung
function and include costs attributable to absence
from school or work. However, costs resulting
from work disability of patients with CF were not
included in their analysis.
Moreover, most studies calculating the costs
of CF are based on a gross-costing approach.
Only Schreyögg et al.,[10] who calculated hospital
costs of CF, Eidt-Koch et al.,[17,18] who focused
on costs for outpatient treatment, and DeWitt
et al.[16] used a micro-costing approach. There are
pros and cons for using a micro-costing versus a
gross-costing approach. Micro-costing has the
advantage of considering certain cost compon-
ents in greater detail. For instance, costs are often
underestimated by gross costing for conditions
requiring expensive drugs, e.g. CF. When com-
paring gross costing with micro-costing, Clement
et al.[19] found that micro-costing leads to higher
cost estimates than the gross-costing approach,
which has to be considered for interpretation of
results. The same authors also found that micro-
costing leads to greater variance than gross cost-
ing. An important advantage of gross costing is
that it is less expensive than micro-costing, but it
is less sensitive. Thus, micro-costing is partic-
ularly recommended in contexts requiring a high
sensitivity of cost estimates.[20] We believe that in
the context of a cost-of-illness study on CF a high
sensitivity of cost estimates is needed to be able to
allocate drug costs with high precision to patients
with different severity levels.
The objectives of this study were to calculate the
average total costs of CF per patient and per year
from a societal perspective; to include all direct
medical and non-medical costs as well as indirect
costs; to identify the main cost drivers; to in-
vestigate whether patients with CF can be grouped
into homogenous cost groups according to defined
severity levels; and to determine the influence of
certain factors on different cost categories.
Methods
The study was conducted at the Department
of Paediatric Pneumology and Immunology at
the Charité Medical School, Berlin, Germany.
Pharmacoeconomics 2012; 30 (9)
766
The department maintains one of the largest
centres for treatment of CF in Europe. Data for
inpatient treatment were collected for 87 patients.
All patients admitted to the unit over a period
of 6 months from January to July 2004 were in-
cluded. A patient was defined as any person with
CF who was admitted to the unit during the
6-month period. Since all patients were discharged
from hospital within the study period, the full
costs for each patient were captured. Costs for the
second 6-month period (July–December 2004) were
assumed to be the same as for the first 6 months.
Thus, costs for the first 6-month period were
doubled. At the same centre, data for outpatient
treatment of 125 patients with CF were collected.
All patients who visited the outpatient unit dur-
ing the year 2004 were included. For both groups
of patients (i.e. inpatient and outpatient), the
collected data included information on utiliza-
tion and prices of drugs that were prescribed by
the centre and that patients received from phar-
macies outside the centre. Fifty-four patients
visited the outpatient unit and were also admitted
to the hospital during the period observed. Since
the outpatient and inpatient units belong to the
same hospital, costs for all patients could be
summarized. Furthermore, it was verified that all
CF patients were exclusively treated by this spe-
cialized centre. Thus, resource consumption for
inpatient and outpatient treatment of 158 patients
was included in the analysis.
Resource Unit Costs
For both inpatient and outpatient treatments,
costs were measured on the basis of the individual
patient care data. In order to calculate total costs
of CF per patient per year, we performed a bottom-
up collection of resource use for particular cost
components. Hence, our method can be classified
as a micro-costing bottom-up approach. Indirect
and direct non-medical costs were also included
in the analysis. Our calculations reflect the soci-
etal perspective.
Costs that were identified in previous stud-
ies[11,21,22] as cost categories that vary greatly in
terms of individual resource utilization were mea-
sured separately for each patient, while the re-
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Heimeshoff et al.
maining costs were summarized as overhead
costs. Those cost categories with high impact on
cost variation were staff costs for patient care,
drug costs and laboratory costs. For inpatient
and outpatient treatment, staff costs for patient
care were calculated by measuring the time de-
voted to each patient for all professions employed
in the unit (clinicians, nursing staff, physiothera-
pists and dieticians). For this reason, each room
was equipped with a stopwatch, which staff mem-
bers pressed when entering and leaving the room.
Staff members were then required to document
the exact time spent in contact with each patient.
Costs were calculated by multiplying the mea-
sured time by the hourly wages of the respective
professions. Moreover, all kinds of further costs
from the employer perspective (i.e. mandatory
contributions, social security contributions and
pension contributions as well as sick and annual
leave) were captured in our staff costs. We also
took all other staff costs for other activities (e.g.
staff meetings), which do not greatly vary in in-
dividual resource utilization, into account. The
latter were estimated and added to the overhead
costs for each patient.
In order to exactly measure the drug costs for
inpatients, all drugs consumed were documented
in medical record files and accuracy was checked
with selected members of the medical staff. Pur-
chasing prices supplied by the hospital pharmacy
were used as the drug prices. These were often
lower than the official listed prices in Germany
because every hospital is able to negotiate bulk
drug discounts.[10] When drugs were prescribed in
the outpatient unit, individual drug consumption,
including name and quantity of the drug pre-
scribed, was documented. Hospitals in Germany
are not allowed to dispense drugs for outpa-
tient treatment and patients must purchase their
drugs from outpatient pharmacies instead. Pur-
chasing prices were taken from the list with offi-
cial selling prices that applied to all pharmacies in
Germany.[23]
To calculate laboratory costs for inpatient
treatment, purchasing costs for substances, de-
vices and other materials, and hourly wages for
each profession at the study hospital were ob-
tained. If services from external laboratories were
Pharmacoeconomics 2012; 30 (9)
Cost of Illness of Cystic Fibrosis
utilized, the prices paid were recorded as costs.
Laboratory costs for outpatient treatment were
calculated identically because services were pro-
vided by the same laboratory.
All other cost categories were classified as
costs with low variation in individual resource
utilization: staff costs for other activities and
certain technical equipment and imputed costs
(e.g. rent for the building, which was determined
at market rate) were summarized as overhead
costs. Furthermore, overhead costs for the hos-
pital not exclusively attributable to the CF unit
(e.g. maintenance, sterilization) were proportion-
ally included. All of these costs were obtained
from the accounting department. As we expected
no major variation in individual resource util-
ization for the cost categories mentioned above,
they were allocated on hospital days per patient
for the inpatient treatment. According to the
accounting department, overhead costs for the
outpatient treatment were one-third of those for
inpatient treatment. These costs were allocated
based on outpatient contacts per patient. More-
over, costs for radiological services provided by
other units were also distributed evenly between
patients since there were only minor variations.
