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EMA approach to fee reduction for orphan medicinal products: one step forward two steps back according to EBE and EuropaBio

Since the adoption of the Orphan regulation in 2000 the European Medicines Agency has continually provided companies with incentives to encourage the development of orphan medicinal products (OMP). These include market exclusivity, as well as fee exemptions and reductions for several other services that have been critical in bringing orphan medicinal products to the market. However, the announcement of changes in the fee structure by the EMA, with changes effective from 1 January 2013, has been of extreme disquiet to rare disease stakeholders. In a letter to the EMA, members of the Joint Task Force on OMP, jointly organised by EuropaBio and European Biopharmaceutical Enterprises (EBE), which is comprised of companies that are involved in bringing orphan medicinal products to the market, expressed deep concern on the gradual changes of the fee structure that has been taking place.
The fee reduction package for non-SME’s producing OMP’s included a 75% fee reduction for protocol assistance as well as a 10% and 100% fee reduction for initial marketing-authorisation applications and pre-authorisation inspections respectively. From 1 January 2013 non-SME’s will have fewer incentives with only 40% fee reduction protocol assistance (scientific assistance) and a complete withdrawal of fee reductions for initial marketing-authorisation applications and pre-authorisation inspections for non-paediatric products.
The incentives for OMP's were introduced for the explicit purpose of “encouraging the development of medicinal products for the diagnosis, prevention and treatment of rare diseases”. Without these incentives bringing the orphan products to the market is not cost-effective for these companies. In the letter the task force quotes the study conducted by the Office of Health Economics which notes that “incentives provided in the legislation greatly fostered innovation and entry into the market of therapies addressing hitherto unmet medical needs”. The letters also emphasises that “the fee waivers and fee reductions were identified by the surveyed companies as the second-most-important incentive, second only to the Market Exclusivity provisions of the Regulation”.
There are several policy initiatives that are currently being encouraged by the European Union such as the setting up of International Rare Disease Research Consortium (IRDiRC) and development of the National Plans for Rare Diseases before the end of 2013, both of which will be highly influential in furthering the cause of rare disease patients. However, equally important are the incentives provided by the EMA in the form of fee reductions which make it viable for companies to develop OMP’s. The cutback of fee reductions is thwarting the efforts of the rare disease community in Europe who have fought very hard to obtain these incentives in the first place. Additionally, the task force fears that these changes by the EMA also increases the attractiveness of the United States as a base for rare disease research. Finally, members of the joint Task Force on OMP acknowledge the strict budgetary constraints that the EMA operates within and are therefore willing to work with the EMA in this regard.
Learn more
Read the letter

National & International Policy Developments
Other European news
UK leads pioneering efforts to eliminate mitochondrial diseases
Due to extensive public support, UK may legalise procedures that prevent children from inheriting the mutations of mitochondrial DNA from their mother. This procedure involves replacing the nucleus of the egg cell with the diseased mitochondria with a healthy donor cell. Two methods for this type of “reproductive-gene-therapy”, the maternal spindle transfer and pronuclear transfer, have been now successfully tested in animals as well as in human cells. Although additional experiments are recommended, an independent scientific review believe that there is "no evidence to suggest that these techniques would be unsafe in humans". Nuclear transfer procedures are banned under the UK Human Fertilisation and Embryology Act, but the government could amend the law for procedures used to treat mitochondrial diseases. The considerable support received during public consultations on this topic was followed by the UK Human Fertilisation and Embryology Authority (HFEA) to voting on “advis(ing) the government on the regulation of the techniques”. After the UK government determines whether a legislation to legalise the procedures will be written, the UK Parliament may pass a law after consultation with the HFEA. The HFEA stresses that if legalised, only a handful of women would be candidates for this kind of procedure but it would be highly beneficial to them and to the society at large. They also emphasised that much more research into the safety and efficacy of this procedure is needed and “the first trials are still likely to be years away”.
Read the article on this topic in Nature

Other International News
Novartis loses patent argument for Gleevec in the Indian Supreme Court
Gleevec (or Glivec as it is known in European market) is an Imatinib mescylate that recieved FDA approval in 2001, for the first-line treatment of patients with chronic myeloid leukemia, an uncommon life-threatening form of cancer. It was similarly approved by EMA as an orphan medicinal product in 2001. Gleevec became a “blockbuster” for Novartis with approval for various cancers and has since made billions in profits and is past its patent protection both in the U.S and Europe.
Novartis filed a patent in the Indian patent office for Gleevec (Imatinib) that comprises a slight change in composition of the drug. However, the Indian Supreme court squashed Gleevec's request and rejected any further appeals in the case. The Indian Supreme court refused the patent on the grounds that the present changes in Gleevec did not represent a true invention. Novartis has expressed critical concern over “India's growing non-recognition of intellectual property rights that sustain research and development for innovative medicines ”. They have recognised the importance of the use of generics after the patents expire, as they provide considerable respite to patients in countries like India .

In a developing country like India, most patients are not entitled to any form social security benefits or health insurance. The cost of Gleevec can come to as much as $70,000 per year for a patient, while a generic costs around $2500. This is a substancial difference for a patient in India, where they can be driven to abject poverty once they are diagnosed with a life-threatening disease like cancer.

On the other hand, it is important for orphan medicinal products to receive incentives from regulatory bodies so that companies are encouraged to produce drugs, which is usually a highly expensive and time-consuming process (Read Editorial). Market exclusivity for a period of time allows a return-on-investment and the necessary benefits for companies developing orphan medicinal products. It is imperative that orphan drugs are given the patent rights as well as other benefits to encourage companies to produce drugs for the rare disease patients. It is necessary that intellectual property is recognised and protected. Gleevec has been an important medication for orphan disease, which is past its patent. Over the years, Gleevec has received billions in profits as a “blockbuster” drug. Its time Gleevec gives way to generics.
Read the Novartis Press release
Read article on this topic in BBC

Recommendations for progress in the field of rare diseases in China
In a recent interview to Terrapin, Ping Guo, Vice president of Beijing YuanTang Institute of Gene science, part of China’s Ministry of Health, has described the progress the Chinese government to trying to make to provide orphan drugs to patients. They are currently trying to further the cause of rare disease patients by encouraging research and development in rare diseases, working on reimbursement strategies, as well as establishing patient services such as a patient register and easy access for medication for rare disease patients. Although China is behind United States and European Union in terms of initiatives benefitting rare disease stakeholders, there are several means by which the industry is serving in this process. According to Ping Guo, some approaches the industry can provide further support is by funding China’s National Patient registry, developing diagnostic tests, creating disease awareness and providing professional education in the area of rare diseases.
Download the interview

