Eur J Clin PharmacolDOI 10.1007/s00228-007-0454-6
Predictors of orphan drug approval in the European Union
Harald E. Heemstra & Remco L. de Vrueh &Sonja van Weely & Hans A. Büller &Hubert G.M. Leufkens
Received: 12 September 2007 / Accepted: 19 December 2007
Conclusion This study showed that experience of a
Objective To encourage the development of drugs for rare
company in developing orphan drugs is an important
diseases, orphan drug legislation has been introduced in the
predictor for subsequent authorisation of other orphan
USA (1983) and in the EU (2000). Recent literature
drugs. The same applies for existing (synthetic) molecules,
discusses factors that may influence the development of
for which much knowledge is available. Further research
new orphan medicinal products in the EU. This study aims
should be directed towards studying the quality of the
to identify predictors for successful marketing authorisation
clinical development program of those designated orphan
of potential orphan drugs in the EU.
medicinal products not reaching approval status.
Methods A comparison between randomly selected author-ised and a matched sample of not-yet-authorised orphan
Keywords Orphan drugs . Rare diseases .
drug designations has been performed. Determinants in the
study included characteristics of the indication, of the productand of the sponsor. Data were collected from the publicdomain only.
Results Orphan drug approval was strongly associated withprevious experience of the sponsor in obtaining approval
In Europe and the United States (USA) together, more than 55
for another orphan drug (OR=17.3, 95% CI=5.6–53.1).
million people suffer from a rare disease. It is estimated that
Furthermore, existing synthetic entities compared to bio-
approximately 5,000 to 7,000 rare diseases exist, and every
technology products tended to have a higher likelihood of
year about 250 new ones are described , This is partly
reaching approval status (OR=3.9, 95% CI=0.9–16.6).
due to our continuously improving knowledge on diseasebiology and genomics, which allows more prevalent diseasesto be broken down into several rare diseases. In addition to
H. E. Heemstra : H. G. M. Leufkens (*)
this, new symptoms, mechanisms and aetiologies are
Division of Pharmacoepidemiology and Pharmacotherapy,
described in literature, representing more new diseases
Utrecht Institute for Pharmaceutical Sciences,Faculty of Science, Utrecht University,
As yet, for many rare diseases, no treatment is available
P.O. Box 80.082, 3508 TB Utrecht, The Netherlands
, ]. The high costs and risks of drug development,
combined with difficulties in conducting clinical trials in
small patient populations and the small market size,
discourage the pharmaceutical industry from developing
drugs for these rare diseases . Finding ways to bring
R. L. de Vrueh S. van WeelySteering Committee on Orphan Drugs,
drugs for rare diseases to patients is therefore an important
P.O. Box 93245, 2509 AE The Hague, The Netherlands
Consequently, several jurisdictions have put forward
incentives to stimulate the development of drugs for rare
Department of Paediatrics, Erasmus Medical Centre,P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
diseases. Following the successful Orphan Drug Act in the
USA, the European Union (EU) introduced its Regulation
indication may influence the perspectives on marketing
on Orphan Medicinal Products in April 2000 ]. The
authorisation, as the risk-benefit balance may be influenced
systems have much in common, although a few differences
by the degree of severity of specific disease classes. The
exist. In the USA, drugs indicated for a maximum of
objective of this study is therefore to identify predictors of
200,000 patients (equivalent to 7 patients per 10,000
successful marketing authorisation in the EU.
residents) are eligible for orphan drug designation. In theEU, an orphan designation will only be provided by theEuropean Commission if the product is intended for the diag-
nosis, prevention or treatment of a life-threatening orchronically debilitating condition that affects fewer than 5 in
Selection of candidate orphan medicinal products
10,000 patients. Moreover, the sponsor should establish thatthere exists no satisfactory method for the diagnosis, treatment
The cohort of 386 designated orphan drugs and orphan
or prevention of this condition, or if such exists, that the new
drug candidates has been followed from the start of the EU
product will be of significant benefit for those affected by that
Regulation on Orphan Medicinal Products in April 2000.