Capital costs were included in the calculations.
All costs incurred in the inpatient and outpatient
units, as well as costs for drugs patients received
at outpatient pharmacies, were summarized as
direct medical costs.
Direct non-medical costs (i.e. travel expenses)
and indirect costs (i.e. productivity losses due to
CF) were also taken into account. Travel expenses
were calculated for every patient based on the
measured distance between the patient’s home
and the hospital multiplied by 0.3 h/km and the
times the patient was admitted to the hospital or
visited the outpatient unit multiplied by two. We
used the human capital approach to calculate
costs associated with productivity losses. These
costs could not be calculated at the individual
level due to missing data. Therefore, the average
rate of patients obtaining employment disability
pensions (i.e. the number of patients unable to
work due to CF) was taken from the CF patient
registry for Germany provided by the Muko-
viszidose eingetragener Verein (e.V.).[8] The German
Adis ª 2012 Springer International Publishing AG. All rights reserved.
767
registry[8] covers 82% of all CF patients in
Germany.[24] CF registries in the UK (70%) and
the US (85.6%) have a similar coverage in their
respective countries.[1,25] The disability rate was
then multiplied with the average yearly earned in-
come per person for Germany in 2004 (h32 569).[26]
The average adult patient sick days due to CF
were obtained from the Mukoviszidose e.V. (un-
published data, 2007) and multiplied with the
average income per day (h89). The method for
calculating the average yearly income and the
average income per day corresponds to the German
recommendations on health economic evaluation
of the Hanover Consensus Group.[15] Further-
more, the productivity loss of parents taking care
of their sick children was considered. The average
number of parents concerned and the average
days of absence from work were also obtained
from the Mukoviszidose e.V. (unpublished data,
2007) and multiplied by the average income
per day.
Data Analysis
In order to investigate whether patients with
different levels of CF severity can be classified
into homogenous cost groups, severity levels were
defined according to a diagnosis-related severity
model and Wilcoxon-Mann-Whitney tests were
performed for different cost categories. Patients
without colonization of the lungs with P. aeru-
ginosa were grouped as mild, while patients with
chronic colonization of the lungs, but without
pulmonary hypertension and respiratory insuf-
ficiency, were classified as moderate. Patients
with P. aeruginosa infection, pulmonary hyper-
tension and global respiratory insufficiency were
classified as severe.
Generalized least squares (GLS) regression
analysis was performed to determine the impact
of diagnosis-related severity, forced expiratory
volume in 1 second (FEV1) and the variables age
and sex on costs per patient for total direct and
drug costs as well as the remaining costs (all di-
rect costs except drug costs). A Gamma regres-
sion with log-link function fitted best according
to residual plots and the Akaike Information
Criterion (AIC) and was therefore chosen. For
Pharmacoeconomics 2012; 30 (9)
768
the regression analysis, the statistical software
STATA[27] was used.
To increase generalizability of the results found
at our study hospital, we performed a sensitivity
analysis using Monte Carlo simulation. The rela-
tive number of patients with mild, moderate
and severe disease and all direct medical costs
except for outpatient drug costs were identified
as variables that could be different for other
CF centres in Germany and influence the costs
calculated.
In order to assume a representative distribu-
tion of patients with different severity levels for
Germany, we obtained the information from the
CF patient registry of the Mukoviszidose e.V.,[8]
which contains data of 82% of all CF patients
in Germany.[24] The relevant information was
the relative number of patients infected with
P. aeruginosa. Forty-nine percent of all CF patients
in Germany were not infected with P. aeruginosa.[8]
Hence, the relative number of patients in the
mild group was 49%, whereas the relative number
of moderate and severe patients (patients of both
groups were infected with P. aeruginosa) was
51%. We are confident that the share of patients
colonized with P. aeruginosa reported by the
German registry (51%) is reasonable, as the US
CF registry, which has a similar coverage, reports
a share of 52.5%.[1] The UK CF registry, which,
however, has a lower coverage, reports a share of
39.4%.[25] As the percentage of patients being in-
fected can vary over time, we defined a con-
fidence interval of 20% around the value of 49%
of patients not infected with P. aeruginosa. For
every iteration of the Monte Carlo simulation,
one value was randomly drawn of the Uniform
distribution between the values 0.39 (0.49 - 20%)
and 0.59 (0.49 + 20%). As the sum of the relative
numbers of patients in the different severity
groups has to be 1, the respective relative number
of patients infected with P. aeruginosa was 1 minus
the randomly drawn number of patients not in-
fected with P. aeruginosa.
The data on hospital costs from the Federal
Statistical Office of Germany suggest that size
and ownership status are two important factors
that cause variation of hospital costs in addition
to disease-related factors.[28] According to the
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Heimeshoff et al.
Mukoviszidose e.V., 60% of all CF patients in
Germany were treated at university hospitals in
2005.[8] University hospitals are usually large
(more than 500 beds) and publicly owned, which
was true for our study hospital as well. Hence, the
costs of these hospitals might be comparable with
the costs of our study hospital. To increase gen-
eralizability beyond our study hospital, we applied
different sizes and ownership statuses derived
from the Federal Statistical Office of Germany
on staff and material costs (including laboratory
costs, overhead costs and drug costs for the in-
patient treatment)[28] found in our study. Thus,
if the staff costs for patient care of private hos-
pitals with less than 100 beds were 83% of those
of public hospitals with more than 500 beds
(according to the data of the Federal Statistical
Office of Germany),[28] we multiplied the staff
costs calculated for our study hospital by 0.83.
The same procedure was performed for labora-
tory costs, overhead costs and drug costs for
the inpatient treatment, which were summarized
as material costs. This was done separately for
costs of the mild CF patients (not infected with
P. aeruginosa) and for the average costs of the
moderate and severe CF patients (infected with
P. aeruginosa). Hence, the costs calculated for our
study hospital served as the basis for the calcu-
lation of costs for hospitals of different size and
ownership status. As drug costs for the outpa-
tient treatment are the same for every pharmacy
in Germany, they were not subject to Monte
Carlo simulation. As 60% of the CF patients in
Germany were treated at university hospitals in
2005,[8] we assumed that the remaining patients
were distributed among the other types of hospi-
tals according to the relative number of these
hospital types in Germany. The estimated staff
and material costs of different types of hospitals,
as well as the estimated relative number of CF pa-
tients who visited the different hospitals, served
as basis for the creation of the distributions of
costs. The distributions that fitted best according
to chi-squared statistics were chosen. For staff and
material costs of patients not infected and in-
fected with P. aeruginosa, exponential distribu-
tions with different parameters fitted best. Hence,
the fixed values of staff and material costs of
Pharmacoeconomics 2012; 30 (9)
Cost of Illness of Cystic Fibrosis 769

