Winstone et al.

Orphanet Journal of Rare Diseases (2015) 10:139

DOI 10.1186/s13023-015-0349-z

RESEARCH Open Access

Review and comparison of clinical evidence

submitted to support European Medicines Agency
market authorization of orphan-designated
oncological treatments
Julie Winstone1, Shkun Chadda1*, Stephen Ralston1 and Peter Sajosi2

Abstract
Background: Clinical trials for treatments indicated for orphan diseases may be limited due to the low prevalence
of such diseases; this can result in implications for both regulatory and health economic perspectives. This study
assessed the pivotal clinical evidence packages submitted to support applications for European Medicines Agency
(EMA) marketing authorizations for treatments for orphan conditions, in relation to the size of the eligible patient
population.
Methods: Approved treatments for EMA-designated orphan conditions (defined as life-threatening or chronically
debilitating conditions that affect ≤5/10,000 people) were identified from the EMA web site. All treatments
reviewed were included in anatomical therapeutic chemical (ATC) category L (antineoplastic and
immunomodulating drugs): this category was selected because it is the largest ATC category, containing almost
50 % of all approved orphan-designated products. Treatments were reviewed if they had been approved within the
past 7 years and had been evaluated in a controlled trial using at least one survival-based clinical endpoint.
Treatments were compared in terms of patient-years (accumulated duration of follow-up), the number of patients
in the pivotal trials and disease prevalence.
Results: As of 1 February 2014, 68 treatments had been approved for orphan-designated conditions, of which 30
belonged to ATC category L and 14 met all inclusion criteria. The number of patients in the pivotal trials ranged
from 162 to 846 (median 485). In terms of patient-years, the longest duration of follow-up was seen in the pivotal
trial of mifamurtide in osteosarcoma, which had 4068 patient-years; excluding this trial, follow-up ranged from 308
to 2906 patient-years (median 1796 years). Osteosarcoma had the second smallest eligible patient population
(0.5/10,000 persons) of the reviewed treatments.
Conclusions: Clinical trials of orphan treatments are often limited by low patient numbers and inadequate
follow-up. Pooling of expertise in single centres and the establishment of rare disease reference networks and
patient registries may facilitate appropriate trial design for orphan-designated treatments. This analysis found that
the pivotal clinical trial for mifamurtide in osteosarcoma had the largest number of patient-years of follow-up,
despite a small eligible patient population, showing that it is possible to conduct studies with an adequate patient
population size and duration of follow-up in patient-years, and a comparative design with clinical, survival-based,
endpoints.
Keywords: European Medicines Agency, Clinical trials, Mifamurtide, Orphan disorders, Orphan treatments,
Osteosarcoma

* Correspondence: [email protected]
1
SIRIUS Market Access, 58 St Kilda Rd, London W13, UK
Full list of author information is available at the end of the article

© 2015 Winstone et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139 Page 2 of 7

