PharmacoEconomics

https://doi.org/10.1007/s40273-019-00872-8

ORIGINAL RESEARCH ARTICLE

Determinants of Orphan Drug Prices in Germany

Franziska Worm1 · Charalabos‑Markos Dintsios2 

© Springer Nature Switzerland AG 2020

Abstract
Background and Objective  Legislation introduced in 2011 in Germany has instituted an early benefit assessment of newly
licensed pharmaceuticals with a subsequent price negotiation. For orphan drugs (ODs) a special legal framework applies,
which accounts for the fact that ODs do not have to prove an added benefit over an appropriate comparative therapy previ-
ously determined by the decision maker. As, in addition, the content of negotiations between pharmaceutical companies and
the payer is confidential, the aim of this study was to identify factors influencing the negotiated prices of ODs.
Methods  Twelve hypotheses on factors influencing the negotiated OD price were derived based on the existing literature
and framework agreement between payers and pharmaceutical unions according to German social legislation. Univariate
analyses were applied to detect statistically significant correlations between annual therapeutic costs of ODs and the hypoth-
esized factors. Bivariate analyses were used to determine confounding factors. In addition, a multiple ordinary least squares
(OLS) regression with backward selection was conducted. Finally, sensitivity analyses assessed the robustness of the results.
Results  Thirty-five ODs were included in the analysis. The univariate analyses and subsequent sensitivity analyses validated
five of the 12 hypotheses formulated. Univariate analyses suggest a statistically significant association between the OD price
and the (i) therapeutic area; (ii) approval for pediatric care; (iii) treatment population size; (iv) cost of comparative therapies;
and (v) European prices. The OLS regression identified European prices as the variable with the strongest association with
the negotiated prices.
Conclusion  We show that German OD pricing is a multivariate phenomenon. However, due to interdependencies, these
results must be treated with caution.

1 Introduction the resulting need, the European Union (EU) introduced

Due to high development costs and low profitability, phar-
maceutical companies have traditionally refrained from
investing in diseases that affect only a small number of
patients [1]. Therefore, rare diseases were neglected or
‘orphaned’, leaving people suffering from these condi-
tions with limited treatment options [2]. In 2000, to address
Electronic supplementary material  The online version of this
article (https​://doi.org/10.1007/s4027​3-019-00872​-8) contains
supplementary material, which is available to authorized users.
* Charalabos‑Markos Dintsios
dintsios@hhu.de
Franziska Worm
franziska.worm@gmx.de
1 and the pharmaceutical company. For ODs a special legal
Health Economics, University Duisburg-Essen, Essen,
Germany
2 already been approved with the orphan designation granted
Institute for Health Services Research and Health Economics,
Medical Faculty, Heinrich-Heine-University Düsseldorf,
Building: 12.49, Moorenstr. 5, 40225 Düsseldorf, Germany
a regulation on orphan medicinal products [3]. However,
even though the budgetary impact of orphan drugs (ODs)
amounted to only 2.1% of the overall drug expenditure in
Germany in 2007 [4], debate regarding the affordability of
ODs emerged [5], predominantly based on the high prices
of ODs in comparison to non-ODs [6]. To control the gener-
ally increasing expenditure on patented pharmaceuticals [7],
Germany followed the example of other European countries
[8] and in 2011 introduced the Act on the Reform of the
Market for Medicinal Products (AMNOG).
Since the introduction of AMNOG, innovative pharma-
ceuticals now undergo an early benefit assessment (EBA).
The resulting appraisal by the Federal Joint Committee
(FJC) forms the basis of the subsequent price negotiations
regarding the new pharmaceutical between the National
Association of Statutory Health Insurance Funds (NA SHI)
framework comes into force as their added benefit has
by the European Medicines Agency (EMA) [9]. The FJC

Vol.:(0123456789)
 F. Worm, C.-M. Dintsios

benefit, if any, is rated on a subgroup level [11, 12] as one of

Key Points for Decision Makers  the four categories: non-quantifiable, minor, considerable,
Policy makers need to consider the criteria for pricing
and reimbursement decisions as well as costs per mem-
ber of the population insured in collectively financed
health schemes.
German orphan drug (OD) pricing is a multivariate
phenomenon. Univariate analyses suggest a statistically
significant association between the OD price and the
therapeutic area, approval for pediatric care, treatment
population size, cost of comparative therapies, and Euro-
pean prices.
As all variables found to be significantly associated with
the negotiated price were correspondingly related to the
European prices, the high correlation between the OD
price and European prices is traced back to the fact that
other European countries consider similar criteria for the
setting of OD prices.
decides the extent of the additional benefit in the absence of
a defined appropriate comparative therapy. For both ODs as
well as non-ODs, the AMNOG process takes 12 months in
total (Fig. 1). During this time, the pharmaceutical is distrib-
uted at a price freely set by the manufacturer. The manufac-
turer is obligated to submit a comprehensive dossier, which
contains information on their rating of the added benefit
according to the studies conducted. Prior to submission of
the dossier, the manufacturer is entitled to seek advice from
the decision-making body, the FJC [10]. The extent of added
and major. After the FJC’s decision, negotiations between
the manufacturer and the NA SHI commence. In case of a
negotiation failure, an official arbitration board will set the
final price within 3 months [13].
The special legal framework for ODs in the AMNOG
process is repealed if an OD exceeds a turnover limit of
€50 million Euros within 12 months of marketing. In this
case, an OD is reassessed with the same procedure as a non-
OD and a new price is negotiated. The content of price nego-
tiations in Germany is confidential. Therefore, the question
arises of which factors influence these price negotiations for
ODs after 8 years of AMNOG being in place?
2 Methods
2.1 Research‑Guiding Hypotheses
A scoping review generated research-guiding hypotheses.
Existing literature on the pricing and reimbursement of
pharmaceuticals, particularly ODs, generated one part of
the hypotheses. The other part was derived from literature
on negotiation techniques and the framework agreement
between NA SHI and pharmaceutical companies’ unions
[14].
The hypotheses and further analyses are structured in
four categories: the pharmaceutical manufacturer’s char-
acteristics, the OD’s characteristics, criteria for the price

Public hearing
Assessment by the
Advice of the Federal Joint
Federal Joint Commiee
Commiee
Orphan drug
Reimbursement price
Appraisal by negoaons (Naonal
Evidence Arbitraon
Manu- Dossier Federal Joint the Federal Associaon of
report in case of
facturer submission Commiee Joint Statutory Health
failure
Commiee Insurance Funds
& Manufacturer)
Non-orphan drug