patients not infected and of patients infected with
P. aeruginosa calculated for our study hospital
were replaced by estimated distributions of costs
for different types of hospitals.
For each iteration of the Monte Carlo simu-
lation, the randomly drawn value of the dis-
tribution of the relative number of patients not
infected with P. aeruginosa was multiplied by the
sum of the randomly drawn values of the dis-
tributions of staff and material costs and the
outpatient drug costs of patients not infected with
P. aeruginosa, and the respective relative number
of patients infected with P. aeruginosa was mul-
tiplied by the sum of the randomly drawn values
of the distributions of staff and material costs and
the outpatient drug costs of patients infected with
P. aeruginosa. Finally, both terms were summar-
ized and supplemented by indirect costs and trav-
el expenses (travel expenses were not subject to
Monte Carlo simulation as they were rather low).
For the generation of the distribution of the es-
timated total costs per patient in Germany, this
procedure was repeated 10 000 times. For the
Monte Carlo simulation, the statistical software
@RISK[29] was used. For further details of the
Monte Carlo simulation, please see the technical
appendix in the Supplemental Digital Content,
http://links.adisonline.com/PCZ/A146.
Results
Data Description
Data from 158 patients were collected and
analysed. The mean age of all patients was 20.09
years, with 27 patients (17%) aged 6 years and
younger, 37 patients (23%) aged 7–18 years, and
94 patients (60%) aged 19 years and older. Fifty-two
percent of all patients were female and the mean
FEV1 value was 58.32%. According to the diagnosis-
related severity index, 46 patients (29%) were clas-
sified as mild, while most of the patients (n = 86;
54.5%) were defined as moderate. Twenty-six pa-
tients (16.5%) formed the severe group (table I).
Seventy-one patients received outpatient treat-
ment only during the observed time period, while
33 patients received inpatient treatment only and
54 patients received both types of treatment.
Table I. Demographics and clinical variables (n = 158)
Variable n (%)
Age
0–6 years 27 (17)
7–18 years 37 (23)
>18 years 94 (60)
Sex
Female 82 (52)
Male 76 (48)
Diagnosis-related severity level
1 = mild (no Pseudomonas aeruginosa) 46 (29)
2 = moderate (P. aeruginosa) 86 (54.5)
3 = severe (pulmonary hypertension and global 26 (16.5)
respiratory insufficiency)
Treatment
Outpatient 71 (45)
Inpatient 33 (21)
Inpatient and outpatient 54 (34)
Patients being treated as inpatients only received
drugs from outpatient pharmacies as well, which
were prescribed by the hospital when patients
were discharged from hospital. Patients classified
as mild according to the diagnosis-related sever-
ity index were mainly treated in the outpatient
unit only. Almost half of the patients classified as
moderate were admitted to the inpatient unit and
also visited the outpatient unit, whereas almost
half of those patients classified as severe were
treated as inpatients only (table II).
The mean total cost per patient per year was
h41 468 (year 2004 values). Direct medical costs
(inpatient and outpatient care including outpatient
drugs) averaged h38 869 per patient per year and
accounted for 94% of total costs. Direct medical
costs ranged from h3876 among mild patients to
h88 096 among patients with severe disease. The
largest single cost factor were drug costs (76% of
total costs), which is due to the high costs for drugs
patients received at the outpatient pharmacy
(72% of total costs). Overhead costs accounted
for 14% of total costs, while staff costs for patient
care and laboratory costs were rather low (2% of
total costs). Direct non-medical costs (i.e. travel
expenses) were marginal (<1% of total costs).
Indirect costs accounted for 6% of total costs and
amounted to h2491 (table III).