Background history of a disease and the potential impact of the pro-

Although definitions of orphan diseases vary, it is gener- posed new treatment could form an additional criterion
ally accepted in most countries that such disorders affect for decision-making on market access and reimbursement
between 1 and 8 individuals per 10,000. Within the policies [10]. A further consideration is that marketing au-
European Union (EU), orphan conditions are defined by thorizations based on limited clinical data could poten-
the European Medicines Agency (EMA) as life- tially expose the patient to increased risk of adverse
threatening or chronically debilitating conditions that events or lack of efficacy, compared with non-orphan
affect no more than 5 in 10,000 people (equivalent to treatments [11]. In view of these issues, the present
approximately 250,000 or fewer people for each condi- study was performed to evaluate the pivotal clinical
tion) in the EU [1–3]. evidence packages presented in the European Public
There are difficulties in balancing the urgent need for Assessment Report for orphan-designated treatments
drugs to treat rare diseases with the requirements for with an EMA marketing authorization.
guaranteed quality, efficacy and safety and, when neces-
sary, making comparisons with existing therapies. Reli- Methods
able methods of evaluating drugs in small numbers of This study reviewed the clinical evidence packages for
patients are problematic, adding to difficulties in produ- treatments approved by the EMA. All treatments in-
cing high-quality dossiers, despite incentives for pharma- cluded in the review belong to anatomical therapeutic
ceutical companies to develop such products and the chemical (ATC) category L (antineoplastic and immuno-
use of less stringent criteria for trials of drugs with des- modulating agents); this category was chosen because it
ignated orphan indications [4]. These problems are evi- is the largest ATC category, containing almost 50 % of
dent even when the efficacy of a potential treatment is all orphan-designated treatments that have received
well established in other indications [1]. For these rea- marketing authorization from the EMA. Treatments
sons, clinical data submitted to support an application were eligible for inclusion in the review if they had been
for marketing authorization of treatments for orphan approved after 31 December 2006 and had been evalu-
conditions may often be less robust than is the case for ated in a comparative trial using at least one survival-
treatments for non-orphan common conditions. In a based clinical endpoint as opposed to short-term surro-
study in 2006, for example, 10 of 18 (55 %) approved gate endpoints. The time limit was imposed to ensure
orphan-designated treatments were authorized ‘under that all included treatments had been evaluated by the
exceptional circumstances’, indicating that the clinical EMA using similar criteria: it is possible that older treat-
dossiers were incomplete and that further studies would ments might have been evaluated using less stringent
be needed to maintain the marketing authorization [4]. criteria than recently approved treatments. Similarly, the
Overall, only nine of the approved treatments (50 %) requirement for comparative studies using survival-
were supported by RCT data: five were supported only based endpoints was imposed because such studies can
by uncontrolled Phase II studies, two by uncontrolled be considered the ‘gold standard’ for clinical trials in on-
open-label studies, and one by a literature analysis alone. cology and are recommended in United States Food and
Other limitations of the submitted data included the use Drug Administration guidance [12]. Eligible treatments
of surrogate endpoints and inadequate durations of were compared in terms of the number of patients in-
follow-up in relation to the natural history of the disease. cluded in pivotal (‘main’) clinical trials submitted to sup-
A subsequent study by the same authors suggested that port the application for marketing authorization, the
this situation persisted throughout the first decade after cumulative duration of follow-up in the pivotal trials,
implementation of orphan drug legislation in the EU [5]. expressed in patient-years, and the prevalence of the
The limitations of the clinical evidence submitted to orphan condition. The number of patient-years of
support marketing authorizations for orphan treatments follow-up was calculated by multiplying the total num-
have a number of implications. Poorly designed pivotal ber of patients in each study (across all treatment arms)
trials may contribute to a low rate of success for such by the study duration; where the study duration was
applications both in the EU [4, 6] and the USA [7]. Fur- not reported explicitly, Kaplan-Meier curves or data ta-
thermore, limited pivotal trial data, together with the bles were used to estimate the duration of follow-up.
high cost of many orphan treatments, may create diffi- Prevalence data for each orphan-designated condition
culties in terms of reimbursement and market access were obtained from the relevant EMA Committee for
[1, 8, 9]. As the number of orphan-designated treat- Orphan Products public summary of opinion [3]: where
ments entering clinical practice increases, it is possible these data were provided as the number of affected pa-
that the data supporting an application for marketing tients in the EU, this was converted to the rate per
authorization may increase. Indeed, it has recently been 10,000 based on the EU population at the time of or-
suggested that submission of objective data on the natural phan designation.
Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139 Page 3 of 7

In addition to patient numbers and duration of follow- from the analysis because only literature reports, rather
up, the quality of the pivotal trials for all orphan prod- than clinical trial data, were provided as pivotal study evi-
ucts approved by the EMA since 31 December 2006 was dence. For the remaining 37 indications, 52 % of the piv-
assessed by means of the Jadad scoring system [13]. In otal studies were Phase III trials, and randomized clinical
this system, a maximum of two points each are given for trial (RCT) data were provided in 57 %. Overall, 73 % of
appropriate randomization and blinding, and a further studies had at least one clinical endpoint, but only seven
point is given if all patients are adequately accounted studies (15 %) included a survival-based clinical primary
for; thus, the maximum possible Jadad score is 5. endpoint.
A total of 14 products met all the inclusion criteria,
Results having been authorized within the previous 7 years and
As of 1 February 2014, 68 treatments with 87 indications supported by comparative trial data with at least one
had received an EMA marketing authorization for survival-based clinical endpoint (Table 1). The median
orphan-designated conditions. The prevalence of the or- number of patients included in the pivotal trials of these
phan indications varied markedly, from 0.00125/10,000 treatments was 485, and the number of patients ranged
persons for N-acetylglutamate synthetase deficiency from 162 in a trial of temsirolimus in mantle cell lymph-
to <4.5/10,000 persons for adrenal insufficiency. oma to 846 in a trial of nilotinib in chronic myelogenous
Of the 68 orphan treatments, 30 belonged to ATC cat- leukaemia (Fig. 1a). The cumulative duration of follow-
egory L (antineoplastic and immunomodulating agents); up, expressed in patient-years, also varied widely
of these, 21 had received a normal marketing authorization, (Fig. 1b), from 308 patient-years in the temsirolimus trial
four had received a conditional authorization, and five in mantle cell lymphoma to 4068 patient-years in a trial
were authorized under exceptional circumstances. The 30 of mifamurtide in osteosarcoma [14]. Follow-up in the
treatments were approved for 41 orphan indications: 19 latter trial appeared to be particularly extensive: when
were approved for a single indication and 11 were ap- this trial was excluded from the analysis, the duration of
proved for two indications. Four treatments were excluded follow-up ranged from 308 to 2906 patient-years, with a