We enrolled all designated orphan medicinal products with a
Designated potential orphan drugs in the EU are entitled
marketing authorisation by the European Commission up to 1
to several incentives, of which a market exclusivity of
October 2006 in our analysis and compared these to a subset
10 years upon authorisation is the most important one ].
of the designated, but not yet authorised, orphan drugs. To
Other incentives are direct access to the centralised
avoid potential bias due to time-related differences in the
procedure for European marketing authorisation, 50% fee
probability of getting authorisation, for each authorised
reductions for regulatory procedures and free scientific
product, a random sample of up to two designated products
advice during the development process [With this
from the same time period (120 days before to 120 days after)
designation procedure, the EU aims to stimulate bottom-up
as the designation date of the authorised product was selected.
initiatives to further develop possible orphan drugs.
Authorised orphan drugs with multiple authorised indications
Thus, an orphan drug designation system creates a ‘pre-
(imatinib, sunitinib and dasatinib) were sampled to up to two
screen’ of promising future orphan drugs. However, to be
unapproved orphan drugs for each indication.
designated does not automatically mean an orphan drug willbe authorised for marketing. A recent study by Joppi pointed
out that in April 2004, only 7.1% of the EU designatedpotential orphan drugs were approved for marketing, ques-
To test our hypothesis, we collected data for each product
tioning whether the incentives are sufficient to provide the
on the indication, the product and the sponsor. Selection of
European market with new orphan drugs [These
data was limited to the public domain. Indication character-
observations give strong impetus to the question of what
istics included data on the type of disease and disease
determines successful development and marketing author-
prevalence for which the product is indicated. Product
isation of an orphan drug. In other words: what makes an
characteristics included data on the type of product,
orphan designation result in an authorisation? A paper by
proposed route of administration and previous approval or
Dear argued that the US Orphan Drug Act is so successful
designation of the molecule in other geographic regions than
because of tax grants, which are not available in Europe [].
the EU. Sponsor characteristics included those details of the
Other factors that have been suggested as relevant in terms of
sponsor that may be indicative for demonstrating the favour-
influencing the likelihood of approval are the potential of the
ability of the product, including the size of the company,
sponsor to carry out suitable clinical trials and the level of
geographic region of drug development and experience of the
patient involvement in the development process How-
company with drug development. A full list of these variables
ever, beyond these suggested factors, additional character-
is shown in Table If available, EMEA definitions were
istics may be of importance that have not been studied yet.
used for the classification of the subcategories and variables.
Since all products have to comply with the criteria of
quality, safety and efficacy, we hypothesise that designated
), European Public Assessment Reports (EPARs),
orphan medicinal products that have not (or not yet)
sponsor websites, annual reports, press releases, and peer-
obtained marketing approval therefore either have unfav-
ourable characteristics or the sponsor of the product has notbeen able to show the favourability of the product
characteristics. The latter can have multiple causes, includ-ing lack of experience or insufficient means for the clinical
Characteristics of approved and unapproved orphan medic-
development program. In addition to this, the type of
inal products were compared using a univariate analysis.
Table 1 Overview of characteristics and definitions of designated
2006). To test whether any of the characteristics were
mutually related, a multivariate model was used in which
the characteristics with statistically significant crude ORswere compared using a backwards selection procedure.
Anti-infectives (J)Alimentary tract and metabolism (A)
From the start of the EU Regulation on Orphan Medicinal
Products (April 2000) up to 1 October 2006, 31 orphan
medicinal products obtained marketing authorisation. One
product (imatinib) has been authorised for four indications,
and two other products (sunitinib and dasatinib) have been
authorised for two indications, resulting in 36 approved
orphan indications. A total of 60 designated (unauthorised)
products were sampled to serve as controls. A small,
Disease duration is generally over 3 months
statistically significant difference in the stage of develop-
ment between the two groups was found for those products
for which clinical trials were initiated, but not yet
completed (P=0.02), while this was not the case for
products for which experimental model studies had been
Innovative synthetic entities (EMEA list B),
initiated or completed (P=0.08), and for products for which
at least one clinical trial was completed (
Of the 31 authorised drug products, the majority (58.3%)
were designated in the first 2 years of the EU Regulation on
Orphan Medicinal Products (2000–2001). Twelve were ap-
proved under exceptional circumstances, and one (sunitinib)
had obtained conditional approval. Seven (22.6%) had received
some form of protocol assistance or scientific advice from the
EMEA. Of the 60 unauthorised designations, at least 43
(71.7%) were still in development in October 2006; of these,
Large (>250 employees or 50M turnover)
one had filed for market authorisation and another one had been
authorised by November 2006. The development of six
products could be classified as halted or on hold. For 11
Small (<50 employees or 5M turnover) and
products, recent data on the development status were not
Table shows an overview of the clinical characteristics
of all 31 authorised orphan drugs for 36 indications, stratified
by indication category and prevalence group of the indica-
other medicinal products as of 1 Oct 2006(anywhere in the world)
tion. Disease categories are based on ATC classes or
combinations thereof that are also used by the Commission
for Orphan Medicinal Products (COMP) of the EMEA [
The majority of the products were intended for oncologic
and immunomodulatory diseases (ATC class L) (16, 44.4%)
or alimentary and metabolic diseases (ATC class A) (9,
25.0%). In addition, most (24, 66.7%) authorised drugs
ATC Anatomical Therapeutic Chemical, NCE new chemical entity,
were intended for diseases with a prevalence lower than 1
in 10,000. Of the 16 approved oncology drugs, 13 (81%)were developed by large companies, 7 (44%) originated
Odds ratios (OR) and 95% confidence intervals (CI) were
from the USA and 5 (31%) from Switzerland. All these
calculated for each characteristic in the three categories.