Adis ª 2012 Springer International Publishing AG. All rights reserved. Pharmacoeconomics 2012; 30 (9)
770 Heimeshoff et al.

Table II. Number of patients who received outpatient treatment only, inpatient and outpatient treatment, or inpatient treatment only in the
different severity groups [n (%)]a
Treatment Mild [n = 46] Moderate [n = 86] Severe [n = 26]
Outpatient only [n = 71] 36 (78) 27 (31.5) 8 (31)
Inpatient and outpatient [n = 54] 8 (17.5) 39 (45.5) 7 (27)
Inpatient only [n = 33] 2 (4.5) 20 (23) 11 (42)
a The table shows the treatment of patients in different severity groups: mild patients were mostly treated as outpatients only (78% of all mild
patients); almost half of the moderate patients were treated as inpatients and outpatients (45.5% of all moderate patients); and almost half
of the severe patients were treated as inpatients only (42% of all severe patients).

The most expensive drugs (according to the
product of consumption and price) for the outpa-
tient treatment are shown in table IV. Antibiotics
such as tobramycin, dornase alfa and colistin were
identified as the drugs with the highest resource
utilization. As the consumption of these drugs rises
with the degree of severity, drug costs for outpatient
care increase with the progression of the disease.
Analyses of Variance
The classification of patients according to the
diagnosis-related severity model revealed that
costs rose with the degree of severity. The relative
cost increase compared with the relatively milder
group was the highest between patients infected
with P. aeruginosa (moderate patients) compared
with patients without infection (mild patients)
and all cost categories rose with the degree of
severity (table V). The Wilcoxon-Mann-Whitney
tests revealed that all cost categories for mild
patients differed significantly (p £ 0.001) from
those of moderate patients. Patients with mod-
erate disease had significantly lower total direct
and drug costs than patients with severe disease,
but laboratory costs and staff costs were not
statistically different.
Generalized Least Squares Regression
The results of the regression analysis are pre-
sented in table VI. In a multiple regression with

Table III. Costs and cost variation for different cost categories (h, year 2004 values) [n = 158]a
Cost categoriesb Mean Median Minimum Maximum SDc
d
Drug costs 31 667 37 782 854 72 291 15 120
Laboratory costs 731 355 26 5231 852
Staff costs for patient care 696 404 30 4113 739
Overhead costs 5775 4263 1103 26 205 4352
Direct medical costs 38 869 42 262 3876 88 096 18 943
Direct non-medical costs 108 97 15 455 80
Total direct costs 38 977 42 287 3940 88 175 18 939
Indirect costse 2491 NA NA NA NA
Total costs 41 468 NA NA NA NA
a Detailed costing data from our hospital were used.
b Drug costs, laboratory costs, staff costs for patient care and overhead costs were summarized as direct medical costs. Total costs were
calculated as the sum of direct medical costs, direct non-medical costs (i.e. travel expenses) and indirect costs (costs of absence from work
and productivity losses due to CF).
c SD indicates the variability of costs.
d For the calculation of drug costs, purchasing prices were taken from the list with official selling prices that applied to all pharmacies in
Germany.[23]
e Only the average is available for indirect costs. For the calculation of indirect costs, data from the CF patient registry provided by the
Mukoviszidose e.V.,[8] data from the Federal Statistical Office of Germany[26] and data from the Mukoviszidose e.V. (unpublished data,
2007) were used.
CF = cystic fibrosis; e.V. = eingetragener Verein; NA = not available; SD = standard deviation.

Adis ª 2012 Springer International Publishing AG. All rights reserved. Pharmacoeconomics 2012; 30 (9)
Cost of Illness of Cystic Fibrosis 771