Table 1 Orphan-designated treatments meeting criteria for review

Generic name Proprietary name Orphan condition Prevalence of orphan condition
Histamine dichloride Ceplene Adult acute myeloid leukaemia in first remission 0.7/10,000
Decitabine Dacogen Adult acute myeloid leukaemia <1/10,000
Pirfenidone Esbriet Adult mild to moderate idiopathic pulmonary fibrosis ≤3/10,000
5-aminolevulinic Gliolan Visualization of malignant tissue during surgery for 1/10,000
acid malignant glioma in adults
Pomalidomide Imnovid Multiple myeloma 2.2/10,000
Ruxolitinib Jakavi Splenomegaly or symptoms in adult patients with 0.5/10,000
primary myelofibrosis
Mifamurtide Mepact Osteosarcoma 0.5/10,000
Sorafenib Nexavar Hepatocellular carcinoma; renal cell carcinoma Hepatocellular carcinoma: 1/10,000;
renal cell carcinoma: not reported
Lenalidomide Revlimid Multiple myeloma 1.3/10,000
Nilotinib Tasigna Adult patients with newly diagnosed Philadelphia- 46,000 persons in EU (calculated as 1.0/10,000
chromosome-positive chronic myelogenous leukaemia based on EU population 457.7 million)
Adult patients with Philadelphia-chromosome-positive
chronic myelogenous leukaemia with resistance or
intolerance to prior therapy including imatinib
Thalidomide Thalidomide Untreated multiple myeloma in adults aged > 1.2/10,000
Celgene 65 years or ineligible for high-dose chemotherapy
Temsirolimus Torisel Renal cell carcinoma; adult patients with relapsed Renal cell carcinoma: 3.5/10,000; refractory
and/or refractory mantle cell lymphoma mantle cell lymphoma: 0.4/10,000
Azacitidine Vidaza Adults not eligible for haematopoietic transplant with 1.1–3/10,000
myelodysplastic syndromes, chronic myelogenous
leukaemia, and acute myeloid leukaemia
Trabectedin Yondelis Treatment of patients with advanced soft tissue 23,000 persons in EU (calculated as 0.6/10,000
sarcoma based on EU population 377 million)
EU European Union
Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139 Page 4 of 7

Fig. 1 Number of patients (a) and cumulative duration of follow-up (b) in included studies. All treatments belonged to ATC class L (antineoplastic
and immunomodulatory agents). For inclusion in the review, treatments were required to have received EMA authorization for orphan-
designated conditions within the previous 7 years, and to be supported by comparative trials with at least one survival-based clinical endpoint.
Duration of follow-up was estimated by multiplying the total number of patients in each study by the study duration, or from Kaplan-Meier
curves if these data were not available. MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; MM, multiple myeloma; OC, ovarian cancer;
RCC, renal cell carcinoma; STS, soft tissue sarcoma

median of 1796 patient-years. A comparison of the dur- randomized and 55 (47.4 %) were blinded; the numbers
ation of follow-up with the reported prevalence of the of trials considered adequately randomized or blinded
orphan condition (Fig. 2) showed that the osteosarcoma were 41 (35.3 %) and 45 (38.8 %), respectively. The trial
indication for mifamurtide, at 0.5/10,000, had the second with the most extensive follow-up, the mifamurtide
smallest eligible patient population of the reviewed treat- osteosarcoma trial, had an overall Jadad score of 3,
ments: only the mantle cell lymphoma indication for reflecting its randomized open-label design.
temsirolimus had a lower prevalence (0.4/10,000).
In general, the quality of the pivotal trials, as assessed Discussion
by Jadad scores, was moderate. The mean (±SD) Jadad The results of this study show that pivotal trials of treat-
score was 2.6 ± 1.8, and the median score was 3 (range ments for orphan conditions are often limited by a
0–5). Of the 116 trials assessed, only 74 (63.8 %) were number of methodological factors, including a lack of
Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139 Page 5 of 7