products were based on synthetic entities, and the majority,
The outcome was defined as a successful EU marketing
12 (75%), were intended for oral use, whereas 4 (25%)
authorisation within the study period (April 2000-October
Table 2 Summary of characteristics of authorised orphan medicinal products from April 2000 to October 2006 ]
Treatment of N-acetylglutamate synthetase (NAGS) deficiency
Treatment of acute promyelocytic leukaemia
Conditioning treatment prior to hematopoietic progenitor cell
Treatment of primary and several secondary forms of pulmonary
Treatment of glycogen storage disease type II (Pompe’s disease)
Treatment of pulmonary arterial hypertension and chronic
Treatment of mucopolysaccharidosis, type I
Treatment of mucopolysaccharidosis, type VI (Maroteaux-Lamy
Treatment of chronic pain requiring intraspinal analgesia
Treatment of anthracycline extravasations
Treatment of gastrointestinal stromal tumours (GIST)
Treatment of familial adenomatous polyposis
Treatment of acute lymphoblastic leukaemia
Treatment of high-grade dysplasia in Barrett’s oesophagus
Treatment of chronic iron overload requiring chelation therapy
Treatment of pulmonary arterial hypertension and chronic
Treatment of pulmonary arterial hypertension and chronic
Treatment of malignant gastrointestinal stromal tumours
Treatment of acute lymphoblastic leukaemia
Treatment of dermatofibrosarcoma protuberans
Treatment of acute lymphoblastic leukaemia
The results of the univariate comparison between author-
strongest for those characteristics that were related to the
ised and not-yet-authorised orphan drugs are shown in Table
experience of the sponsor with drug development. Previous
For the categories of product characteristics and sponsor
authorisation of an orphan drug by the sponsor was
characteristics, a statistically significant association was
associated with a 16-fold increase in the chance of author-
observed for all the determinants except for the continent
isation compared to no previous authorisation (OR=16.2,
of drug development and for products with a previous
95% CI=5.5–47.4), whereas previous authorisation of other
orphan designation outside the EU. The association was
drugs and previous designation of another potential orphan
Table 3 Results for the comparison between authorised and not-yet-authorised orphan medicinal products
OR Odds ratio, 95% CI 95% confidence interval, ATC Anatomical Therapeutic Chemical, NA not applicable, OD orphan drug
drug by the sponsor yielded odds ratios (95% CI) of 11.5
entities (NCEs)] such as imatinib was not statistically
(3.2–42.2) and 8.0 (2.5–25.7) respectively. Furthermore,
significant compared to biotechnology products (OR=2.0,
previous authorisation outside the EU was also associated
95% CI=0.7–6.1), existing synthetic entities, such as arsenic
with higher chances for authorisation in the EU (OR=4.0,
trioxide and busulfan, were associated with higher chances
95% CI=1.1–14.5). Finally, the type of product is partly
of market authorisation (OR=3.3, 95% CI=1.1–10.6).
