1 December 2010 print
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Editorial
 
UK physicians claim loopholes are undermining the Orphan Drug Regulation’s intended purpose
 
A series of articles published in the 16 November issue of the British Medical Journal (BMJ) depict perceived exploitation of Regulation (EC) No 141/2000 (the Orphan Drug Regulation) - legislation intended to stimulate the development of medicinal products for rare diseases by providing incentives to the biopharmaceutical industry. An Open Letter from 20 UK neurologists and paediatricians addressed to Prime Minister David Cameron and Health Secretary Andrew Lansley calls attention to the practice of "licensing drugs that are already available rather than developing new treatments." Citing the case of the product 3,4-diaminopyridine, used for rare diseases Lambert-Eaton myasthenic syndrome and congenital myasthenic syndrome, available on an unlicensed basis for about €1000 per patient/year, but which is now being licensed, rebranded and remarketed to the tune of between €45,000-€82,000 per patient/year, the authors call for "urgent review" of the Orphan Drug Regulation which they feel can, in such cases, "...severely limit[] the availability of existing treatments". Another article in the same issue queries What Makes an Orphan Drug? and synthesises how certain loopholes in the Orphan Drug Regulation can lead to price gouging. Meanwhile, an Editorial further defines the Problem of the Orphan Drugs by furnishing other examples of repackaging, rebranding or recycling existing chemicals in order to gain profits. Evoking the "unintended consequence of exploitation of the rules for profit" the authors concede that while industry needs encouragement to develop orphan products, it must "accept value based pricing when it arrives in the next [UK] Pharmaceutical Price Regulation Scheme." The authors call for a mechanism similar to the French Agence Générale des Equipements et Produits de Santé, which allows for the legitimate fabrication and distribution of unlicensed rare disease products when a licensed product is not available. They also state that physicians should be allowed to "prescribe a drug that meets the individual patient's needs but is not licensed for the specific indication, even if a licensed medicine exists for the same indication". Other stakeholders, however, point out the benefits of licensing - including the obligation to monitor product safety and efficacy and track disease outcome. Licensing also provides vital post-marketing information and helps capture elusive data essential to such small populations.

What is "fair"?
Another BMJ article on the topic explores whether a Competition Law investigation is needed to determine whether orphan drug pricing is fair. Such an investigation could look at profit margins, return on investment, or manufacturer cost base, for example. Asserting that "current high pricing hinders access to treatment and contravenes the aim of the Orphan Regulation", the authors lament the fact that the Orphan Drug Regulation failed to "create an oversight body to regulate prices and protect consumers from market abuse, by contrast with other state sanctioned monopolies". Article 102 of existing competition law "prohibits abuse by one or more undertakings of a dominant position within the internal market or in a substantial part of it. ... Such abuse may, in particular, consist in: (a) directly or indirectly imposing unfair purchase of selling prices or other unfair trading conditions...". However, no conclusive definition of "fair" is provided within Article 102. Despite this, the authors assert that "...the Article 102 investigation route could offer the most direct and effective mechanism to curb excessive pricing even if no abuse in ultimately found". It must be remembered, as stakeholders would certainly agree, that "A sufficient profit motive must be preserved to ensure that the industry continues to attract the necessary capital to fund drug development". The authors conclude by suggesting that "while competition law potentially offers a direct and effective route to address the difficult problem of orphan drug pricing, it may also inspire a less contentious resolution: the prospect of regulatory action could motivate a constructive dialogue on acceptable pricing levels, and even result in further EU orphan legislation."

Apples and oranges
One must be careful not to mix apples with oranges. The Orphan Drug Regulation was designed to promote the research and development of orphan medicinal products at the EU level with the understanding that price issues would continue to be determined at the Member State-level. The complex question of pricing has, in fact, been under scrutiny at the EU level since the Orphan Drug Regulation was adopted in 2000, and continues to be a priority for policy makers and other stakeholders. Recent evidence of this can be found in the March 2010 Call for Tender concerning the creation of a mechanism for the exchange of knowledge between Member States and European authorities on the scientific assessment of the clinical added value for orphan medicines (learn more). Furthermore, the EU Health Pharmaceutical Forum Final Conclusions and Recommendations, Improving Access to Orphan Medicines for All Affected EU Citizens put forward ideas to ensure the timely and equitable access for all EU citizens to orphan medicines (learn more). Finally, the proposal for the creation of a Working Party within the European Medicines Agency for the assessment of the Clinical Added Value of Orphan Drugs (CAVOD) seeks to increase collaboration between Member States and EU-level authorities. The BMJ articles serve as a reminder to move forward the process of making orphan products accessible and affordable while continuing to encourage their development.

 


 
Spotlight on...
 