Fig. 2 Cumulative duration of follow-up in relation to the reported prevalence of the orphan conditions. Prevalence data derived from the rele-
vant EMA Committee for Orphan Medicinal Products public summary of opinion for each treatment [3]. EMA, European Medicines Agency; MCL,
mantle cell lymphoma; MDS, myelodysplastic syndrome; MM, multiple myeloma; OC, ovarian cancer; RCC, renal cell carcinoma; STS, soft
tissue sarcoma

randomization or blinding, low patient numbers (median inadequate number of patients. A study by Joppi et al.,
485) and limited follow-up (median 1796 patient-years). It for example, found that pivotal trials in treatments for
is important to emphasize however that, notwithstanding Fabry disease included only 41 and 56 patients out of a
these limitations, all the treatments were approved by the potential patient population of 10,000 in Europe [4]. By
EMA. contrast, the present study found evidence that a small
These findings are consistent with previous studies patient population need not necessarily be a barrier to
that have found significant limitations in the design of adequate patient recruitment. The pivotal study of mifa-
clinical trials for orphan treatments both in the EU [4, 5] murtide in osteosarcoma had the largest number of
and the USA [7]. Factors contributing to these limita- patient-years of follow-up and the fourth largest number
tions include a lack of pooling of manpower and re- of patients of all reviewed treatments, despite the low
sources for rare diseases. The lack of specialist centres prevalence of osteosarcoma (0.5/10,000). Indeed, it is
with multidisciplinary teams with expertise in particular noteworthy that only one indication, for temsirolimus in
rare diseases can result in a lack of data to understand mantle cell lymphoma, had a smaller eligible patient
the natural history of the disease or to inform clinical population (Fig. 2); this pivotal trial also had the smallest
and transitional research. This situation may be im- number of patients and the shortest cumulative follow-
proved by the establishment of sustainable patient regis- up. Three pivotal trials, for pirfenidone in idiopathic pul-
tries for specific rare diseases and European reference monary fibrosis, lenalidomide in multiple myeloma, and
networks of patient registries [15], which should facili- nilotinib in chronic myeloid leukaemia, included more
tate active and prospective monitoring of clinical inter- patients than the mifamurtide trial; however, in each
ventions for rare diseases [16]. case the prevalence of the orphan condition was higher
Orphan drug policies may be unsatisfactory from sev- than that of osteosarcoma (≤3/10,000, 1.3/10,000 and
eral viewpoints. For example, access to orphan drugs 1.0/10,000, respectively).
may be restricted in patients with some rare diseases, Although this analysis has focused on patient numbers
and funds may not be made available to pay for therap- and duration of follow-up as a measure of trial quality, a
ies when they have been developed [17]. Against this number of other potential measures are available, in-
background, the low prevalence of orphan disorders (<5/ cluding the Jadad scoring system [13] and the criteria of
10,000 population in the EU) remains a major problem the Oxford Centre for Evidence-based Medicine [18]
in the design of pivotal clinical trials [4]. Even when the and the Cochrane Collaboration [19]. Application of the
prevalence is relatively high compared with other orphan Jadad system to the studies included in this analysis con-
conditions (as is the case for many of the products in- firmed that the trials had significant limitations with re-
cluded in this review), trials may still be conducted in an spect to randomization or blinding, as discussed below.
Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139 Page 6 of 7