Assessment by the
Instute for Quality
and Efficiency in
Health Care
Wrien comments

3 months 3 months 6 months 3 months

Fig. 1  General steps of the Act on the Reform of the Market for Medicinal Products (AMNOG) process
Determinants of Orphan Drug Prices in Germany
negotiation listed in the framework agreement, and further
characteristics.
2.1.1 The Pharmaceutical Manufacturer’s Characteristics
2.1.1.1  Hypothesis 1: The Manufacturer’s Origin as Declared
in  the  Dossier has  a  Negative Influence on  the  Negotiated
Price Unless It is Germany  According to Chang [15], nego-
tiation techniques vary with culture. The occurrence of
communication issues such as non-verbal expressions, role
interpretations, attitudes, and cognitive patterns might also
be concentrated on manufacturers of ODs as historically
these are small biotech companies that have expertise in rare
diseases [16] and have no national affiliates, in comparison
with ‘big pharma’ companies.
2.1.1.2  Hypothesis 2: The Manufacturer’s Experience Posi-
tively Influences the  Negotiated Price As the AMNOG
procedure has been in effect for 8 years, the question arises
of whether manufacturers can reach higher prices the more
experience they gain? The confidentiality of the price nego-
tiations makes it impossible for manufacturers to learn from
previously conducted negotiations in general. Lauenroth
and Stargardt [17], who analyzed factors influencing the
negotiated price of non-ODs, controlled for the number of
negotiations previously experienced by the manufacturer.
Moreover, not only the total experience but also experience
exclusively with the AMNOG process of ODs is assumed
to determine the negotiated price as manufacturers of ODs
are usually one-product manufacturers. Consequently, the
number of OD negotiations previously experienced is also
included in this analysis.
2.1.2 The Orphan Drug’s Characteristics
2.1.2.1  Hypothesis 3: The Therapeutic Area Influences
the  Negotiated Price in  an  Unknown Way  The therapeutic
area for which the OD is approved has already been noted
as a value-driving factor by Korchagina et  al. [1], Picavet
et al. [18], and Lauenroth and Stargardt [17]; thus, the exist-
ing literature is followed, and therapeutic area is included in
our analyses as it is assumed that certain therapeutic areas
reach a higher negotiated price. However, this influence is
thought to be caused by the underlying diseases and their
characteristics being cumulated into therapeutic areas. As
the inclusion of the diseases would cause extreme heteroge-
neity, which would not lead to reliable results, the therapeu-
tic area is instead used as a proxy.
2.1.2.2  Hypothesis 4: The Disease’s Severity has  a  Positive
Influence on the Negotiated Price  The hypothesis that the
severity of the disease has a positive influence on the negoti-
ated price is proposed because the value attributed to ODs
treating severe diseases is assumed to be higher than that
ascribed to ODs treating less severe diseases. That similar
value judgements exist is shown in the scoping review of
Paulden et  al. [19] who identified severity of the disease
as a value argument related to OD prices. To investigate
this influence, the manufacturer’s dossier for each OD was
skimmed for the terms ‘fatal’ or ‘deadly’.
2.1.2.3  Hypothesis 5: Approval for Pediatric Care has a Posi-
tive Influence on  the  Negotiated Price  Lately, discussions
on the need for a greater investment in clinical development
for children in Europe have arisen [20]. Because most of
the pharmaceuticals applied in the pediatric population have
not been studied or authorized for such use, the European
Commission launched the Pediatric Regulation in 2007 to
foster the development and accessibility of pharmaceuticals
in pediatric care [21]. The introduction of this regulation
shows the need for drugs approved for pediatric care. Con-
sequently, it is supposed that the value at which treatments
approved for the use in pediatric care are rated exceeds the
value of pharmaceuticals treating adults.
2.1.2.4  Hypothesis 6: The Population Size Targeted
has a Negative Influence on the Negotiated Price  The Euro-
pean Orphan Medicinal Product Regulation was introduced
in 2000 to incentivize the research and development of ODs
as they were neglected by pharmaceutical manufacturers
due to very low patient numbers and the related improb-
able return on investment [6]. In addition to the incentives
received by the granted orphan designation, manufacturers
need higher prices to compensate for the lower population
size in order to achieve a return on their investments [22].
Existing European studies found a significant inverse cor-
relation between the population size treated by the OD and
their prices [1, 6, 23, 24]. However, evidence is still needed
for ODs in Germany.
2.1.3 Criteria for the Price Negotiation Listed
in the Framework Agreement
The framework agreement [14] states criteria that should be
considered during price negotiations. The actual influence
of the criteria on the negotiated price is still unknown and
needs to be studied empirically.
2.1.3.1  Hypothesis 7: A  Quantifiable Added Benefit
Appraised by  the  Federal Joint Committee has  a  Positive
Influence on  the  Negotiated Price The hypothesis that
a quantifiable added benefit appraised by the FJC has a
positive influence on the negotiated price is based on sec-
tion 6 (1) of the framework agreement [14]. This influence
has also been assessed by Schlander et al. [23], who inves-
tigated determinants of non-oncological OD prices. Their