Guidance Documents and Recommendations
Experts recommendations for managing Familial Hypercholesterolemia
A recent review published in Journal of Managed Care Pharmacy discusses the recommendations released by National Lipid Association (NLA) for the treatment of Familial hypercholesterolemia (FH) and other disease management options. FH is a genetic disorder of lipid metabolism that can cause life-threatening elevation of circulating low-density lipoprotein cholesterol (LDL-C) levels. Due to the high risk of cardiovascular disease (CVD) and CVD related events in these patients an “early screening, early diagnosis, reduction of risk factors, and aggressive treatment” is recommended. A combination and adjunct therapy with necessary doses of statins to bring LDL-C down to an acceptable concentration is advised for these patients. Experts also recommend apheresis as well as other novel therapies such as the mipomersen- an antisense oligonucleotide recently approved by FDA as an adjunct therapy to decrease levels of LDL-C, apolipoprotein B, total cholesterol, and non-high density lipoproteincholesterol (non-HDL-C) in homozygous FH patients. Experts have also highlighted the important role of managed care organizations in various aspects of screening, treatment, as well as reimbursement of the extensive drug treatments needed by these patients.
Read the open access article

ACMG recommendations on reporting incidental findings in Clinical Exome and Genome Sequencing: NSCG responds to it
In order to address the increasingly important issue of reporting incidental findings from whole genome or exome sequencing, the American College of Medical Genetics and Genomics (ACMG) has published the “ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing”. These recommendations have been published in Genetics in Medicine and are also available on their website www.acmg.net. So far there were no guidelines on how incidental or secondary findings that arise from interpreting an individual’s genetic code should be reported. The ACMG has proposed several recommendations that form a consensus, after a year-long deliberation, of a “working Group comprised of medical and laboratory geneticists from leading institutions and outside reviewers”. ACMG has put together “a minimum list of conditions, genes, and variants that are recommended to be returned whenever clinical sequencing is performed”.
They strongly recommend pre-test counselling and advocate that the individual be given all the information relating to these conditions prior to undergoing whole genome sequencing. ACMG emphasises this is an iterative process and state that this list should be re-evaluated as and when more empirical evidence is available. With the advent of the fast-growing technology of genome and exome sequencing these recommendations are a stepping stone to start addressing the myriad ethical, social and legal questions that might come about. Although ACMG expects only about 1-2% of patients to be affected by the unexpected incidental findings, they believe that it will provide life –saving information to those affected.

The National Society of Genetic Counselors (NSGC) has subsequently released a press statement “applaud(ing) the efforts of ACMG providing guidance to laboratories and clinicians as we begin to integrate new genome sequencing technologies into clinical practice”. They have endorsed the effort of ACMG to take into account the current context while creating these recommendations as it “represents a break from past practices, which prioritized a patient’s right not to know genetic information that was predictive rather than diagnostic in nature”. NSGC also emphasises the importance of Pre-test counselling and extensive information dissemination on available genetic tests so that patients can make an informed decision.
Read the ACMG press release
Consult the Pubmed abstract
Read the NSCG press release

Experts discuss approval Non-Invasive Prenatal Testing for high risk pregnancies
A Screening update published in American Journal of Medical Genetics published an interview of expert views on the approval of the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) to “offer noninvasive prenatal testing (NIPT) to women at high risk of delivering babies with Down syndrome and trisomies 13 and 18”. The high risk women are described as women “over age 35, those with a prior pregnancy affected by a fetal trisomy, those with an increased risk of aneuploidy due to conventional serum screening or ultrasound findings, or those who are carriers of a balanced Roberstonian translocation with increased risk of fetal trisomy 13 or 21”. Most experts agree with the position of ACOG and SMFM and believe that it is part of “the brave new world”. The article shows consensus on ACOG and SMFM’s opinion on extensive pre-test counselling explicitly mentioning that the test is only for the three trisomies, and fetal sex. Experts highlight that although NIPT can accurately identify about 98% of cases of Down syndrome, they recommend that mothers should be advised of the false positives. They emphasise that NIPT should not be a part of routine prenatal testing and should not be given to patients with average risk or to mothers with multiple gestations. Due to the possibility of false positives, post-test counseling for women with positive results who “should be referred for genetic counseling and offered invasive prenatal diagnosis for confirmation of test results”. The views in the article also endorsed the need for continual education of practioners and parents as more empirical data is obtained.
Read the open access article

Bioinformatics, Registries and Data Management
Recon 2: the most comprehensive map of human metabolism available

Recon 2, is a comprehensive community-driven, consensus representation of human metabolism. This map of metabolic interactions has been constructed after several “jamboree meetings” where experts “refined and consolidated biochemical knowledge from existing reconstructions and published literature”. Recon 2 which is built from Recon 1 is a comprehensive metabolic resource as well as an effective predictive model for inborn errors of metabolism (IEM) as it has predicted changes in metabolite biomarkers for 49 IEM’s with 77% accuracy when compared to experimental data. Additionally Recon 2 has also mapped exometabolomic data, protein expression data and allows comparative analysis of cell type–specific models. Although Recon 2 is an extraordinary effort, it has not mapped the entire human metabolism as it includes 1800 out of approximately 20000 protein-coding genes in the human genome. Thus this map has to be constantly updated, as empirical evidence becomes available, to expand its coverage. The process utilised to construct this metabolism map has been described in detail in a recent article by Thiele et al. in Nature Biotechnology and the tool is freely available at http://humanmetabolism.org/. The authors believe that Recon 2 will facilitate many future biomedical studies and also aid in identifying the most effective treatment modalities for various diseases.
Consult the PubMed abstract

Screening and Testing
Opt-out approach for pilot study to screen for Spinal Muscular atrophy
A study published in American Journal of Medical Genetics suggests an “opt out approach” for a population-based pilot study of newborn screening for Spinal Muscular Atrophy (SMA) funded by the National Institutes of Health. In order to study the acceptability of this “opt-out approach”, as opposed to permission/consent models with the general population, the attitudes of the families were assessed by means of a focus group. They were provided with extensive information about various aspects of the screening as well as about SMA beforehand. Analysis of the study revealed that the participants generally and “considered this pilot study to be low risk and of potential benefit to infants and families” but were also supportive of the “opt-out approach” and appreciated extensive information dissemination.
Consult the PubMed abstract