In addition to inadequate patient numbers and follow- of the pivotal studies were Phase III trials and RCT
up, pivotal trials of orphan treatments may also be lim- data were provided in 57 % of the pivotal studies. Be-
ited by the use of surrogate endpoints rather than clin- cause this analysis was restricted to ATC category L
ical survival-based endpoints. In the present study, five products, and the prevalence of oncological orphan
of the 30 ATC category L treatments were excluded diseases is often higher than that of many non-
from the review for this reason. Although desirable, the oncological orphan diseases, the results may not be ap-
use of survival-based clinical endpoints may make it dif- plicable to the latter situation.
ficult to demonstrate statistically significant treatment This study shows that problems relating to low patient
effects in trials of orphan treatments where, as noted numbers, or other methodological limitations, do not
above, patient numbers and duration of treatment may necessarily preclude approval of an orphan product. The
be limited [7, 20]. Conversely, it may be easier to dem- pivotal clinical trial for mifamurtide in osteosarcoma
onstrate significant treatment effects on surrogate end- had the largest number of patient-years of follow-up
points, but such endpoints are less likely to be acceptable (4068 patient-years) of any of the reviewed treatments,
to regulators [7, 21]. The choice of endpoint therefore re- despite a small eligible patient population (0.5/10,000
flects a balance between the need for adequate statistical persons); by contrast, the next largest study, of thalido-
power in the trial and the requirements of regulatory mide in multiple myeloma, had 2906 patient-years of
authorities [7]. follow-up in an eligible population of 1.2/10,000 persons.
A further issue is the lack of randomization or blind- Furthermore, each of the three treatments with the lon-
ing, or both, in many pivotal trials of drugs for orphan gest durations of follow-up were limited by a lack of
conditions. It is noteworthy that more than a third of blinding or (in the case of the thalidomide and trabecte-
the trials reviewed in the present study were non- din trials) the use of suboptimal endpoints. Nevertheless,
randomized, and less than 40 % were appropriately ran- each of these trials was considered adequate to support
domized or blinded. Indeed, the three trials with the approval of the treatment by the EMA.
most extensive follow-up in terms of patient-years (mifa- The low prevalence of orphan diseases is an important
murtide in osteosarcoma, thalidomide in untreated mul- factor in the limited patient numbers and inadequate
tiple myeloma, and trabectedin in ovarian cancer) all follow-up in many of the clinical trials included in the
had randomized open-label designs. In many cases, the dossiers. Pooling of expertise through the establishment
lack of randomization may reflect the small number of of rare disease reference networks and patient registries
patients with the condition; there are also ethical consider- may improve this situation.
ations relating to the use of placebos in life-threatening
conditions for which no alternative therapy is available for Abbreviations
use as a comparator. ATC: Anatomical therapeutic chemical; EMA: European Medicines Agency;
EU: European Union; RCT: Randomized controlled trial.
In the present study, treatments were only eligible
for review if they had received EMA approval after 31
December 2006, in order to maximize the likelihood Competing interests
PS is employed by Takeda Pharmaceuticals International GmbH, Zurich,
that all reviewed treatments had been evaluated accord- Switzerland, who sponsored the research.
ing to similar criteria. The finding that methodological
issues relating to pivotal trials of the approved products Authors’ contributions
were similar to those reported by Joppi et al. in 2006 [4] JW provided strategic input with regard to the rationale for selecting
suggests that the criteria for evaluation of orphan treat- appropriate treatments for comparison, planned and carried out the search
strategy and implementation and helped to draft the manuscript; PS
ments have not become more stringent over time. A re- planned the search strategy, performed the data review and helped to draft
cent study, which reviewed the EMA evaluations of 17 the manuscript. SR and SC were involved in the project concept, planning,
orphan drugs and 51 non-orphan drugs conducted dur- data review and interpretation of the findings. All authors reviewed the
manuscript and approved the final draft.
ing 2009–2010, concluded that the regulatory standards
applied to orphan drugs were as rigorous as those ap-
plied to non-orphan drugs [22]. Acknowledgements
This research was funded by Takeda Pharmaceuticals International GmbH,
Zurich, Switzerland. Medical writing support was provided by Michael Shaw.
Conclusions Editorial support was provided by Jenny Fanstone. At the time of analysis SR,
The results of this analysis show that 30 treatments be- SC and JW were engaged by PHMR London, UK.
longing to ATC category L (antineoplastic and immu- Author details
nomodulating agents) received an EMA marketing 1
SIRIUS Market Access, 58 St Kilda Rd, London W13, UK. 2Takeda
authorization for 41 orphan indications between 31 Pharmaceuticals International GmbH, Zurich, Switzerland.
December 2006 and 1 February 2014. Of the 37 indica- Received: 28 May 2015 Accepted: 1 October 2015
tions for which clinical trial data were presented, 52 %
Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139 Page 7 of 7