Table IV. Drug costsa according to severity level (h, year 2004 values) [mean – standard deviation]
Drug (trade name)b Diagnosis-related severity level (n = 72)
Mild (n = 38) Moderate (n = 21) Severe (n = 13)
Tobramycin (Tobi) 1307 – 5252 9146 – 12 864 13 754 – 17 090
Dornase alfa (Pulmozyme) 4470 – 5513 6528 – 5789 9887 – 6943
Colistin (Colistin CF) 2340 – 4227 5631 – 8330
Itraconazole (Sempera) 230 – 941 333 – 743 2123 – 2968
Pancreatin (Kreon) 396 – 724 1160 – 1005 2318 – 1798
Azithromycin (Zithromax) 33 – 148 684 – 621 710 – 612
Salmeterol, fluticasone (Viani) 255 – 514 476 – 525 413 – 572
Ciprofloxacin (Ciprobay) 54 – 209 442 – 694 304 – 375
Pantoprazole (Pantozol) 12 – 75 208 – 339 568 – 2047
Tobramycin (Gernebcin) 164 – 1012 511 – 1728 526 – 1627
a For the calculation of drug costs, purchasing prices were taken from the list with official selling prices that applied to all pharmacies in
Germany.[23]
b The use of trade names is for product identification purposes only and does not imply endorsement. The manufacturers are as follows:
Tobi, Chiron; Gernebcin, Infectopharm; Pulmozyme, Genentech; Colistin CF, Grünenthal; Sempera, Janssen-Cilag; Zithromax,
Pfizer; Viani, GlaxoSmithKline; Ciprobay, Bayer; Pantozol, Altana Pharma Deutschland; and Kreon, Solvay Arzneimittel GmbH.
CF = cystic fibrosis.

age, sex, diagnosis-related severity levels (with
mild patients as the reference) and FEV1 as in-
dependent variables and total direct costs per pa-
tient as the dependent variable (regression 1), the
diagnosis-related severity coefficients for moder-
ate and severe patients (patients with P. aeruginosa
and patients with pulmonary hypertension and
global respiratory insufficiency), as well as FEV1,
were highly significant (p £ 0.01). Furthermore,
the coefficients rose with the degree of severity,
while the increase compared with the relatively
milder group was higher for the coefficient for
moderate patients. Age and sex were not signifi-
cant. The result of the regression with FEV1 ex-
cluded from the analysis (regression 2) was almost
the same, but the coefficients indicating the rela-
tive increase in costs for moderate and severe
patients compared with the costs for mild patients
rose even more and the coefficient for age was
positive and significant. For the regression with
FEV1, age and sex as dependent variables (re-
gression 3), FEV1 was negative and highly signifi-
cant as well. In order to show the effects of drug
costs, which accounted on average for 76% of total
costs, two more models were tested, one with drug
costs per patient (regressions 4–6) and the other
with remaining costs per patient (regression 7–9)
as the dependent variables. For drug costs (regres-
sions 4–6), the results were comparable with those
of the regressions with total direct costs as the
dependent variable (regressions 1–3): sex had al-
most no influence and age was highly significant
for the regression with FEV1 excluded (regression 5),
whereas FEV1 was negative and highly significant in

Table V. Results of variance analyses for diagnosis-related severity levels (h, year 2004 values) [mean – standard deviation]a
Cost categories Diagnosis-related severity level (n = 158)
Mild (n = 23) Moderate (n = 83) Severe (n = 25)
Total direct costs 16 721 – 7169 46 087 – 13 076 54 804 – 15 109
Drug costs 13 032 – 6590 37 257 – 9042 46 146 – 10 725
Laboratory costs 157 – 143 879 – 858 1256 – 1026
Staff costs for patient care 238 – 156 849 – 773 1118 – 956
a All cost categories of mild patients differ significantly (p < 0.001) from those of moderate patients. Total direct costs and drug costs of
moderate patients differ significantly (p < 0.001) from those of severe patients, while laboratory costs and staff costs of moderate patients
were not statistically different from those of severe patients.

Adis ª 2012 Springer International Publishing AG. All rights reserved. Pharmacoeconomics 2012; 30 (9)
772 Heimeshoff et al.

Table VI. Results of generalized least squares regressions.a Values in parentheses are z-values
Dependent variable
Total direct costs/patient Drug costs/patient Remaining direct costs/patient
Reg. 1 Reg. 2 Reg. 3 Reg. 4 Reg. 5 Reg. 6 Reg. 7 Reg. 8 Reg. 9
N 134 157 134 134 157 134 134 157 134
Constantb 10.43** 9.72** 11.22** 10.10** 9.46** 11.00** 9.33** 8.24** 9.71**
(73.64) (98.71) (71.39) (76.94) (93.66) (71.26) (28.54) (42.02) (34.30)
Age -0.00 0.00 0.00 -0.00 0.01 0.00 -0.01 0.00 -0.00
(-1.57) (2.24)* (0.19) (-1.34) (2.80)** (0.26) (-0.94) (0.06) (-0.01)
Sex 0.00 -0.05 0.07 -0.01 -0.06 0.06 0.06 -0.04 0.11
(0.92) (-1.02) (1.07) (-0.18) (-1.06) (0.96) (0.54) (-0.04) (1.02)
FEV1 (%) -0.01** -0.01** -0.01** -0.01** -0.02** -0.02**
(-5.08) (-8.55) (-3.92) (-7.93) (-5.19) (-6.83)
Diagnosis-related severity level
Mildc 0.00 0.00 0.00 0.00 0.00 0.00
Moderate 0.79** 0.94** 0.81** 0.95** 0.66** 0.89**
(11.81) (13.28) (13.08) (13.35) (4.14) (5.96)
Severe 0.83** 1.11** 0.93** 1.16** 0.28 0.87**
(8.60) (12.26) (10.10) (12.73) (1.20) (4.58)
a The coefficients are the results of a GLS model using Gamma regression with log-link function. Regressions 1–3, as well as 4–6 and 7–9,
differ regarding the independent variables included.
b Where the regression line intercepts the y-axis, representing the amount the dependent variable ‘y’ will be when all independent variables are 0.
c The reference category is mild.
FEV1 = forced expiratory volume in 1 second; GLS = generalized least squares; Reg. = regression; * p < 0.05, ** p < 0.01.