Ethical, Legal & Social Issues
Cost of amyotrophic lateral sclerosis in Taiwan
In a recent article published in Tsai et al investigated the incidence and cost of amyotrophic lateral sclerosis between 1999 and 2008 in Taiwan. The authors found that“between the years 2006 through 2008, the average annual incidence and prevalence of ALS calculated from their database was 0.51 and 1.97 (per 105) respectively”. The study revealed that the average medical expenditure for ALS patients is higher than people suffering from other conditions such as dialysis and cancer and is 16-fold higher than in the general population of Taiwan in 2008. However, the authors also emphasised that healthcare of ALS patients in Taiwan has improved.
Consult the abstract

New EURORDIS website section focusing on Pharmacovigilance helps rare disease patients report problems with their medicines

EURORDIS http://www.eurordis.org/, the non-governmental patient-driven alliance of patient organisations representing 571 rare disease patient organisations in 52 countries and covering over 4000 diseases, encourages patients to take an active role in managing their disease. The latest endeavour is the new Pharmacovigilance section on the EURORDIS website. Pharmacovigilance refers to the monitoring of medicines, particularly in the area of safety and side effects. New treatments are becoming increasingly available for rare diseases, and many of these may be tested on smaller patient cohorts than treatments for more common illnesses. Thus, even after a treatment has been tested and approved, it is crucial to continue tracking the benefits and risks patients experience while taking it and to be especially vigilant for side-effects that patients might experience.
EURORDIS’ new Pharmacovigilance section emphasises the importance of reporting any problems a patient experiences with their medicine – whether a prescription drug or an over-the-counter treatment. Letting other members of the community, including the manufacturers of treatments and the agencies responsible for regulating their use, know when an undesired side-effect is experienced helps to improve the medicines available. The new Pharmacovigilance section offers guidance on how to report an adverse effect. Members of the public can report a side effect themselves or ask their health professional to do so. Many patient organisations also offer assistance on reporting side effects. The new section provides a list of available rare disease help lines in Europe, where assistance with reporting an adverse effect can be found. The new Pharmacovigilance section also explains how to check if other patients have reported a similar event. In April 2012, the European Medicines Agency starting making public the suspected adverse drug reaction reports filed by patients, consumers, health professionals or members of the biopharmaceutical industry and stored in the EudraVigilance database. The European Database of Suspected Adverse Drug Reaction Reports (http://www.adrreports.eu/) extracts data from EudraVigilance, allowing the public to view the adverse effects reported for different medicines. One can search for a specific medicine, and sort any existing data on reported side effects by type of reaction reported, age, gender, or geographic location. The new section, available in seven languages, has already received praise from the European Medicines Agency. EURORDIS hopes that by helping patients learn how to report adverse effects, medicines for rare diseases will become safer and more effective.
Learn more


New Syndromes

A new antibody deficiency syndrome associated with an inherited autosomal dominant mutation in TWEAK

The authors identified an autosomal-dominant deficiency in TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) in a kindred with recurrent infection and impaired antibody responses to protein and polysaccharide vaccines. The proband patient developed complicated pneumococcal meningitis in early childhood, and a review of the family medical history revealed that the proband, his elder sister and their father had a history of frequent ear or sinopulmonary infections since infancy. This new common variable immunodeficiency (CVID) features in all these three family members include cutaneous papillomatosis (multiple warts), absence of antibody responses to T-cell-dependent and polysaccharide antigens, low levels of IgM and IgA, and, in the children, low levels of IgG. The authors also highlight an increased number of TCRαβ+ CD4– CD8– T cells (double negative T cells) in these three patients.

Consult the PubMed abstract

Proc Natl Acad Sci U S A ; 110(13):5127-32 ; 26 March 2013
The 3q26.33-3q27.2 microdeletion syndrome

The authors describe three unrelated patients of European descent carrying an overlapping 3q26.33-3q27.2 microdeletion. Shared common clinical features are: neonatal hypotonia, severe feeding problems, specific facial features (flat profile, medially sparse eyebrows, epicanthal folds, and flat nasal bridge and tip), abnormal dentition, recurrent upper airways infections, developmental delay, intellectual disability, and severe growth impairment. One of these patients, with a smaller internal deletion, presents a milder phenotype.

Consult the PubMed abstract

Eur J Med Genet. ; 56(4):216-21 ; April 2013

New Genes

Congenital disorder of glycosylation: mosaicism of the UDP-galactose transporter SLC35A2 causes an X-linked disorder with abnormal transferrin glycosylation in infancy
Consult the PubMed abstract
To read more about "Congenital disorder of glycosylation"

Am J Hum Genet. ; 92(4):632-6 ; 4 April 2013
Autosomal recessive complex spastic paraplegia: a homozygous mutation in TFG, impairing endoplasmic reticulum structure, identified in two siblings with an early-onset disease
Consult the PubMed abstract
To read more about "Autosomal recessive complex spastic paraplegia"

Proc Natl Acad Sci U S A ; 110(13):5091-6 ; 26 March 2013
Inclusion body myopathy/Paget disease of bone/FTD/ALS: mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 are responsible in some families
Consult the PubMed abstract
To read more about "Inclusion body myopathy with Paget disease of bone and frontotemporal dementia"
To read more about "Amyotrophic lateral sclerosis"

Nature ; 495(7442):467-73 ; 28 March 2013
Left ventricular noncompaction: mutations in the NOTCH pathway regulator MIB1 at cause in autosomal-dominant pedigrees
Consult the PubMed abstract
To read more about "Left ventricular noncompaction"

Nature Medicine ; 19(2):193-201 ; February 2013
Osteogenesis imperfecta: mutations in WNT1, mostly recessive, responsible in different forms of early-onset bone fragility
Consult the PubMed abstracts
To read more about "Osteogenesis imperfecta"
To read more about "Osteogenesis imperfecta type 4"