results did not indicate an association between the additional
benefit and the negotiated price [23]. In contrast, Lauenroth
and Stargardt [17] and Theidel and von der Schulenburg
[25] demonstrated a significant relationship for non-ODs.
2.1.3.2  Hypothesis 8: Comparable Therapies’ Annual Thera-
peutic Costs and Their Availability have a Positive Influence
on  the  Negotiated Price  Michel and Toumi [22] assumed
that ODs that are the first treatment in their indication bene-
fit from higher prices than ODs with comparative therapies.
The hypothesis that the availability of comparative therapies
influences OD prices has also been statistically proven by
both Korchagina et al. [1] and Picavet et al. [18]. However,
for Germany, the availability of comparative therapies has
not been found to be correlated with the negotiated OD price
[23]. Going beyond the existing literature, this paper addi-
tionally aims to investigate the influence of the comparative
therapies’ annual therapeutic costs (AnTCs), if available, on
the negotiated OD price as this is one of the criteria for the
price negotiation listed in the framework agreement [14].
2.1.3.3  Hypothesis 9: Orphan Drug Prices in  Other Euro-
pean Countries have a  Positive Influence on  the  Negoti-
ated Price  In preparation for the price negotiations, the
pharmaceutical’s manufacturer is obligated to submit
information on the price of the pharmaceutical in other
European countries in which it is already distributed [14].
By including the European price as a criterion for the
price negotiations, the negotiating parties can investigate
the value judgement of other countries and obtain a refer-
ence value.
2.1.4 Further Characteristics
2.1.4.1  Hypothesis 10: Anticipation of  a  Renegotiation
Influences the  Negotiated Price in  an  Unknown Way The
AMNOG process comprises different factors leading to a
reassessment of the pharmaceutical’s added benefit by the
FJC and to subsequent renegotiations. Two of those are con-
sidered to influence the negotiated price of an OD: an excess
of the €50 million turnover limit within 12 months of mar-
keting; and a temporal limitation of the FJC decision, at the
expiry of which the manufacturer is obliged to submit real-
world evidence [26]. At the time of the price negotiations,
the OD will have been marketed for 6 months and both par-
ties are able to get an impression of the respective distribu-
tion figures. A change in the negotiation technique due to
an upcoming renegotiation seems plausible, as the temporal
duration of the negotiated price is limited. Since the NA
SHI needs a low price to start the renegotiation with and
the manufacturer needs a high price until renegotiation, the
pressure of negotiations for both parties increases, which is
F. Worm, C.-M. Dintsios
considered to result in a notable price difference between
ODs with and without a temporal limitation [26].
2.1.4.2  Hypothesis 11: Actual and Anticipated Uptake have
a  Negative Influence on  the  Negotiated Price The patient
population reached in reality is usually lower than the SHI
target population size considered in the EBA [27]. Conse-
quently, Cassel and Ulrich [27] advise that a distinction be
made between the epidemiology and market potential as
only the latter is regarded as important for price negotia-
tions. The actual market uptake 6, or at most 9, months after
launch of the OD can be considered during the price nego-
tiations. Any subsequent evolving market potential has to be
anticipated based on the observable actual uptake.
2.1.4.3  Hypothesis 12: The Budgetary Impact has  a  Nega-
tive Influence on the Negotiated Price  In 2016 the budget-
ary impact of ODs on the German SHI amounted to 3.7%
of the overall drug expenditure on outpatient care [28].
However, the budgetary impact of individual ODs varies.
We consider this variability of the OD budgetary impact to
be relevant to the price negotiations since the NA SHI has
an incentive to keep the impact as low as possible. At the
same time, the pharmaceutical manufacturers’ probability
of return on investment is higher the higher the associated
budgetary impact.
2.2 Data Extraction
All ODs that had completed price negotiations up to the end
of January 2018 were identified from the website of the FJC.
The underlying dataset does not contain ODs for which the
arbitration board set the price. The outcome variable is the
AnTCs per patient post negotiations. The AnTCs define the
average therapy costs incurred by treating a patient over the
course of a year. They were used as different package sizes,
durations of treatments, and dosages make a comparison of
the individual negotiated package prices inaccurate.
Whenever a dosage range due to different age groups or
indications led to an annual consumption range, the average
was used for further calculations. For the negotiated prices,
the pharmacies’ sale price (PSP) was considered to calculate
the AnTC. For factor IX preparations predominantly distrib-
uted directly to specialist centers, the manufacturer’s sale
price (MSP) plus value-added tax (VAT) was used instead.
If multiple package sizes existed, consistent with the FJC,
the cheapest per unit was chosen. For combination therapies,
only the AnTCs of the evaluated ODs were calculated to
ensure that the outcome variable is free of confounders as
only the price of the innovative pharmaceutical is negotiated.
The previously derived research-guiding hypotheses lead
to one or more variables with a potential influence on the
price of ODs. Table 1 includes the explanatory variables,
Determinants of Orphan Drug Prices in Germany
their distributions, as well as the sources they were gathered
from.
To find out if the OD is not exposed to any competition
in its authorized label, meeting an unmet need, the clini-
cal practice guidelines of each indication were scanned for
comparative therapies that were available at market entry of
the applicable OD. If no clinical practice guidelines were
traceable, information from the pharmaceutical manufac-
turer regarding comparative therapies in the second module
of the dossier was browsed and an internet search was car-
ried out. In cases in which the OD was reassessed in a non-
orphan EBA, the appropriate comparative therapies defined
by the FJC were also documented.
Treatment costs for non-drug comparable therapies were
calculated according to the German inpatient remuneration
system. Calculations of the average annual treatment costs
of comparable therapies were weighted by their use (Elec-
tronic Supplementary Material: Supplement Calculation of
AnTC of Comparable Therapies). Whenever several applica-
tion areas were assessed for one OD, the uptake-weighted
AnTCs of each therapeutic area according to the described
approach were calculated (Electronic Supplementary Mate-
rial Table 1).
To obtain an estimation of the EU reference prices, a
pool of countries from within the defined countries in the
framework agreement between NA SHI and pharmaceutical
companies’ unions [14] in which the pharmaceuticals were
marketed prior to or during the German price negotiations
had to be assumed as this information is unavailable. To
do so, documentation from a large pharmaceutical com-
pany’s three most recent price negotiations in accordance
with AMNOG were analyzed. The market entry sequencing
decisions of pharmaceutical manufacturers is expected to
mostly be based on the countries’ market regulations, size,
and expected market sales as well as their impact on interna-
tional reference pricing and, therefore, vary only slightly. All
countries with available prices for each pharmaceutical were
listed and those named in all three most recent price negotia-
tions were extracted. The resulting country pool consisted
of Denmark, Finland, France, the UK, Austria, Sweden,
and Italy. Since Germany might itself be a reference price
country for these countries, a self-referencing bias should be
avoided. However, using the list prices of the European ref-
erence countries is not a risk for circular reasoning regard-
ing the negotiated German price. Although German prices
are part of the country-specific price baskets, the negotiated
German prices are only valid after 12 months and the launch
prices are not used within these country-specific baskets.
All available list prices were purchase power corrected with
Germany as the price index. Subsequently, the result was
weighted by the population share of the country in relation
to the total population across all countries of the previously
defined pool (Electronic Supplementary Material Table 2).
The calculation of the actual and anticipated uptake of the
ODs is specified in the Electronic Supplementary Mate-
rial (Supplement Calculation of the Actual and Anticipated
Uptake of the ODs).
Finally, to compare the market uptake between ODs,
a function of each OD’s proportional market uptake was
estimated using the plotting software Graph version 4.4.2
(https​://www.padow​an.dk/). As at the time of price negotia-
tions both parties do not know the uptake of the OD after
9 months, this proportional market uptake was called the
‘anticipated uptake’ (Electronic Supplementary Material
Tables 3 and 4). To allow for better interpretability, we pre-
sented the budgetary impact results as mean values. For all
other skewed data, median values were primarily reported.
2.3 Statistical Analyses
To test the hypotheses, first, a descriptive analysis for each
variable in the dataset is applied. Following the descrip-
tive analysis, a log-transformation is used to address skewed
data. Univariate analyses are conducted to assess the correla-
tion between the negotiated prices and the explanatory vari-
ables. Bivariate correlations between statistically significant
explanatory variables are then also calculated to identify
confounders.
For the univariate and subsequent bivariate analyses, sev-
eral tests are used depending on the variable’s characteristics
and distributions. For log-transformations, parametric tests
are applied. For data that are not transformed, but also not
assumed to be Normally distributed, non-parametric tests
are chosen. Since log-transformation might produce noise
[42], the original data are also kept and non-parametric tests
are applied to compare the obtained results with each other.
Consequently, the Chi-squared (χ2) test or Fisher’s exact test
in combination with the Phi-coefficient or Cramer’s V are
considered in cases in which both variables were nominal.
If both variables are continuous, scatter plots are depicted
and Spearman or Bravais-Pearson correlation coefficients
are calculated.
To check for the correlation between a nominal and
continuous variable, a Welch’s test, Student’s t test or
Mann–Whitney U test is applied, the point-biserial correla-
tion is determined, or the continuous variable is classified
to calculate Cramer’s V. The χ2 test or Fisher’s exact test
in combination with Cramer’s V is considered if a nomi-
nal ordinal combination exists. To check for the correlation
between an ordinal variable and a continuous variable, a
scatter plot is considered.
In addition to the scatter plot, and depending on the vari-
able’s distribution, a post hoc pair-wise comparison, analysis
of variance, or Kruskal–Wallis H test is conducted to check
for a significant difference between the means of the ordinal
variables’ groups. If significant, this test is followed by a
 F. Worm, C.-M. Dintsios