all regressions. The coefficients indicating the rel-
ative cost increase rose with the degree of severity
as well and were higher than those of the regres-
sion with total direct costs as a dependent variable.
For the model without drug costs (regressions
7–9), age and sex had a minor influence as well and
FEV1 was highly significant in all cases, but the
results for the coefficients indicating the relative
increase were different (regressions 7 and 8): the
coefficient for the moderate patients was positive
and higher than the one for severe patients in both
regressions and the diagnosis-related coefficient
for severe patients was not significant if FEV1 was
included (regression 7). With FEV1 excluded, both
coefficients, for moderate and severe patients,
were highly significant (regression 8).
Sensitivity Analysis
The results of Monte Carlo simulation are pre-
sented in figure 1. The figure shows the cumula-
tive distribution of the estimated yearly costs per
patient with CF for 10 000 iterations. The main
result was that total yearly costs per patient were
estimated to be lower than h37 300 with a prob-
ability of 90%. The minimum total yearly cost per
patient was estimated to be h30 104 and the
maximum h46 085. The mean distribution of total
costs per patient per year was h34 474 and thus
about h7000 lower than the calculated total costs
of our study population.
Discussion
In this study, the total averaged costs per pa-
tient with CF, including all direct medical and
non-medical costs as well as indirect costs, were
calculated on the basis of measured individual
resource utilization in Germany from a societal
perspective and the main cost drivers were iden-
tified. Furthermore, it was tested if patients
could be classified into different severity groups

Adis ª 2012 Springer International Publishing AG. All rights reserved. Pharmacoeconomics 2012; 30 (9)
Cost of Illness of Cystic Fibrosis 773

according to a diagnosis-related severity model, confirmed by the results of the regression ana-
and the influence of certain factors on different lysis. Furthermore, the impact of the CF severity
cost categories was investigated. Moreover, a sen- level on drug costs was higher than on total direct
sitivity analysis was performed. costs. Monte Carlo simulation showed that total
The main results of the study were the follow- yearly costs were lower than h37 300 with a prob-
ing: the mean total cost per patient per year was ability of 90%. Therefore, costs were overestimated
h41 468, with direct costs accounting for 94% of in this study, which was mainly due to the higher
total costs. Indirect costs amounted to h2491 per prevalence of P. aeruginosa in our study pop-
patient per year and thus accounted for a rather ulation. Seventy-one percent of our study pop-
low share of total costs. If we had used the friction- ulation was infected with P. aeruginosa compared
cost method, which is preferred by some health with only 51% of all CF patients in Germany.[8]
economists, indirect costs would have most likely As mentioned earlier, the costs calculated in
been even lower.[30] Drug costs for prescribed this study are difficult to compare with those cal-
drugs from the outpatient pharmacy were iden- culated in other studies because either the method
tified as the main cost driver, accounting for 72% or the costs included are different. However, there
of total costs and leading to higher outpatient are a few studies measuring individual resource
costs than inpatient costs. The relative cost in- use and focusing on costs of CF in Germany.[9,10,17]
crease was highest for patients infected with Eidt-Koch et al.[17] analysed outpatient and drug
P. aeruginosa compared with the relatively milder costs from an economic perspective and took the
group (patients without P. aeruginosa), which was burden (time and money) for patients into ac-
count. Their results for average yearly drug costs
90.4% 9.6% per patient (h21 604) were different from the drug
⎧
⎪
⎪
⎪
⎨
⎪
⎪
⎪
⎩
⎧
⎪
⎪
⎪
⎪
⎪
⎪
⎨
⎪
⎪
⎪
⎪
⎪
⎩

1 costs for outpatients in our study (h29 664).

30 100 37 300
These differences might be due to different study
0.8
settings and study designs. Eidt-Koch et al.[17]
Share of patients

calculated costs based on data that were collected

0.6
0.4
0.2
0
30 32 34 36 38 40 42 44 46
Yearly costs per patient ( × 1000)
Fig. 1. Cumulative distribution of yearly costs per patient. The as-
sumptions of the Monte Carlo simulation were as follows: the relative
number of patients in a severity group can vary about 20%; drug
costs for inpatient treatment, laboratory costs, overhead costs
(summarized as material costs) and staff costs for patient care vary
due to differences in the ownership status and size of the hospital;
and drug costs for outpatient treatment and indirect costs are fixed.
For every iteration of the Monte Carlo simulation, we randomly drew
the number of patients not infected and infected with Pseudomonas
aeruginosa, as well as the staff costs of patient care and the material
costs, and we calculated the sum of the relative number of patients
not infected with P. aeruginosa multiplied by the costs of patients not
infected and the relative number of patients infected with P. aeruginosa
multiplied by the costs of patients infected and supplemented these
with travel expenses and indirect costs. The yearly costs per pa-
tient with cystic fibrosis in Germany were estimated 10 000 times.
The figure shows the share of patients with lower costs than the
respective value of the x-axis. Ninety percent of all estimates showed
costs lower than h37 300.
over a 4-week period in different CF treatment
units and micro-costing was not performed in
such detail as in our study.
Schreyögg et al.[10] measured hospitalization
costs of CF per case from a healthcare provider’s
perspective. The present study and that of Schreyögg
48 et al.[10] were based on the same data and should
thus have led to the same results for hospitaliza-
tion costs; however, Schreyögg et al.[10] calculated
costs per case and not per patient, thus results are
difficult to compare. Furthermore, Baumann et al.[9]
calculated direct costs for inpatient and outpa-
tient treatment and for drugs patients received
from the pharmacy from a payer perspective. They
found that costs per patient per year amounted to
h23 989. The lower costs compared with our study,
even after sensitivity analyses were performed,
may be due to costs being calculated using reim-
bursement rates. There is evidence that inpatients,
particularly those treated with costly drugs, are un-
derpaid in the current German diagnosis-related
groups (G-DRG) system due to the compression