Am J Hum Genet. ; 92(4):565-74 ; 4 April 2013
Am J Hum Genet. ; 92(4):590-7 ; 4 April 2013
J Med Genet. ; 50(5):345-8 ; May 2013
Autosomal recessive nonsyndromic intellectual deficit and hyperphosphatasia intellectual deficiency syndrome: mutations in PGAP2, involved in GPI-anchor synthesis, identified
Consult the PubMed abstracts
To read more about "Autosomal recessive nonsyndromic intellectual deficit"
To read more about "Hyperphosphatasia-intellectual deficiency syndrome"

Am J Hum Genet. ; 92(4):575-83 ; 4 April 2013
Am J Hum Genet. ; 92(4):584-9 ; 4 April 2013
Adams-Oliver syndrome: recessive mutations in EOGT found at cause in three families, highlighting a developmental role of O-GlcNAcylation
Consult the PubMed abstract
To read more about "Adams-Oliver syndrome"

Am J Hum Genet. ; 92(4):598-604 ; 4 April 2013
Perrault syndrome: mutations in CLPP identified in three families and mutations in LARS2 discovered in two other families
Consult the PubMed abstracts
To read more about "Perrault syndrome"

Am J Hum Genet. ; 92(4):605-13 ; 4 April 2013
Am J Hum Genet. ; 92(4):614-20 ; 4 April 2013
Scalp-ear-nipple syndrome: missense mutations in KCTD1 found responsible in all ten families tested
Consult the PubMed abstract
To read more about "Scalp-ear-nipple syndrome"

Am J Hum Genet. ; 92(4):621-6 ; 4 April 2013
2-hydroxyglutaric aciduria: SLC25A1 mutations cause combined D-2- and L-2-hydroxyglutaric aciduria in 12 children and agenesis of corpus callosum and optic nerve hypoplasia in one
Consult the PubMed abstracts
To read more about "2-hydroxyglutaric aciduria"

Am J Hum Genet. ; 92(4):627-31 ; 4 April 2013
J Med Genet. ; 50(4):240-5 ; April 2013
Autosomal recessive cortical myoclonic tremor and epilepsy: association with a mutation in the potassium channel associated gene CNTN2 in a family
Consult the PubMed abstract
To read more about "Benign adult familial myoclonic epilepsy"

Brain ; 136(Pt 4):1155-60 ; April 2013
Distal myopathy, Welander type: a mutation in the TIA1 gene, encoding a protein involved in splicing and translational regulation, found responsible
Consult the PubMed abstracts
To read more about "Distal myopathy, Welander type"

Hum Mutat. ; 34(4):572-7 ; April 2013
Ann Neurol. ; doi: 10.1002/ana.23831. [Epub ahead of print] ; 13 December 2012
Primary dystonia, DYT4 type: mutations in the β-tubulin 4a gene (TUBB4A) at cause
Consult the PubMed abstract of the first article
Consult the abstract of the second article

To read more about "Primary dystonia, DYT4 type"

Ann Neurol. ; doi: 10.1002/ana.23832. [Epub ahead of print] ; 13 December 2012
Ann Neurol. ; doi: 10.1002/ana.23829. [Epub ahead of print] ; 13 December 2012
Autosomal dominant spondylocostal dysostosis: first identification of a causal gene, TBX6, in one family
Consult the PubMed abstract
To read more about "Autosomal dominant spondylocostal dysostosis"

Hum Mol Genet. ; 22(8):1625-31 ; 15 April 2013
Walker-Warburg syndrome: two homozygous missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) found responsible in a family
Consult the PubMed abstract
To read more about "Walker-Warburg syndrome"

Hum Mol Genet. ; 22(9):1746-54 ; 1 May 2013
Arthrogryposis with oculomotor limitation and electroretinal anomalies: gain-of-function mutations in the mechanically activated ion channel PIEZO2 identified in two kindreds
Consult the PubMed abstract
To read more about "Arthrogryposis with oculomotor limitation and electroretinal anomalies"

Proc Natl Acad Sci U S A ; 110(12):4667-72 ; 19 March 2013
Distal arthrogryposis: the neuronal endopeptidase ECEL1 is associated with a distinct recessive form
Consult the PubMed abstract
To read more about "Distal arthrogryposis"

Hum Mol Genet. ; 22(8):1483-92 ; 15 April 2013
Double outlet right ventricle: a ZIC3 mutation detected in a female with isolated DORV
Consult the PubMed abstract
To read more about "Double outlet right ventricle"

Am J Med Genet A. ; 161(4):792-802 ; April 2013
Common variable immunodeficiency: a homozygous PRKCD mutation (c.1352+1G>A) identified in a boy with B cell deficiency and severe autoimmunity
Consult the PubMed abstract
To read more about "Common variable immunodeficiency"

Blood ; [Epub ahead of print] ; 14 January 2013
Autoimmune lymphoproliferative syndrome: a homozygous mutation in PRKCD (c.1840C>T) in a patient with B cell hyperproliferation, NK dysfunction and chronic low grade EBV infection
Consult the PubMed abstract
To read more about "Autoimmune lymphoproliferative syndrome"

Blood ; [Epub ahead of print] ; 21 February 2013

Research in Action

Clinical Research
Fabry disease: long term enzyme replacement therapy does not prevent disease progression, but longer treatment duration may lower the risk of developing additional complications
Consult the PubMed abstract
To read more about "Fabry disease"

Orphanet Journal of Rare Diseases ; 8:47 ; 25 March 2013
Glycogen storage disease due to acid maltase deficiency: a prospective international observational study shows a positive effect of enzyme replacement therapy on survival in adults
Consult the PubMed abstract
To read more about "Glycogen storage disease due to acid maltase deficiency"

Orphanet Journal of Rare Diseases ; 8:49 ; 27 March 2013
Nonacetaminophen acute liver failure: N-acetylcysteine did not improve 1-year survival in paediatric patients in a placebo-controlled study
Consult the PubMed abstract
Hepatology ; 57(4):1542-9 ; April 2013
Precursor B-cell acute lymphoblastic leukaemia: marked antitumour efficacy of 19-28z chimeric antigen receptor-modified T cells in adults with relapsed disease
Consult the PubMed abstract
To read more about "Acute lymphoblastic leukemia"

Sci Transl Med. ; 5(177):177ra38 ; 20 March 2013
Indolent and mantle-cell lymphomas: bendamustine and rituximab more effective and less toxic than rituximab-CHOP as first-line treatment in a phase 3 study
Consult the PubMed abstract
To read more about "Follicular lymphoma"
To read more about "Waldenström macroglobulinemia"
To read more about "Mantle cell lymphoma"