Table 1  Explanatory variables, distributions, and sources

Variable Distribution Source

Manufacturer’s origin Manufacturer dossier, module 1 [29]

{
Dichotomized: x = 1, x = Germany
0, x ≠ Germany
Manufacturer’s experience Continuous FJC website [29]
Therapeutic area Categorical FJC website [29]
Severity of the disease Manufacturer dossier, module 2 [29]
{
Dichotomized: x = 1, x = fatal/deadly
0, x ≠ non fatal/deadly
Approval for pediatric care FJC appraisal [29]
{
1, x = approved
Categorical, dichotomized: x =
0, x ≠ not approved
SHI target population size Continuous FJC appraisal [29]
Prevalence Continuous Orphanet [30], EMA assessment report [31]
Ultra-orphan status Calculations based on the prevalence data
{
Dichotomized: x = 1, x = yes
0, x ≠ no

Additional benefit extent FJC appraisal [29]

{
1, x = quantifiable
Categorical, dichotomized: x =
0, x ≠ not quantifiable

Absolute soloist Applicable practice guidelines

{
Dichotomized: x = 1, x = yes
0, x ≠ no

Comparable therapies’ AnTC Continuous Applicable practice guidelines, FJC website

[29], German Drug Directory (Lauer ­Taxe®)
[32], INSIGHT Health data base, Engelhardt
et al. (2014)a [33], Adam et al. [34], flat rate
catalogs, federal base rates

European prices (AnTC) Continuous DK: Danish Medicines Agency [35]

FI: Kela Medicinal products database [36]
FR: L’assurance maladie en ligne. Base des
Médicaments et Informations Tarifaires [37]
UK: British National Formulary [38]
AT: Hauptverband der österreichi-schen Sozial-
versicherungsträger. Erstattungskodex [39]
SE: Dental and Pharmaceutical Benefits Agency.
Databas läkemedel [40]
IT: Federazione nazionale unitaria titolari di
farmacia. Cerca un farmaco [41]
Temporal limitation of the deci- FJC website [29]
{
1, x = yes
sion Dichotomized: x = 0, x ≠ no

Excess of the €50 million turno- FJC website [29]

{
Dichotomized: x = 1, x = yes
ver limit 0, x ≠ no

Actual and anticipated uptake Continuous INSIGHT Health data base, SHI target popula-
(t6, t9, t12, t18, t24) tion size

Budgetary impact (t6, t9) Continuous German Drug Directory (Lauer ­Taxe®) [32]
FJC appraisal [29]