Adis ª 2012 Springer International Publishing AG. All rights reserved. Pharmacoeconomics 2012; 30 (9)
774
effect that typically occurs in early stages of
newly introduced DRG systems.[31] This effect is
due to the possibly inaccurate assignment of costs
to different DRGs by the participating calcula-
tion hospitals. Cost calculations might be based
on length of stay, as more accurate measures are
often missing at the time the new reimbursement
system is introduced. This leads to an under-
estimation of costs of cases with high drug costs
or expensive technologies but a relatively short
length of stay.
The result of high outpatient drug costs was
confirmed by Baumann et al.,[9] who found home
drug treatment to be the most important single
cost factor. This may be explained by different
regulations for inpatient and outpatient drugs in
Germany. Prices for inpatient drugs can be ne-
gotiated freely between hospitals and manufac-
turers, while there are fixed margins for outpatient
pharmacies and wholesalers as well as uniform ex-
manufacturer prices throughout Germany for
drugs dispensed in outpatient care.
The share of drug costs in our study (76% of
total costs) is rather high compared with other
studies.[3,32,33] This difference may be explained
by a combination of different factors. First, other
studies from Germany also found higher shares
of drug costs than in non-German studies, point-
ing to structural differences in healthcare sys-
tems. Hence, Baumann et al.[9] found drug costs
for outpatient treatment to be 47% of all total costs.
As costs for outpatient treatment accounted for
59% of total costs in their study, drug costs for
outpatient treatment accounted for about 80% of
all outpatient treatment costs.[9] Moreover, Eidt-
Koch et al.[17] came to a similar result as they
found drug costs to be 91% of all outpatient treat-
ment costs. In general, several studies have shown
that Germany has higher drug prices than most
other countries.[34,35] Second, most other studies
relied on a gross-costing approach. As mentioned
in the Introduction section, micro-costing usually
leads to higher cost estimates than gross-costing
approaches.[19] Third, as most other studies used
the payer perspective, drug costs are likely to
be underestimated due to the compression ef-
fect occurring in reimbursement systems.[31] Fourth,
Krauth et al.[6] found earlier studies underestimated
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Heimeshoff et al.
actual drug costs, as cost-intensive therapies have
increased drug costs substantially in recent years.
This is in line with the findings of DeWitt et al.,[16]
who found costs of care for CF patients with mild
impairment in lung function to exceed $US43 000
and drug costs to account for more than 85% of
total costs. The authors argued that one reason
for their finding of relatively high costs may re-
flect the evolution of practice patterns over time
or variations in clinical practice between different
CF treatment centres.[16]
The finding that costs rise with progression of
the disease is also confirmed by previous studies.
Robson et al.[21] divided patients into four severity
levels according to frequency of hospitalization
and medical utilization. Their ratio of mild to
severe cases was much higher than in our study,
which may be due to different definition of the
four groups. Lieu et al.[32] classified patients into
three groups according to FEV1 values. Because
very mild and mild cases were grouped together
in their first group, their results are difficult to
compare with ours. Moreover, Eidt-Koch et al.[36]
divided patients into subgroups according to their
co-morbidities, infection status (bacterial coloni-
zation of the lung vs no colonization) and FEV1
values and found significant differences in out-
patient drug costs between the patient groups for
all criteria. Finally, the result that costs are higher
for patients suffering from a chronic infection
with P. aeruginosa is confirmed by Braccini et al.[37]
The authors compared the costs of treatment of
initial infection and chronic infection with P. aeru-
ginosa and found the latter to be considerably
higher.
A regression approach to explore the impact
of patients’ demographic and clinical variables
was conducted in five other studies. Johnson
et al.[11] ran an ordinary least squares (OLS) regres-
sion model including the variables age, sex, body
mass index (BMI), FEV1, the presence or absence
of P. aeruginosa, Burkholderia cepacia or other
organisms, and therapy of recombinant human
deoxyribonuclease (DNase) as independent vari-
ables and ‘Ln (annual costs)’ as the dependent
variable. The model explained 82% of the variance
of annual costs. Moreover, Baumann et al.[9] con-
structed a stepwise regression including colonization
Pharmacoeconomics 2012; 30 (9)
Cost of Illness of Cystic Fibrosis
status of the lung with P. aeruginosa and FEV1 as
dependent variables. The coefficient of determin-
ation was 0.64. Schreyögg et al.[10] investigated
the influence of the variables age, sex, BMI, FEV1
and diagnosis-related severity and explained 31%
of the variance of their dependent variable ‘Ln
(hospitalization costs per case)’. Ouyang et al.[12]
performed an OLS regression for patients with
CF who were stratified by age into three groups
and included gender and complication dummy
variables as independent variables. They found
various complications (e.g. malnutrition, trans-
plantation, diabetes and infection with P. aeru-
ginosa) to influence total expenditures. DeWitt
et al.[16] used a generalized linear model with a
Gamma error distribution and log link to detect
factors influencing total costs. Almost all studies
support our finding that the influence of demo-