The Lancet ; 381(9873):1203-10 ; 6 April 2013
Enteropathy-associated T-cell lymphoma: autologous stem cell transplantation provides long-term remission in the majority of patients transplanted in first remission
Consult the PubMed abstract
To read more about "Enteropathy-associated T-cell lymphoma"

Blood ; 121(13):2529-2532 ; 28 March 2013
Systemic sclerosis: a retrospective assessment of autologous haemopoietic stem-cell transplantation
Consult the PubMed abstract
To read more about "Systemic sclerosis"

The Lancet ; 381(9872):1116-24 ; 30 March 2013
Sickle cell anaemia: preoperative transfusion was associated with decreased perioperative complications in a randomised, controlled, multicentre clinical trial
Consult the PubMed abstract
To read more about "Sickle cell anemia"

The Lancet ; 381(9870):930-8 ; 16 March 2013
Malignant atrophic papulosis: effective treatment with treprostinil in two patients with MAP or MAP-like lesions
Consult the PubMed abstract
To read more about "Malignant atrophic papulosis"

Orphanet Journal of Rare Diseases ; 8:52 ; 4 April 2013
Mixed cryoglobulinaemia associated with lymphoma: fludarabine, cyclophosphamide, and rituximab (FCR) regimen appears as an effective treatment in seven severe and refractory cases
Consult the PubMed abstract
To read more about "Mixed cryoglobulinemia"

Arthritis Care Res (Hoboken) ; 65(4):643-7 ; April 2013
Primary mediastinal large B-cell lymphoma: therapy with dose-ajusted-EPOCH-rituximab obviated the need for radiotherapy in a single-group, phase 2, prospective study
Consult the PubMed abstract
To read more about "Primary mediastinal large B-cell lymphoma"

NEJM ; 368(15):1408-16 ; 11 April 2013
Gene Therapy
Usher syndrome type 1: sustained rescue of hearing and vestibular function with a single neonatal injection of antisense oligonucleotides in a mouse model
Consult the PubMed abstract
To read more about "Usher syndrome"

Nature Medicine ; 19(3):345-50 ; March 2013
Leber congenital amaurosis: S/MAR-containing DNA nanoparticles promote persistent retinal pigment epithelium gene expression and improvement in RPE65(-/-) mice
Consult the PubMed abstract
To read more about "Leber congenital amaurosis"

Hum Mol Genet. ; 22(8):1632-42 ; 15 April 2013
Duchenne muscular dystrophy: microdystrophin ameliorates muscular dystrophy in the canine model
Consult the PubMed abstract
To read more about "Duchenne muscular dystrophy"

Molecular Therapy ; 21(4):750-7 ; April 2013
Therapeutic Approaches
Fragile X syndrome: rescue of FMR1 knockout mice phenotype by the small-molecule PAK inhibitor FRAX486
Consult the PubMed abstract
To read more about "Fragile X syndrome"

Proc Natl Acad Sci U S A ; 110(14):5671-6 ; 2 April 2013
X-linked centronuclear myopathy: enzyme replacement therapy rescues weakness and improves muscle pathology in model mice
Consult the PubMed abstract
To read more about "X-linked centronuclear myopathy"

Hum Mol Genet. ; 22(8):1525-38 ; 15 April 2013
Acute myeloid leukaemia: fenretinide, a well-tolerated vitamin A derivative, appears as a potent agent that selectively targets leukaemia stem cells
Consult the PubMed abstract
To read more about "Acute myeloid leukemia"

Proc Natl Acad Sci U S A ; 110(14):5606-11 ; 2 April 2013
B-cell chronic lymphocytic leukaemia: remarkable efficacy of a humanised monoclonal antibody specific for CD44
Consult the PubMed abstract
To read more about "B-cell chronic lymphocytic leukemia"

Proc Natl Acad Sci U S A ; 110(15):6127-32 ; 9 April 2013
Menkes disease: L-threo-dihydroxyphenylserine corrects neurochemical abnormalities in a mouse model, but without arrest of global brain pathology nor improvement of somatic growth
Consult the PubMed abstract
To read more about "Menkes disease"

Ann Neurol. ; 73(2):259-65 ; February 2013
Amyotrophic lateral sclerosis: molecular chaperone HSP110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm
Consult the PubMed abstract
To read more about "Amyotrophic lateral sclerosis"

Proc Natl Acad Sci U S A ; 110(14):5428-33 ; 2 April 2013
Diagnostic Approaches

Autosomal dominant nonsyndromic sensorineural deafness type DFNA: predicting genotypes from phenotypes to guide genetic screening with the software system AudioGene
Consult the PubMed abstract
To read more about "Autosomal dominant nonsyndromic sensorineural deafness type DFNA"

Hum Mutat. ; 34(4):539-45 ; April 2013

Patient Management and Therapy

Autoinflammatory diseases: results from the Eurofever Registry and a literature review proposed as a basis for therapeutic guidelines
Consult the PubMed abstract
To read more about "Familial mediterranean fever"
To read more about "Cryopyrin-associated periodic syndrome"
To read more about "TRAPS syndrome"
To read more about "Mevalonate kinase deficiency"
To read more about "Pyogenic arthritis - pyoderma gangrenosum - acne"
To read more about "Sterile multifocal osteomyelitis with periostitis and pustulosis"
To read more about "NLRP12-associated hereditary periodic fever syndrome"
To read more about "Marshall's syndrome with periodic fever"

Arthritis and Rheumatism ; 72(5):678-85 ; May 2013
Low-risk papillary and differentiated thyroid cancers: two reviews
Consult the abstract of the first review
Consult the abstract of the second review

To read more about "Papillary or follicular thyroid carcinoma"

The Lancet ; 381(9871):1046-57 ; 23 March 2013
The Lancet ; 381(9871):1058-69 ; 23 March 2013
Aristolochic acid nephropathy: a narrative review on epidemiology, diagnosis, and management
Consult the PubMed abstract
Ann Intern Med. ; 158(6):469-77 ; 19 March 2013