AnTC annual therapeutic cost, AT Austria, DK Denmark, EMA European Medicines Agency, FI Finland, FJC Federal Joint Committee, FR
France, IT Italy, SE Sweden, SHI Statutory Health Insurance
a
 Insight Health GmbH & Co. KG is a neutral service provider that extracts prescription information from different databases [33]
Determinants of Orphan Drug Prices in Germany
post hoc multiple comparison test, the Dunn’s test, which
shows which group is responsible for the identified differ-
ence. Subsequently, Spearman’s rank correlation analysis is
applied to indicate the relationship between the most domi-
nant group and the continuous variable. The sizes of the
correlation coefficients are interpreted in accordance with
the classifications of Cohen [43].
Furthermore, a multiple ordinary least squares (OLS)
regression analysis of the variables suggesting a strong cor-
relation is applied. Backward selection by p value with a
stopping rule at a p value of 0.05 is thought to identify the
best explanatory variables for the negotiated price. To deter-
mine the model fit, the Akaike Information Criterion (AIC)
is used. Since we used the procedure only for an exploratory
model specification to identify potential significant explan-
atory variables, we abstained from a split-sample design,
which would be proper for the identification of predictors.
2.4 Sensitivity Analyses
The sensitivity of the approach is tested in several ways
using univariate analysis with different datasets. First, OD
price outliers are removed from the dataset, as some of the
applied statistical analyses are sensitive to outliers. Sub-
sequently, univariate analyses of the factors that initially
showed a correlation are repeated. As a second robustness
check, the upper and lower bounds of the SHI target popu-
lation size and the European prices are considered instead
of the average values accounted for in the initial analyses.
Additionally, the European prices are replaced by the OD
prices in Denmark in all statistical analyses of interest. The
reason for doing this is that the website of the Danish Medi-
cines Agency [35] provides a history of drug prices from
1998, which allows us to access the OD prices at the time of
the FJC appraisal and thus reduces possible variance due to
price changes over time. If the sensitivity analyses show a
robustness of the univariate outcomes, bivariate and multiple
OLS analyses outcomes are regarded as equally robust.
3 Results
In total, price negotiations were completed for 254 EBAs
by 31 January 2018; of these, a total of 58 involved ODs.
Twenty-three of the EBAs for ODs had to be excluded from
the following analyses. Fifteen EBAs were excluded due to
exceeding the €50 million turnover limit (three), expiration
of the FJC appraisal (two), and a label extension (ten). These
ODs had already undergone a negotiation and, therefore,
had a different negotiation basis than the other ODs, which
would bias the analyses. In six cases the negotiations failed
and the arbitration board had to set a price; two ODs opted
out. The resulting dataset, therefore, contains 35 ODs with
negotiated prices for analyses (Fig. 2).
3.1 Descriptive Analysis
A total of 28 manufacturers had submitted dossiers for these
35 active substances. Only six of the manufacturers are not
located, as declared in the dossier, in Germany; other manu-
facturers’ origins are France, Sweden, Switzerland, and the
UK. Seventeen manufacturers (48.57%) had no experience
with the AMNOG process at the time of their OD EBA.
However, two (5.71%) manufacturers had already experi-
enced 13 EBAs. Nevertheless, the 75th percentile shows that
three-quarters of the manufacturers had experienced at most
three EBAs prior to submitting the dossier of their OD.
When looking at the number of EBAs for a substance
with an orphan indication, 80% of the manufacturers had
no experience of EBAs before the AMNOG process of the
applicable OD. The remaining 20% had already experienced
up to five EBAs for an OD at the time of dossier submission.
Figure 3 shows that almost half of the ODs in the sample
(48.57%) are indicated for oncological diseases, followed by
22.86% indicated for metabolic diseases.
In five of the 35 manufacturers’ dossiers the disease is
described as fatal or deadly. Most of the ODs are approved
for an application in adults (77.14%), followed by the com-
bined group of children and adults (14.29%), solely children
(5.71%), and elderly people (2.86%).
With 18 patients, the average SHI target population size
of the active substance cholic acid is by far the lowest. The
largest average SHI target population size is 22,500 patients.
The median of the average SHI target population sizes is
830. The OD prevalence data vary between 0.25/100,000
and 39.00/100,000 people, with a median of 11.90/100,000
people. Of the 35 ODs, seven (20%) are ultra-ODs with
Fig. 2  Flowchart of the selection of the study sample. EBA early ben-
efit assessment

a prevalence of less than one in 50,000 people. The FJC
appraised 13 (37.14%) ODs with a quantifiable (three con-
siderable and ten minor) and 22 (62.86%) with a non-quanti-
fiable added benefit. Comparable therapies for 23 ODs were
identified. The median uptake-weighted average compara-
ble therapies’ AnTC is €59,931.04 (€7049.23–401,378.60).
The European prices were only available for 30 substances,
as some ODs in the dataset had not been priced in any of
the selected pool countries. Of these, the median AnTC is
€89,284.14 (€6436.60–2,522,956.00).
A total of 19 ODs have been or need to be renegotiated
due to a time limitation of the FJC appraisal (11), a label
extension (seven), or because they exceeded the €50 mil-
lion turnover limit (five). The gap in market uptake within
ODs rises with time. Six months after market entry, the
actual uptake across all 35 ODs ranged from zero patients to
1471 patients treated. After 9 months, the uptake increases
to 1663 patients (rise of 13%), although, again, some ODs
had not been utilized by any patient. Even after 2 years of
marketing, it is anticipated that some ODs will not treat any
patient, whereas one OD is estimated to be used by 1568
patients. The median uptake is 18 patients in t6, 33 in t9, 36
in t12, 37 in t18, and 41 in t24 (t = month). As the actual
uptake in t6 and t9 was used to calculate the OD budgetary
impact on the SHI, the variable also varies widely. The mean
budgetary impact after 6 and 9 months of marketing equals
€12,547,655.30 and €13,333,521.59, respectively.
The mean average negotiated AnTC per patient per year
is €217,693.70 (€7320.98–2,363,670.00). The largest and
Fig. 3  Therapeutic areas of
negotiated orphan drugs
49%
Blood and the blood-forming organs
Digestive system
Metabolic
Oncological
Respiratory system
F. Worm, C.-M. Dintsios
second largest values represent upwards outliers, as their
AnTCs are considerably higher than the others (Fig. 4).
The median average negotiated AnTC is €92,198.08. The
range of discounts between launch prices and negotiated
prices is high; however, the two upward outliers drive this
range. When excluded, the range between the AnTC is more
than halved and equals €467,713.70. The median discount
following the exclusion of outliers is then €17,032.31. Addi-
tionally, in general, higher launch prices, set by the pharma-
ceutical manufacturer at the market entry of the drug, also
result in higher negotiated prices. Table 2 summarizes the
descriptive statistics of the outcome variable and all explana-
tory variables.
Histograms, box plots and the summary statistics of the
average SHI target population size, prevalence, AnTC of
comparative therapies, budgetary impact, as well as the
negotiated AnTC suggest a right skewness of the data. Addi-
tionally, the Shapiro–Wilk test, which is recommended for
sample sizes smaller than 50 [44], is statistically significant
at a 95% level for all previously listed variables. Therefore,
the data are transformed by taking the logarithm. As a result,
parametric tests for the log-transformed variables and non-
parametric tests for the original data are applied. The histo-
gram, box plot, and summary statistics as well as the Sha-
piro–Wilk test also confirm that the actual and anticipated
uptake as well as the pharmaceutical manufacturers’ total
EBA experience and experience with OD indications in the
EBA is not Normally distributed. Nevertheless, due to a high
3% 3% 6%
6%
6%
3%
23%
3%
Therapeutic area
Cardiovascular
Infectious
Nervous system
Others
Determinants of Orphan Drug Prices in Germany
Fig. 4  Price comparison pre-
and post-negotiations. AnTC
annual therapeutic cost
number of zero values we do not transform this variable and
rather employ non-parametric tests.
3.2 Univariate Analyses
Collectively, Table 3 shows all variables found to be sig-
nificantly associated with the negotiated price. It is con-
cluded that the statistical analysis does not reject five of the
12 hypotheses proposed: the influence of the (i) therapeutic
area; (ii) approval for pediatric care; (iii) target population
size; (iv) AnTC of comparable therapies; and (v) European
prices on the price negotiated for ODs.
3.3 Bivariate Analyses
Table 4 depicts the resulting correlation matrix. In cases in
which continuous variables had to be categorized, the data
ranges were again observed and trichotomized. From Table 4
we can see that, except for two pairs (comparative therapies’
AnTC and approval for pediatric care; comparative thera-
pies’ AnTC and SHI target population size), all variables that
are statistically significantly (p < 0.05) associated with the
negotiated price are correspondingly related to each other.
3.4 Multiple Ordinary Least Squares Regression
Once confounders were identified using bivariate analyses,
a multiple OLS regression analysis with five of the seven
explanatory variables in Table 3 (only one population size
measurement) was applied. Since the SHI target population
size is a continuous variable with a consistent source, it is
chosen to be the representative variable for the different pop-
ulation size measurements in the following analysis. This
way, backward selection is started with the following explan-
atory variables: therapeutic area, approval for pediatric care,
SHI target population size, comparative therapies’ AnTC,
and European prices. Through backward selection, first the
therapeutic area, then the comparable therapies’ AnTC, the
SHI target population size, and finally the approval for pedi-
atric care were eliminated from the regression. The back-
ward selection identifies the European prices as the variable
most strongly associated with the negotiated price of an OD
(p < 0.05). If the European prices change by 1%, we would
expect the negotiated prices to change by 0.966%. The over-
view of the selection process shows that the AIC got smaller
with each selection step, indicating a better model fit with
each non-significant variable being removed (Table 5).
3.5 Sensitivity Analyses
To verify the results, several sensitivity analyses were con-
ducted in which univariate analysis with varying datasets
was repeated. For greater comparability with the results of
the initial univariate analyses, Electronic Supplementary
Material Table 5 lists all results of the sensitivity analyses.
In the first sensitivity analysis (column a), OD negotiated
prices outliers were identified (sebelipase alfa, asfotase alfa,
pitosant) and excluded. As a second robustness check, upper
(column b) and lower bounds (column c) of the negotiated
prices, the SHI target population size, and the European
prices instead of average values are considered. Subse-
quently (column d), European prices were replaced with
OD prices in Denmark as a price history allows the relevant
prices at the time of FJC appraisal in Germany to be cho-
sen. To check the sensitivity of the investigated correlation
between the weighted average AnTCs of the comparative
 F. Worm, C.-M. Dintsios