graphic variables (age, sex, BMI) is rather small,
while clinical variables explain a larger part of the
cost variation.
Our study has a number of strengths compared
with previous approaches. To our knowledge,
this is the first study to measure total individual
costs of illness per patient with CF from a societal
perspective. Moreover, our approach is more
comprehensive than previous ones. Besides the
consideration of direct medical costs for 158 pa-
tients, direct non-medical costs (i.e. travel ex-
penses) and indirect costs (i.e. productivity losses
due to CF and costs of absence from work) were
taken into account. A further strength is that we
measured individual resource consumption for
relevant cost categories and thus followed a micro-
costing approach. Although previous studies
were also based on individual patient data, re-
source use was usually based on expert estimates
rather than on actual resource consumption. In
contrast, our study relied on data based on actual
resource consumption. Name and proportion of
drugs taken were registered for every patient and
multiplied by the relevant prices. This was very
important for the accuracy of the calculation be-
cause drug costs accounted on average for 76% of
total costs and there were large differences be-
tween the patients. Staff costs for patient care and
laboratory costs were also based on measured
resource consumption. In order to increase the
Adis ª 2012 Springer International Publishing AG. All rights reserved.
775
robustness of our findings and to be able to gen-
eralize the results to the societal perspective, a
sensitivity analysis using Monte Carlo simulation
was performed.
One limitation of the study is that data were
collected in only one hospital and that the Monte
Carlo simulation was the only method to generalize
our findings with regard to Germany. Similar to
other cost studies utilizing primary data, only a
comparatively small number of patients could be
included in the analysis. Despite our demonstra-
tion of results comparable with other studies, the
general validity of our results would increase if
data were also collected from other study sites.
Data for conducting cost-of-illness studies should
ideally be obtained from a large number of
patients at several hospitals. Moreover, although
we performed a Monte Carlo simulation, un-
certainty regarding drug costs for inpatient care
remains. We only have information on drug pri-
ces for our study hospital and do not have in-
formation on drug prices for other hospitals with
specialized centres for CF. Finally, changes in
treatment patterns of CF patients since the study
year, especially a shift from inpatient therapy to
outpatient and home-based therapy, should be
considered when interpreting our results. It can
be expected that the trend towards outpatient
and home-based therapy may have reduced costs,
particularly for patients with low disease severity.
Finally, we could have included pancreas in-
sufficiency as a potential cost driver, which is
used as an additional indicator of severity in
clinical studies.[12] However, according to our
review of cost studies on CF, none of the studies
have identified a significant impact from pan-
creas insufficiency on costs in a multiple regres-
sion, which was confirmed in a recent study by
Ouyang et al.[12]
Conclusion
The share of indirect costs as a percentage of
total costs for CF was rather low at the time our
study was conducted. However, the relevance of
indirect costs is likely to increase in the future, as
life expectancy increases, which is likely to lead to
a rising work disability rate and thus increase
Pharmacoeconomics 2012; 30 (9)
776
indirect costs. Moreover, calculating individual
costs per patient is important because there are
great differences in individual resource utilization
(especially for drug costs), a result that was con-
firmed by previous studies. Hence, direct costs
rise with the degree of severity. Compared with
the relatively milder group, the largest increase
in costs was found for patients infected with
P. aeruginosa. Chronic infection with the bacter-
ium leads to an increase in drug costs, which were
identified as the main cost driver. Thus, substantial
savings could be achieved by decreasing the pre-
valence of patients chronically infected with
P. aeruginosa.
Acknowledgements
This work was planned and written by Mareike Heimeshoff,
Helge Hollmeyer, Jonas Schreyögg, Oliver Tiemann and
Doris Staab, and the final version was approved by all the
authors. There was no external funding for this study, and
none of the authors have any potential conflicts of interests
that are directly relevant to the content of this paper.
The conceptual work was mainly done by Jonas Schreyögg
and Oliver Tiemann. Doris Staab and Helge Hollmeyer were
responsible for the data collection process and provided all
medical information. Helge Hollmeyer calculated part of the
costs. Mareike Heimeshoff was responsible for the data ana-
lysis and for the preparation of a draft of the paper, which was
supported by Jonas Schreyögg and Oliver Tiemann. Results
were interpreted and written by all authors. The guarantor for
the overall content of this paper is Mareike Heimeshoff.
The authors would like to thank the Munich Center of
Health Sciences, based at Ludwig-Maximilians University of
Munich, for their support.
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Correspondence: Mrs Mareike Heimeshoff, Institute for
Health Care Management and Health Economics, Faculty
of Economics and Business Administration, University of
Hamburg, Esplanade 36, 20354 Hamburg, Germany.
E-mail: mareike.heimeshoff@wiso.uni-hamburg.de
Pharmacoeconomics 2012; 30 (9)