associated with market authorisation. Although the associa-
The results from the multivariate model, which assessed
tion for innovative synthetic entities [e.g. new chemical
whether any of the statistically significant characteristics
Table 4 Multivariate analysis of predictors of marketing authorisation
overcome this hurdle is EMEA’s dedicated SME office,
which addresses the regulatory needs of SMEs [These
incentives seem to be good steps forward to guide smallerand relatively inexperienced companies through the regu-
latory maze in the development process. Although 80
procedures for protocol assistance had been completed by
April 2005 ], we found that only 4 of the products that
were approved in that period had obtained scientific advice
or protocol assistance from the EMEA. Furthermore, of the
OR Odds ratio, 95% CI 95% confidence interval, OD orphan drug
31 products authorised by October 2006, only 7 (22.6%)
a Adjusted for significant variables in the univariate analysis (includ-
received protocol assistance or scientific advice. In contrast,
ing other ODs approved and type of product), followed by a
28 (77.8%) of the 36 approved orphan indications were
backwards elimination procedure. Predictors in the table are those thatremained in the multivariate analysis
developed by a company that had successfully broughtanother orphan drug to the market in Europe or the USA.
were related, are shown in Table . This model yielded two
The development of imatinib is a good example of this. It
independent predictors of successful marketing authorisa-
was developed by a large company with extensive
tion, namely the experience of the sponsor having other
experience in developing and marketing medicinal products
orphan medicinal products authorised and the type of
product. The association was strongest for the authorisation
The other independent predictor that was identified
of other orphan products by a sponsor (OR=17.3, 95% CI=
was the type of product. Although not significant, it shows
5.6–53.1). Moreover, we found a tendency toward an
that the odds of authorisation for products based on existing
association for the type of product, with an OR (95% CI)
synthetic entities may be about four times higher compared
of 3.9 (0.9–16.6) for existing synthetic entities compared to
to biotechnological products. Only 6 of the 31 orphan drugs
biotechnology products, while no association was observed
approved in the EU up to October 2006 were of
for innovative synthetic entities compared to biotechnology
biotechnological origin; of these, 5 are used for enzyme
products (OR=1.9, 95% CI=0.5–7.7).
replacement therapy for metabolic disorders. This finding isnot unexpected, as the development of existing syntheticentities into drug products is generally considered much
more straightforward than the development of a biotechproduct. This group also includes orphan drugs based on
This study reveals two independent characteristics of an
existing approved therapies, such as celecoxib and sildena-
orphan medicinal product that are associated with market-
fil, for which development was only a matter of an
ing authorisation: the experience of a company in develop-
indication extension. This can be one of the reasons why
ing drug products and the type of drug product in
the relatively young European Regulation on OMPs has
yielded such a high share of orphan drugs based on existing
First, we showed that experience of a company in
obtaining authorisation for orphan drugs was identified as
In contrast to the EU, half of the biotechnological
the most important predictor of market authorisation.
products approved in the USA in the period 1982–2002
Companies that have successfully brought an orphan drug
were designated orphan drugs []. The US Orphan Drug
to the market increase their odds of obtaining market
Act is therefore frequently mentioned as one of the key
authorisation for consecutive orphan drugs more than 17-
factors that has stimulated the US biotech industry in its
fold. These results are in line with opinions expressed by
growth. Several of the world’s largest, US-based biotech
many experts, however they are now supported by real data
companies have in common that their first approved
and emphasise the importance of an experienced partner in
product was an orphan drug ]. This is illustrated by
bringing a product to the market for small and medium-
the fact that of the six approved biotech OMPs in the EU,
sized enterprises (SMEs) whose experience is often limited
five were originally developed in the USA. Since the US
This observation is verified by the fact that many
Orphan Drug Act was initiated nearly 25 years ago, those
former SMEs with one or more approved orphan drugs
companies have grown from SMEs to multinational
have acquired the necessary experience by bringing on
companies and have since acquired much more experience
board experienced management at an early stage.
in drug development than the current European biotech
The EMEA has addressed this issue by offering protocol
companies with orphan drug designations in their portfolio.
assistance and scientific advice to sponsors of designated
On the other hand, the small number of European biotech
orphan drugs. Another important recent incentive to
orphan drugs is compensated for by the relatively large
number of orphan products based on existing synthetic
small patient populations were really the key problem, we
molecules. Examples of these are the products from the
would see a larger share of orphan drugs for relatively
French SME Orphan Europe, which are all based on
common rare diseases in the EU, and only a very small
existing molecules. This underlines that experience of a
share of orphan drugs indicated for the very rare diseases.
company is even more important for the relatively more
However, in our analysis, we found no association between
complex biotechnological products. Since much clinical
prevalence of the indication and market authorisation.