Table 2  Descriptive statistics of the outcome variable and all explanatory variables

Variable N Value (%) Minimum Maximum Median Mean

Outcome variable
 Reimbursement price (€) 35 7320.99 2,363,670.00 92,198.08 217,693.70
Explanatory variables
 Manufacturer’s origin (1 = Ger- 35 29 (82.86%)
many)
 Manufacturer’s experience (total) 35 0 (48.57%), 1 (5.71%), 2 (11.43%),
3 (5.71%), 4 (8.57%), 5 (8.57%), 7
(2.86%), 12 (2.86%), 13 (5.71%)
 Manufacturer’s experience (OD) 35 0 (80.00%), 1 (11.43%), 2 (2.86%), 3
(2.86%), 5 (2.86%)
 Therapeutic area 35 A (5.71%), B (5.71%), C (5.71%), D
(2.86%), E (22.86%), F (2.86%), G
(48.57%), H (2.86%), I (2.86%)
 Severity of the disease (1 = fatal/ 35 5 (14.29%)
deadly)
 Approval for pediatric care (1 = yes) 35 7 (20.00%)
 SHI target population size (N) 35 18 22,500 830 2564
 Prevalence (N/100,000) 35 0.25 39.00 11.90 13.78
 Ultra-orphan status (1 = yes) 35 7 (20.00%)
 Additional benefit extent 35 con (8.57%), min (28.57%), nq
(62.86%)
 Absolute soloist (1 = yes) 35 12 (34.29%)
 Comparable therapies’ ATC​ 23 7049.23 401,378.60 59,931.04 100,361.40
 European prices (ATC) 30 6436.60 2,522,956.00 89,284.14 233,191.80
 Temporal limitation of the decision 35 11 (31.43%)
(1 = yes)
 Temporal limitation of the decision 35 11 (31.43%)
(1 = yes)
 Excess of the €50 million turnover 35 5 (14.29%)
limit (1 = yes)
 Actual and anticipated uptake
  t6 35 0 1471 18 134
  t9 35 0 1663 33 162
  t12 35 0 1645 36 180
  t18 35 0 1303 37 201
  t24 35 0 1586 41 223
 Budgetary impact
  t6 35 0 128,139,166.55 2,843,912.10 11,218,905.41
  t9 35 13,748.64 133,746,953.98 4,918,772.19 13,333,521.59

ATC​Anatomical Therapeutic Chemical, OD orphan drug, SHI Statutory Health Insurance, t time in months
Therapeutic areas: A diseases of the blood and blood-forming organs, B cardiovascular diseases, c diseases of the digestive system, D infectious
diseases, E metabolic diseases, F diseases of the nervous system, G oncological diseases, H other diseases, I diseases of the respiratory system
Additional benefit extent: con considerable, min minor, nq non-quantifiable

therapies, the unweighted average of the comparative ther-
apies’ AnTCs are inserted into the analysis (column  e).
Finally, it was tested whether a change in the additional
benefit extent of ivacaftor from considerable (the highest
extent across all subgroups) to marginal (the lowest extent
across all subgroups) would impact the results (column f).
In summary, the results of the sensitivity analyses suggest a
robustness of all factors discovered in the previous sections
to be associated with the negotiated price (see Electronic
Supplementary Material Table 5).
Determinants of Orphan Drug Prices in Germany

Table 3  Variables statistically Variablea Correlation coefficient N Correlation (p value)

significantly associated with the
negotiated reimbursement price Therapeutic area Cramer’s V 35 0.745*** (0.000)
Approval for pediatric care Point-biserial 35 0.694*** (0.000)
SHI target population size Bravais-Pearson 35 − 0.521** (0.001)
Prevalence Bravais-Pearson 35 − 0.627*** (0.000)
Ultra-orphan status Point-biserial 35 0.688*** (0.000)
Comparative therapies’ ATC​ Bravais-Pearson 23 0.586** (0.003)
European prices (ATC) Bravais-Pearson 30 0.979*** (0.000)

ATC​Anatomical Therapeutic Chemical, SHI Statutory Health Insurance

*p < 0.05, **p < 0.01, ***p < 0.001
a
 The SHI target population size, prevalence, comparative therapies’ ATC, and European prices (ATC) are
log-transformed