Orphan Drugs
Regulatory News
A new model for the drug development pipeline
An article published in Science Translational Medicine has suggested revamping the current model of drug development and has elucidated a comprehensive new model. According to the authors the current inadequacies in the drug development system has made it a sluggish process due to which significantly numbers of drugs approvals do not materialise. This is greatly detrimental to patients who are waiting for treatments. Additionally, the entire drug development processes is extremely expensive and a time consuming venture. The authors reject the current linear model of drug development which they believe is grossly oversimplified and defunct and propose a model called Navigating the Ecosystem of Translational Sciences (NETS) “that is sufficiently complex” with a “collection of interconnected processes with iterative feedback loops, rather than a series of discrete steps but allows these normally disparate players to assemble”. This model according to the authors mirrors the needs of the 21st century drug development as the process reflects the concerns of all stakeholders instead of one. The model emphasises that for successful drug development it is imperative that basic science, therapeutic target discovery, nonclinical research, regulatory science and clinical research function collaboratively. In addition to revamping the current model, the author also suggests changes in the current grant system so that it encourages novel research for the current needs.
Consult the Journal

The regulatory success of Protein Replacement therapies
A recent article published in Science Translational Medicine discusses the high percentage of approval rate of Monogenic Protein Replacement Therapies (MPRT) making a case for expanded investment into MPRT’s. The authors analysed the regulatory approval rates of MPRT’s compared to other orphan drugs and other drug classes and show that greater than 85% of MPRT’s are approved. The authors ascribe the regulatory success of MPRTs on high understanding of “clinical pathogenesis, mechanism of action, and ability to manufacture the MPRT” blood components and many lysosomal enzymes and due to this they require smaller clinical trials. The authors recognise that the probability of success for MPRT’s for lysosomal or blood disorders is high because of the vast amount of research on the mechanism of this disease and success rates for targets of other diseases may not be the same. Nevertheless, the authors feel that this high probability of approval for MPRT’s should be the basis of providing incentives for the development of protein replacement therapies for several other monogenic diseases that do not have an approved therapy.
Consult the Journal

Political and Scientific News
Small clinical trials: challenges and support
Performing clinical trials for orphan drugs is often challenging due to the limited sample size available. A standard randomised controlled trial, “the gold standard for clinical trials” is often not possible in these circumstances. To analyse these drug trials “a number of alternative trial designs” are possible, however choosing the best statistical strategy is not always straightforward.
Two recent articles have reviewed the strategies currently used in clinical trials with a small sample size. An article appearing in Science Translational Medicine has provided a review of the advantages and challenges associated with the orphan drug trial process. They have described real world examples of the use of statistical tools in clinical trials with small numbers. They explain that the use of the statistical method differs with the “disease-treatment-outcome”. The statistical method used when the treatment is expected to provide considerable benefit from the current available therapies is different from the method used when a moderate to large or moderate to small benefit is expected. When a marked improvement is expected, usually in circumstances when the treatment is developed due to better understanding of the disease, a randomised clinical trial is not warranted. However, when this is not the case, a randomised clinical trial is expected, especially in cases where only a small to moderate benefit from the current treatment is expected. The authors recommend that to “permit appropriate interpretation and maximise the usefulness of the results” the study design should be “prospectively defined with a clear statement of primary objectives and a prespecified statistical analysis plan to address those objectives and should be “reported in a complete and transparent fashion, including discussion of limitations that arise from small sample size (as will be seen by wide confidence intervals) and potential biases”.
Consult the PubMed abstract

The other article, which is published in the Orphanet Journal of Rare Diseases has proposed an algorithm as a “tool for the choice of an appropriate trial design in the development of orphan drugs for a given disease-treatment-outcome situation”. The authors identified the algorithm which is based on the characteristics of 12 possible trial designs. According to the authors, this algorithm should help choosing a clinical trial design which is challenging when it comes to orphan drug trials due to the limited sample size.
Consult the open access article



Funding announced to develop treatment for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
The Ataxia of Charlevoix-Saguenay Foundation is offering an annual research grants for work aimed at developing treatments for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Such funding is offered regardless of where the research is being conducted.
Application deadline- 23 May 2013. Further information and the application form can be obtained on the Foundation’s website

Funding available to investigate treatment for Plexiform Neurofibroma
The Neurofibromatosis Therapeutic Acceleration Program (NTAP) invite proposals for projects that help the acceleration of the development of effective treatment of plexiform neurofibromas at any time. Application deadline is June 14 2013.
NTAP is a privately funded research program housed within Johns Hopkins University in Baltimore, Maryland who have funded several research projects that advance the knowledge of Neurofibromatosis.
For further details

NORD announces seed grants for rare disease research
NORD has announced funding opportunities in 6 areas of rare disease research. NORD has invited applicants from within the US and overseas to apply with a letter of intent by 15 May 2013. Full proposals are due by 11 September 2013. Researchers with projects in the following areas are encouraged to apply

RFPs for Pseudomyxoma Peritonei (PMP), Spring 2013
Two grants are available through NORD ($50,000/grant) for research related to Pseudomyxoma Peritonei (PMP).

RFP for Growth Failure in Children with Cardiofaciocutanous (CFC) Syndrome
Funding is available ($30,000) for research on growth failure in children with cardiofaciocutaneous (CFC) syndrome.

RFP for Glycine Encephalopathy, aka Nonketotic Hyperglycinemia, Spring 2013
Funding for research related to Glycine Encephalopathy, aka Nonketotic Hyperglyinemia, is available through NORD's Research Seed Grant Program ($34,000).

RFP for Adult Primary Lateral Sclerosis (PLS)
Funding is available ($30,000) for research on Primary Lateral Sclerosis (PLS).