experience is already available, especially for existing
Moreover, of the 36 indications for which an orphan
synthetic molecules, this emphasises that, next to the
medicinal product has been approved in the EU, 24 (67%)
experience of a company, experience with a drug product
had a prevalence of less than 1 per 10,000. In addition to
this, Dear stated that, although small patient numbers may
Except for products indicated for alimentary tract and
hamper clinical trials for very rare diseases, it is not likely
metabolism-related diseases (ATC class A), none of the
to be a problem for more prevalent rare diseases [
characteristics related to the type of the indication showed a
We need to consider other critical factors for the success
statistically significant association with market authorisa-
of the development of an orphan drug. The level of patient
tion. This finding matched with our hypothesis that only the
involvement may also influence successful development
characteristics of the drug product itself or the development
and subsequent authorisation of orphan drugs []. More-
program of the sponsor determines the chances for market
over, the registration dossiers of authorised orphan drugs
authorisation. An interesting observation here is that the
are often of poor quality, including inappropriate study
number and type of products intended for oncologic
design, lack of active comparators and inadequate end-
indications suggest that the Regulation also provides
points , ]. Although this criticism is primarily directed
support for the development of the more classical antican-
against orphan drugs already authorised, it is very possible
cer drugs. In fact, this is one of the most successful niches
that these dossiers are just the ‘tip of the iceberg’. If that is
in orphan drug development in the EU so far.
the case, many orphan drugs will not reach the market
Recent literature has discussed factors that influenced the
because the sponsor will not be able to show evidence of
development of orphan medicinal products in Europe [
favourable characteristics of the product due to the poor
]. One of the issues that has been raised in these
quality of the dossier. Since this study has been based on
papers is the absence of tax credits in the EU, compared to
data from the public domain, several of these factors could
the USA. The reason for this is that taxation is still a
not be included, which is a limitation of the study. Future
national affair in the EU, which is not regulated at the
research to investigate the quality of the clinical develop-
Community level. Although this is compensated for by a
ment program of designated (unauthorised) orphan drugs
longer period of market exclusivity in the EU and
additional benefits on a national level [Joppi and Dear
Another possible limitation of the study was the risk of
suggest that this may yield fewer orphan drugs than in the
biased outcomes due to possible differences in the stage of
USA , While our analysis cannot fully produce a
development of the products between the two groups that
conclusive answer to this discussion, it gives some useful
were compared. For this reason, the controls were randomly
clues that the absence of tax credits alone is not the reason
sampled from the same calendar period as the cases, so that
for the lower number of approved products in the EU.
the chance that products would obtain approval was as
Approximately one-third of the European orphan desig-
equal as possible. Moreover, we compared the stage of
nations were originally developed in the USA (data on file).
development at the time of the application for orphan
However, in our analysis, no association was found
designation based on data from the available Summaries of
between the continent of drug development and market
Opinion of the EMEA. Here it was shown that, although
authorisation. These results suggest that the absence of tax
slight differences existed, the two groups were roughly
credits in the EU does not discourage companies from
equal with regard to their stage of development at time of
applying for an orphan designation in the EU.
Wästfelt described the problems of performing adequate-
The relatively small number of products that have so far
ly powered RCTs in small patient populations with rare
been approved in the EU as compared to the enormous
diseases, which are even more problematic in the multicul-
number of rare diseases emphasises that the promises of the
tural and multilingual setting of the EU compared to the
European Regulation on OMPs have yet to be fulfilled.
USA []. Moreover, the USA has a successful infrastructure
This paper has studied the characteristics of several of the
for conducting trials in patient populations with rare
early approved orphan drugs, the majority of them
diseases, which is coordinated by the Rare Diseases
authorised within the first 2 years of the Regulation. Now
Clinical Research Network and supported by the Office of
that the Regulation is about to enter its ninth year of
Rare Diseases of the National Institutes of Health []. If the
existence, the rate of orphan drug approval is gradually
increasing and more and more orphan drugs are entering
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RÉSUMÉ DES CARACTÉRISTIQUES DU PRODUIT DÉNOMINATION DU MÉDICAMENT Chlorure de méthylthioninium Proveblue 5 mg/ml solution injectable 2. COMPOSITION QUALITATIVE ET QUANTITATIVE Chaque ml de solution contient 5 mg de chlorure de méthylthioninium. Chaque ampoule de 10 ml contient 50 mg de chlorure de méthylthioninium. Pour la liste complète des excipients, voir rubrique 6.
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