Table 4  Correlation matrix
Thera- Approval for SHI target popu- Prevalence Ultra-orphan Comparable European prices
peutic pediatric care lation size status therapies’ ATC​ (ATC)
area

Therapeutic area 1 0.816*** (0.001) 0.631** (0.005) 0.558* (0.047) 0.816** (0.001) 0.723*** (0.000) 0.683* (0.002)
Approval for 1 − 0.450** − 0.706*** 0.821*** (0.000) 0.328 (0.127) 0.678*** (0.000)
pediatric care (0.007) (0.000)
SHI target popu- 1 0.444** (0.008) − 0.420* (0.012) − 0.184 (0.402) − 0.553** (0.001)
lation size
Prevalence 1 − 0.818*** − 0.497* (0.016) − 0.666***
(0.000) (0.000)
Ultra-orphan 1 0.486* (0.019) 0.690*** (0.000)
status
Comparative 1 0.656* (0.002)
therapies’ ATC​
European prices 1
(ATC)

The SHI target population size, prevalence, comparative therapies’ ATC, and European prices (ATC) are log-transformed. Cramer’s V, point-
biserial, Bravais-Pearson, and Spearman correlation coefficients used
ATC​Anatomical Therapeutic Chemical, SHI Statutory Health Insurance
*p < 0.05, **p < 0.01, ***p < 0.001

4 Discussion of a defined appropriate comparative therapy), a discount

Particularly against the background of only slowly increas-
ing prescription volumes but almost doubled OD turnovers
from 2011, the year of AMNOG commencement, to 2016
[45], determinants of OD prices within the AMNOG context
are of major interest. In Germany, pharmaceutical manufac-
turers freely determine the launch price of innovative phar-
maceuticals for the first 12 months of marketing. In compari-
son with other European countries with a health technology
assessment [22], this regulation guarantees patient access
simultaneously with the market authorization. However,
the freely set prices constitute the foundation of the price
negotiations on which, in the case of ODs (in the absence
is negotiated. Pharmaceutical manufacturers are, thus, able
to choose their own basis for the negotiations with the NA
SHI. This initial price setting is described in the literature
as ‘anchoring’ [46]. Accordingly, it represents the foremost
determinant of OD prices in Germany.
In our study, the total experience of the manufacturers
does not show a significant correlation with the negotiated
price. This outcome diverges from the result of Lauenroth
and Stargardt [17]. The fact that their study investigates non-
OD pharmaceuticals in Germany implies that, in contrast
to non-ODs, the manufacturer’s experience does not influ-
ence the negotiated price of ODs. This conclusion is sup-
ported by Picavet et al. [18], who observed a statistically
significant relationship between their measurement for the
 F. Worm, C.-M. Dintsios

Table 5  Ordinary least squares Independent variable Coefficient SE t statistic p Value adj R2 AIC
regression models with
transformed and untransformed (1) Log–Log reimbursement price model with 5 independent variables
independent variables
 Coefficient − 0.8105 2.0815 − 0.3894 0.7028 0.9178 10.6820
 Therapeutic area 0.0475 0.1339 0.3546 0.7282
 Pediatric indication 0.3250 0.1931 1.6830 0.1146
 Log SHI Target population 0.0412 0.0671 0.6135 0.5494
 Log comparable therapies’ ATC​ 0.0603 0.0949 0.6354 0.5354
 Log European prices 0.9778 0.1883 5.1920 0.0001***
(2) Log–Log reimbursement price model with 4 independent variables
 Coefficient − 0.3180 1.2226 − 0.2601 0.7983 0.9178 8.8902
 Pediatric indication 0.3498 0.1889 1.8520 0.0838
 Log SHI Target population 0.0603 0.0532 1.1340 0.2745
 Log comparable therapies’ ATC​ 0.0596 0.0946 0.6303 0.5380
 Log European prices 0.9346 0.1400 6.6840 0.0000***
(3) Log–Log reimbursement price model with 3 independent variables
 Coefficient 0.6957 0.5409 1.2860 0.2096 0.9558 4.0974
 Pediatric indication 0.1887 0.1415 1.3340 0.1939
 Log SHI target population 0.0191 0.0295 0.6486 0.5223
 Log European prices 0.9323 0.0380 24.560 0.0000***
(4) Log–Log reimbursement price model with 2 independent variables
 Coefficient 0.9692 0.3997 2.4250 0.0223** 0.9569 2.4626
 Pediatric indication 0.1807 0.1353 1.3550 0.1930
 Log European prices 0.9193 0.0360 25.570 0.0000***
(5) Log–Log reimbursement price model with 1 independent variable
 Coefficient 0.4837 0.2676 1.8070 0.0815* 0.9560 2.1765
 Log European prices 0.9655 0.0222 43.550 0.0000***

adj adjusted, AIC Akaike Information Criterion, SE standard error, SHI Statutory Health Insurance
*p < 0.1, **p < 0.05, ***p < 0.001