RFP Available for Research Related to Dubowitz Syndrome
Funding is available ($30,000) for research on Dubowitz Syndrome
For further details

Jerome Lejeune Foundation announces Prix International Sisley-Jérôme Lejeune
Prix International Sisley-Jérôme Lejeune awards € 30,000 to researchers who work towards finding therapies for genetic diseases that lead to intellectual disability. The deadline for submissions is 12 May 2013.
For further in formation on Prix International Sisley-Jérôme Lejeune

Call for Abstracts from researchers studying Rare Diseases for publication in the Journal of General Internal Medicine
The Effective Health Care Program within the US Department of Health and Human Services’ Agency for Healthcare Research and Quality is accepting abstract submissions for a journal supplement on research methods for evaluating patient health outcomes in rare diseases. The proposed supplement will focus on innovative patient-centered health outcomes research methodology and its application to rare diseases or drugs/devices used to treat such patients. Abstract submissions are due by May 31, 2013.
For Further Information


Partnersearch, Job Opportunities
Position for Bioinformatics Group at The Institute of Genetic Diseases Imagine
The Institute of Genetic diseases at Necker Enfants-Malades Hospital, in Paris invites applications from the area of bioinformatics, computational biology, and/or statistical genetics. Imagine, is an multidisciplinary research center, supported by a rare disease Foundation. Application deadline is 15 May.
Learn more about the Institute
Learn more about the position

Research Associate/ Postdoctoral Scientist: to lead on impact activities for EU network
Position open for dynamic scientist to work on the EU funded RD-Connect project. Candidates with PhD in relevant area (e.g. Genetics), high level of knowledge in Omics/translational research field, interest is healthcare and demonstrated experience in the industry are encouraged to apply. You will join an international, multidisciplinary team at the Newcastle Muscle Centre led by Professors Kate Bushby, Volker Straub and Hanns Lochmüller and situated within the Institute of Genetic Medicine at the International Centre for Life in Newcastle upon Tyne. Learn more

Courses & Educational Initiatives
International Summer School “Clinical practice guidelines on rare diseases”
Date: 8-12 July, 2013
Venue: Rome, Italy

Istituto Superiore di Sanità is inviting applications from participants who would like to learn more about development process of clinical practice guidelines.
The following topics will be covered:
o Identifying key clinical issues to be included (scope)
o Developing review questions using PICO and planning the systematic review
o Identifying evidence: formulating, executing and documenting a search strategy
o Assessing the quality of relevant studies, summarizing and interpreting the body of evidence to make recommendations
o Obtaining formal consensus in the absence of evidence (Delphi-like method)
o Appraising synthesis documents: guidelines and systematic reviews
The course format consists of brief presentations followed by individual or small group exercises.
This course is free of charge and application/registration is currently open. Please, feel free to circulate this information to those who may have an interest in attending.
For further details


What's on Where?

International Rare Diseases Research Consortium Conference 2013
Date: 16-17 April 2013
Venue: Dublin, Ireland

IRDiRC will team up researchers and organisations investing in rare diseases research in order to deliver 200 new therapies for rare diseases and means to diagnose most rare diseases by the year 2020.
For further details

World Federation of Hemophilia 13th International Musculoskeletal Congress 2013
Date: 18-21 April 2013
Venue: Chicago, USA

This Congress brings together world-leading orthopaedic surgeons, haematologists, and physiotherapists specialized in the treatment and care of patients with bleeding disorders. Participants will spend three days not only analyzing and discussing new medical developments but also looking at problems and issues in different parts of the world.
For further details

7th Alstrom Syndrome International Family Conference and Scientific Symposium
Date: 9-13 May 2013
Venue: Massachusetts, USA

Medical professionals and scientists will hold Symposia on Thursday, 9 May and Saturday 11 May.
For further details

Autoinflammation 2013: 7th International Congress of the International Society of Systemic Auto-Inflammatory Diseases
Date: 22- 26 May 2013
Venue: Lausanne, Switzerland

The meeting will offer a unique opportunity to gather experts from all over the world to discuss the latest scientific and clinical issues on different topics, including the challenges of the new treatments for autoinflammatory diseases such as familial Mediterranean fever; new monogenic autoinflammatory diseases; systemic-onset JIA; Behçet; granulomatous diseases; amyloidosis; and other conditions.
For further details

4th International DSD (Disorders of Sex Development) Symposium
Date: 7-9 June 2013
Venue: Glasgow, UK

This symposium should be of interest to health care staff, clinical and basic scientists and parent & patient support groups. Plenary Sessions planned include: Priorities for the Future, Drug-based Therapeutic Interventions, Care & Communication, Navigating the Information Highway, Management of the Retained Gonad.
For further details

12th European Symposium on Congenital Anomalies
Date: 12-14 June 2013
Venue: Zagreb, Croatia

Topics include 50 years after thalidomide therapy, Childhood morbidity and mortality due to congenital anomalies, Medication in pregnancy, Prevention of congenital anomalies, Prenatal diagnosis, Preconceptional and prenatal care, Environmental risks, Outcomes of children with a congenital anomaly, Public health policies, Genetics of congenital anomalies, Health care for children with congenital anomalies
For further details

10th HHT Scientific Conference
Date: 12-15 June 2013
Venue: Cork, Ireland

HHT is a genetic disorder that causes abnormalities of blood vessels. The conference will include presentations on basic research on HHT to clinical research, drug development as well as policy issues.
For further details

World Orphan Drug Congress Asia
Date: 18 June 2013
Venue: Singapore

This commercial one-day event will bring together orphan drug manufacturers and developers to expedite orphan drugs for patients.
For further details
6th International Conference on Children's Bone Health
Date: 22-25 June 2013
Venue: Rotterdam, Netherlands

The conference is to try to get a better understanding in healthy and disease states of bone development by discussing molecular pathways as well clinical characteristics.
For further details

Fifth BHD Symposium and Second HLRCC Symposium
Date: 28-29 June 2013
Venue: Paris, France

This conference will be an excellent opportunity for stakeholders of Birt-Hogg-Dubé Syndrome to participate and network. The conference will comprise of invited lectures by worldwide experts, followed by panel discussion, and will also include a poster exhibition.
For further details

9th European Cytogenetics Conference
Date: 29 June - 02 July 2013
Venue: Dublin, Ireland

An opportunity for cytogeneticists to come together to discuss developments ranging from applications in prenatal or cancer diagnosis to chromosome biology in epigenetics and evolution.
For further details

8th International Prader-Willi Syndrome Conference
Date: 17-21 July 2013
Venue: Cambridge, UK

An opportunity for all involved worldwide in research, working or living with people with PWS to present current research and explore best practice in clinical and day to day management of PWS.
For further details

Orphan Drugs Summit 2013
Date: 11-13 September 2013
Venue: Copenhagen, Denmark

This commercial event will highlight several burning topics revolving market authorisation of Orphan Medicinal Products such as market access, regulatory framework, clinical trial development as well as financing
For further details

2nd Conference of 'EB-CLINET - Clinical Network of EB Centres and Experts'
Date: 17-18 September 2013
Venue: Salzburg, Austria

The conference will present and discuss the work packages initiated during the 2012 EB clinet meeting.
For further details