References
1. Aronson JK. Editors' view. Rare diseases and orphan drugs. Br J Clin
Pharmacol. 2006;61:243–5.
2. Orphanet. [http://www.orpha.net/consor/cgi-bin/Education_About
OrphanDrugs.php?lng=EN&stapage=ST_EDUCATION_EDUCATION_
ABOUTORPHANDRUGS_EUR]
3. European Medicines Agency www.ema.europa.eu.
4. Joppi R, Bertele V, Garattini S. Orphan drug development is progressing too
slowly. Br J Clin Pharmacol. 2006;61:355–60.
5. Joppi R, Bertele V, Garattini S. Orphan drugs, orphan diseases. The first
decade of orphan drug legislation in the EU. Eur J Clin Pharmacol.
2013;69:1009–24.
6. Putzeist M, Heemstra HE, Garcia JL, Mantel-Teeuwisse AK, Gispen-De Wied
CC, Hoes AW, et al. Determinants for successful marketing authorisation of
orphan medicinal products in the EU. Drug Discov Today. 2012;17:352–8.
7. Heemstra HE, Leufkens HG, Rodgers RP, Xu K, Voordouw BC, Braun MM.
Characteristics of orphan drug applications that fail to achieve marketing
approval in the USA. Drug Discov Today. 2011;16:73–80.
8. McCabe C, Claxton K, Tsuchiya A. Orphan drugs and the NHS: should we
value rarity? BMJ. 2005;331:1016–9.
9. Blankart CR, Stargardt T, Schreyögg J. Availability of and access to orphan
drugs: an international comparison of pharmaceutical treatments for
pulmonary arterial hypertension, Fabry disease, hereditary angioedema and
chronic myeloid leukaemia. Pharmacoeconomics. 2011;29:63–82.
10. Hughes-Wilson W, Palma A, Schuurman A, Simoens S. Paying for the
Orphan Drug System: break or bend? Is it time for a new evaluation system
for payers in Europe to take account of new rare disease treatments?
Orphanet J Rare Dis. 2012;7:74.
11. Kesselheim AS. Ethical considerations in orphan drug approval and use. Clin
Pharmacol Ther. 2012;92:153–5.
12. U.S. Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER), Center for
Biologics Evaluation and Research (CBER). Guidance for Industry. Clinical trial
endpoints for the approval of cancer drugs and biologics. May 2007.
Available at: http://www.fda.gov/downloads/drugsGuidanceCompliance
RegulatoyInformation/Guidance/UCM071590.pdf.
13. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et
al. Assessing the quality of reports of randomized clinical trials: is blinding
necessary? Control Clin Trials. 1996;17:1–12.
14. Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, et
al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy
improves overall survival – a report from the Children's Oncology Group. J
Clin Oncol. 2008;26:633–8.
15. Parker S. The pooling of manpower and resources through the
establishment of European reference networks and rare disease patient
registries is a necessary area of collaboration for rare renal diseases. Nephrol
Dial Transplant. 2014;29 Suppl 4:9–14.
16. Drummond M, Towse A. Orphan drug policies: a suitable case for treatment.
Eur J Health Econ. 2014;15:335–40.
17. Kesselheim AS, Gagne JJ. Strategies for postmarketing surveillance of drugs
for rare diseases. Clin Pharmacol Ther. 2014;95:265–8.
18. Oxford Centre for Evidence-based Medicine. Levels of evidence (March
2009). Available at: http://www.cebm.net/oxford-centre-evidence-based-
medicine-levels-evidence-march-2009/.
19. The Cochrane Collaboration. Cochrane Handbook for Systematic Reviews of
Interventions. Available at: http://handbook.cochrane.org/index.htm#part_3_
special_topics.htm.
20. Ruberg S, Cairns V. Providing evidence of efficacy for a new drug. Stat Med.
1998;17:1813–23. Submit your next manuscript to BioMed Central
21. Eichler HG, Pignatti F, Flamion B, Leufkens H, Breckenridge A. Balancing and take full advantage of:
early market access to new drugs with the need for benefit/risk data: a
mounting dilemma. Nat Rev Drug Discov. 2008;7:818–26. • Convenient online submission
22. Putzeist M, Mantel-Teeuwisse AK, Llinares J, Gispen-De Wied CC, Hoes AW,
• Thorough peer review
Leufkens HG. EU marketing authorization review of orphan and non-orphan
drugs does not differ. Drug Discov Today. 2013;18:1001–6. • No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution

Submit your manuscript at

www.biomedcentral.com/submit