manufacturer’s experience and the negotiated OD price for
only one of the six European countries investigated.
The univariate analysis and sensitivity analysis determine
a strong relationship between the therapeutic area and the
negotiated price. This result corresponds with the finding of
Korchagina et al. [1], who identified a significant correlation
of the Anatomical Therapeutic Chemical (ATC) class with
the annual cost of ODs in France. Because the therapeutic
area is a proxy of the underlying disease treated by the OD, it
is concluded that the therapeutic area is a mediator variable
associated with all variables related to the treated condition
as well as to the price.
Hypothesis 4, which predicts a relationship between the
disease’s severity and the negotiated OD price, is the only
hypothesis related to the OD characteristics that was not
shown to be statistically significant. This is surprising as
several authors attribute a high relevance to the condition’s
severity for medical decision-making regarding ODs [19].
The data source used to define the severity of the disease
might be insufficient.
The extent of added benefit was not shown to signifi-
cantly affect the negotiated OD price, a result that proves
the analysis of Schlander et al. [23]. This result might be
linked to the special legal framework of ODs that guaran-
tees a proven additional benefit and gives the FJC exclusive
decision-making power over the extent of the added benefit.
Consequently, the FJC and SHI desire further development
of the AMNOG and call for an unrestricted EBA of ODs
for which comparative therapies are available. In 2014, a
rapid report by the Institute for Quality and Efficiency in
Health Care (Institut für Qualität und Wirtschaftlichkeit im
Gesundheitswesen; IQWiG) considered the possibility of an
unrestricted EBA for ODs. The report found that a conven-
tional assessment of ODs is, in general, possible. However,
compromises should be made with respect to the diseases’
rarity when considering the statistical validity. Such a com-
promise could be raising the customarily accepted p value
of 0.05 to a higher level [47].
The aim of several studies has been to verify an inverse
relationship between the patient population size treated
by the OD and the negotiated price. Firstly, Medic et al.
[6] studied the association between OD prices in several
European countries and ultra-orphan status by calculating
correlation coefficients. Six European countries showed a
Determinants of Orphan Drug Prices in Germany
significant association. However, a continuous measure of
the patient population size might be more relevant to assess
an association with OD prices. In our study, both continu-
ous measures of the treatment population size show a strong
inverse relationship with the negotiated OD prices. Three
studies support this result (Korchagina et al. [1], Onakpoya
et al. [24], and Schlander et al. [23]). The equally signifi-
cant results of these studies lead to the conclusion that OD
prices in any indication are higher the lower the number of
patients suffering from the condition. The multicollinearity
of the measurements for the population size again seems to
be moderated by the underlying therapeutic area. The size of
the prevalence’s correlation coefficient exceeds the correla-
tion coefficient of the SHI target population, which suggests
that during negotiations the prevalence of the disease has
a greater association than the SHI target population. One
explanation for this difference in the coefficients’ sizes might
be the uncertainty associated with the SHI target population
as well as the inconsistency of the calculation method [48].
Unexpectedly, the assumption of a significant correlation
between the availability of comparable therapies and the
negotiated price was not met. Existing literature considering
this question are equivocal [1, 18, 23]. The variation in avail-
ability of comparable therapies due to country-specific deci-
sion-making policies [49] might be an explanation for the
differences in significance observed. Additionally, it could
be assumed that in Germany only the AnTC of comparable
therapies and not the availability of alternative therapies
is relevant. The results indicate an appropriateness of the
method to determine the comparable therapies’ AnTCs and
constitute a contribution to the literature. However, whether
the comparable therapies’ AnTCs determine the negotiated
price or only build a reference basis cannot be concluded
from our results.
The variable found to have the strongest association
with the negotiated price was the OD price in other Euro-
pean countries. However, this strong association might be
explained by two limitations of the study. Firstly, list prices
were used to calculate the reference price as confidential
rebates were unknown and an estimation was avoided to
prevent inaccuracy. Secondly, as all variables found to be
significantly associated with the negotiated price were cor-
respondingly related to the European prices, the high cor-
relation between the OD negotiated price and the European
prices is traced back to the fact that other European coun-
tries consider similar criteria for the price setting of ODs
[1, 18, 19]. Accordingly, it is assumed that the height of the
European prices does not determine the OD price but rather
represents a directive value.
Besides the limitations on the variable level already out-
lined, further important limitations must be noted. First,
although information from all initial EBAs available was
used, the sample size is small. Furthermore, the small
sample size potentially caused some influential explanatory
variables to become non-significant. Consequently, interpre-
tation of the results must be done with caution. Secondly,
data availability is a limitation. Compromises made between
the negotiation parties and soft factors affecting the nego-
tiation outcome remain unobserved and cannot be consid-
ered in the analysis. Third, the informative value of some
variables is limited. This is due to the data sources used
to construct the variables and the assumptions required to
generate them.
Despite these limitations, we believe this study to con-
tribute to the literature as it helps increase the transparency
of the price negotiations for ODs in Germany. Against the
background of budgetary constraints and affordability con-
cerns, more studies regarding the subject of OD pricing and
reimbursement are needed. For example, a preference analy-
sis such as the Swedish study by Wiss [50] is expected to
reveal the German population’s true willingness to pay for
ODs. If conducted in Germany, policy makers would have an
evidence base that could be used in the discussions regarding
the alteration of AMNOG in relation to ODs. Furthermore,
policies regarding the pricing of ODs are becoming of major
European interest. To make an informed decision on the
introduction and alteration of respective regulations, Euro-
pean policy makers need information on price determinants
and a comparison with existing systems. Yet, present Euro-
pean literature is rare and does not include Germany, the big-
gest pharmaceutical market in Europe [51]. In the past, the
impartial head of the FJC raised the question of whether the
pharmaceutical industry is following a strategy of ‘orphani-
zation’ because of the automatically granted added benefit
for ODs [52]. As a consequence, payers (NA SHI) and the
IQWiG favored a conventional assessment of ODs, but the
lawmaker, the Federal German Parliament, did not accept
this argument and left the regulation on ODs untouched.
Furthermore, payers proposed that the turnover threshold
limit of ODs for a conventional assessment be lowered and
suggested the ability to claim retroactive maintenance of
the negotiated price from the beginning of market entrance
(for all pharmaceuticals). However, neither the proportion
of ODs nor their prices justify these claims as, on average,
one-third of new compounds are ODs, and less than 4% of
the pharmaceutical budget is spent on ODs [53]. The results
of our analysis show similar prices of ODs in the early mar-
ket entrance countries, mitigating the allegation of Germany
being a high-price country for ODs.
5 Conclusion
A strong statistically significant association was found
between the OD negotiated price and the (i) therapeutic area
in which the OD is applied; (ii) OD approval for pediatric

care; (iii) treatment population size; (iv) costs of compara-
tive therapies; and (v) OD European prices. Consequently,
German OD pricing seems to be a multivariate phenomenon.
When applying a multiple OLS regression, the European
prices for ODs showed the strongest significant association
with the negotiated price. However, due to interdependen-
cies, these results must be treated with caution.
Acknowledgements  Franziska Worm was affiliated with Health Eco-
nomics, University Duisburg-Essen, Essen, Germany at the time of
preparation of the manuscript.
Author Contributions  FW and CMD developed the concept of the sub-
mitted manuscript and wrote the manuscript together. FW together with
CMD gathered the data used. FW calculated the statistical analyses
and CMD replicated and reviewed them. Both act as guarantors of
the article.
Data Availability Statement  The Electronic Supplementary Mate-
rial contains all the data used or references their publicly available
sources. There are no data used from sources with restricted or confi-
dential access, with one exception (European countries’ pool for price
sequence based on the experience of a large pharmaceutical company).
Compliance with Ethical Standards  Drug Anal. 2015;23(4):595–608.
Funding  No funding was received for this study.
Conflict of interest  FW has no conflicts of interest. As well as his aca-
demic affiliation, C-MD is employed by Bayer Vital GmbH, Germany.
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