Mitochondrial Disease: Translating biology into new treatments
Date: 2-4 October 2013
Venue: Cambridge, UK

This is a brand new conference that will discuss mitochondrial medicine. During this interactive conference several experts will speak about translational mitochondrial medicine. Abstracts are due by 16 July 2013 and the registration deadline is on 20 August 2013
For further details

Orphan Drug & Rare Disease Seminar “Accelerating access to therapeutic innovation”
Date: 17-18 October 2013
Venue: Marseille; France

This event, jointly organised by Eudipharm, F-Crin and OrphanDev, will aim to address issues that to help fill the current discrepancies in translational research for rare diseases and creating awareness of clinical research sectors.
For further details

3rd European Rett Syndrome Conference Maastricht, “Research Update & Preventive Management”
Date: 17-19 October 2013
Venue: Maastricht, The Netherlands

This conference aims to gather renowned researchers and clinicians working in the area of Rett Syndrome, to encourage interdisciplinary international cooperation. The conference also aims to provide stakeholders with the latest information on treatment of symptoms as well as preventative manangement.
For further details

Thalassemia International Federation World Congress
Date: 19-23 October 2013
Venue: Abu Dhabi, United Arab Emirates

Topics for this conference includes “all aspects of prevention, management and care of thalassemia and sickle cell disease and a one-day patient programme”.
For further details

First International Primary Immunodeficiencies Congress (IPIC)
Date: 7-8 November 2013
Venue: Estoril, Portugal
The International Patient Organisation for Primary Immunodeficiencies (IPOPI) announces the First International Primary Immunodeficiencies Congress (IPIC), a congress for all stakeholders with an interest in primary immunodeficiencies (PIDs). IPIC will provide a two-day programme focusing on clinical developments including PIDs pathogenesis, treatment, management of complications and more. Access to diagnosis and care, SCID newborn screening and other key world developments will also be addressed.
For further details

14th International Congress on Neuronal Ceroid Lipofuscinoses (Batten Disease)
Date: 22-25 October 2014
Venue: Córdoba- Argentina

Batten disease is a common name for a group of rare, neurodegenerative genetic disorder affecting approximately 1 in 30,000 individuals. There is presently no known cure for Batten disease


Orphanews International, the newsletter of the European Union Committee of Experts on Rare Diseases
Orphanews International is supported by the European Commission's DG SANCO (EUCERD Joint Action N° 2011-22-01)
and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Ségolène Aymé
Editor: Divya Unni
Contact Us
Editorial Board: Ségolène Aymé, Kate Bushby, Catherine Berens, Barbara Cagniard, Virginie Hivert, Helena Kaariainen, Odile Kremp, Yann Le Cam, Jordi Llinares-Garcia, Antoni Montserrat, Catherine Pouzat, Charlotte Rodwell, Jaroslaw Waligora

EUCERD Country Representatives: Helmut Hintner (Austria), Pol Gerits (Belgium), Rumen Stefanov (Bulgaria), Ivo Baric (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek Jr. (Czech Republic), Marianne Jespersen (Denmark), Inna Vabamae (Estonia), Helena Kaariainen (Finland), Alain Garcia (France), Birgit Schnieders (Germany), Christos Katamis (Greece), Zsuzsanna Lengyel (Hungary), Thor Thorarinsson (Iceland) , John Devlin (Ireland), Annick Raas-Rotshild (Israel), Bruno Dallapiccola (Italy), Antra Valdmane (Latvia), Romalda Baranauskiene (Lithuania) , Yolande Wagener (Luxembourg), Miriam Dalmas (Malta), Jolande Huizer (Netherlands), Stein Are Aksnes (Norway), Jacek Gralinski (Poland), Alexandre Diniz (Portugal), Emilia Severin (Romania), Borut Peterlin (Slovenia), Frantisek Cisareik (Slovak Republic), Isabel Pena-Rey (Spain), To be nominated (Sweden) , Sabina Gallati (Switzerland), Edmund Jessop (UK)
EUCERD ECDC Representative: Andrew Amato
EUCERD Patient Organisation Representatives: Dorica Dan, Yann Le Cam, Christel Nourissier, Bianca Pizzera
EUCERD Pharmaceutical Industry Representatives: Wills Hughes-Wilson, Kevin William Loth, Samantha Parker, Barbara Valenta
EUCERD Rare Disease Projects under Health Programmes Representatives: Ségolène Aymé, Jean Donadieu, Dian Donnai, Laura Fregonese, Ester Garne, Domenica Taruscio, Joan Luis Vives Corrons, Thomas Wagner, Susan Webb
EUCERD Rare Diseases Research Projects under Framework Programmes for Research and Technological Development Representatives: Jean-Yves Blay, Kate Bushby, Marc de Baets, Olaf Hiort, Sophie Koutouzov, Gerard Wagemaker
EUCERD European Commission Participants: Catherine Berens, Iiro Eerola, Jordi Llinares-Garcia (EMA), Georgios Margetidis, Jaroslaw Waligora, Antoni Montserrat Moliner, Michael Huebel, Bruno Sepodes (EMA-COMP)

Orphanet Partner Country Representatives: Tamara F. Sarkisian (Armenia), Hugh Dawkins (Australia), Till Voigtlander (Austria), Rumen Stefanov (Bulgaria), Ana Stavljenic-Rukavina (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), John Rosendahl Ostergaard (Denmark), Vallo Tillmann (Estonia), Riitta Salonen (Finland), Joerg Schmidtke (Germany), Helen Michelakakis (Greece), András Becskeházi (Hungary), Andrew Green (Ireland), Lina Basel (Israel), Bruno Dallapiccola (Italy), Tomoko Kodama (Japan), Jana Lepiksone (Latvia), André Mégarbané (Lebanon), Viadutis Kucinskas (Lithuania), Yolande Wagener (Luxembourg), Abdelaziz Sefiani (Morocco), Gert-Jan van Ommen (Netherlands), Stein Are Aksnes (Norway), Malgorzata Krajewska-Walasek (Poland), Jorge Sequeiros (Portugal), Cristina Rusu (Romania), Dragica Radojkovic (Serbia), Laszlo Kovacs (Slovakia), Borut Peterlin (Slovenia), Francesc Palau (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Ugur Ozbek (Turkey), Dian Donnai (UK)
For more information on the European Union Committee of Experts on Rare Diseases
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