Clinical Utility Gene Cards, now available on Orphanet, provide guidance for the genetic testing of rare conditions
 
EuroGentest, the EU-funded Network of Excellence for genetic testing, has developed disease-specific points to consider regarding clinical indications for genetic testing - the Clinical Utility Gene Cards (CUGCs). These documents, providing clinicians and clinical geneticists with guidance on genetic testing for specific conditions in real settings of clinical genetic services, are now available on the Orphanet website for a number of diseases. (Consult the list of CUGS available on Orphanet)

The CUGCs focus on Mendelian diseases. According to the ACCE (Analytical validity, Clinical validity, Clinical utility and Ethical, legal and social implications) evaluation scheme, they mainly address two sections: the clinical and analytical validity (informative value) of available genetic tests, and clinical usefulness in diagnostic, predictive, and prenatal settings. While the analytical validity of most tests does not present major problems, little if any, information is available in the literature on utility aspects of the molecular tests on rare diseases performed routinely in most laboratories. EuroGentest solicits the CUGCs from a selected international group of experts. Authors are identified based on criteria such as their publication record and practical experience. The CUGC drafts are peer-reviewed and published by the European Journal of Human Genetics (EJHG). All published documents are freely available through the EJHG or EuroGentest, as well as Orphanet. The CUGCs represent the state-of-the-art at the time of publication. They will undergo punctual revisions in order to stay current with advances in medical and scientific technology and information. Existing CUGCS have been developed for a variety of rare inherited disorders, including Ehlers–Danlos syndrome types I–VII, Lynch syndrome, haemochromatosis, Marfan syndrome type 1 and related phenotypes, DiGeorge syndrome, velocardiofacial syndrome, Shprintzen syndrome, and chromosome 22q11.2 deletion syndrome.

OrphaNews Europe interviewed Anna Dierking, of the Institute of Human Genetics, Hannover Medical School, Germany, who commissions the CUGCS for EuroGentest :

OrphaNews Europe: How did the idea of developing the CUGCs come about? How was it determined which elements to include?

Anna Dierking: The basic principle of the CUGC guidelines, the evaluation of clinical utility in genetic testing, is based on the ACCE framework. ACCE, which stands for Analytical validity, Clinical validity, Clinical utility and Ethical, legal and social issues, was developed by the Centers for Disease Control and Prevention. Based on the general concept developed by EuroGentest, the German Society of Human Genetics established disease-specific indication criteria for genetic testing. After an initial phase of translating and revising the German-authored documents, EuroGentest decided to first move this to the European and now to a global level and thereby open it to the whole scientific community.

OrphaNews Europe: Is the information requested uniform for each card?

Anna Dierking: Basically yes. The questionnaire is the same for all diseases. We divided it into four parts – the first and second covering disease and test characteristics. The third and fourth are dealing with clinical utility of genetic testing in all possible settings, namely differential diagnostics, predictive testing, risk assessment in relatives and prenatal testing. In some cases not all four settings are relevant; therefore we have an overview on the first page of each CUGC showing what areas are answered in the following.

OrphaNews Europe: How long is the developmental procedure for a card?

Anna Dierking: This mainly depends on the number of contributing authors and the subsequent peer-review process. The general deadline is two months, but most authors ask for a short extension.

OrphaNews Europe: What has been the reaction to the cards from the genetics community?

Anna Dierking: The feedback from the scientific community was thoroughly positive. A few experts were surprised by the format, as there was nothing comparable so far, but everyone complimented the quality of the documents and called it an important project.

OrphaNews Europe: Who do the cards most benefit and why?

Anna Dierking: The CUGCs address all stakeholders: clinicians, geneticists, referrers, service providers, patients and payers. Compared to other guidelines, CUGCs enable quick guidance and a compact overview of the state-of-the-art. The standardised format makes it easy to navigate in the gene cards. Once you have used one, you know where to find very quickly the information you need in any other. The annual revisions and thus the rather prompt inclusion of new developments and findings make the CUGCs most beneficial for clinicians and clinical geneticists and in the broader sense also patients.

OrphaNews Europe: How many new cards are to be developed annually?

Anna Dierking: We are aiming at a total of 500 CUGCs by the end of 2014. In the upcoming EuroGentest 2 project, we plan to create 300 new documents - 150 in the first year, 100 in the second year and 50 in the last year. The number of new documents per year is declining in this period, while the number of documents undergoing annual updates is rising.

For further information
Anna Dierking, MSc
EuroGentest Unit 3
Institute of Human Genetics
Hannover Medical School
Carl-Neuberg-Str. 1
D-30625 Hannover
Fax. +49 511 532 8192
Anna Dierking, MSc

 


 
EU Policy News
 
Cross-border health care directive takes another step forward with specific amendment for rare disease patients
 
As was reported in the 20 October issue of OrphaNews Europe, the Council of the European Union in September adopted its first-reading position on a draft directive for cross-border healthcare. The directive, considered crucial to equitable rare disease diagnostics and treatment access across the EU, directly concerns the application of patient rights in cross-border healthcare and seeks to eliminate obstacles hindering patients from seeking treatment in another Member State. On 27 October, the Committee on the Environment, Public Health and Food Safety of the European Parliament adopted by an overwhelming majority the draft recommendation put forward by rapporteur Françoise Grossetête, which includes a consolidated amendment that would give patients diagnosed with or suspected of having a rare disease the “right to access healthcare in another Member State and to receive reimbursement even if the diagnosis and/or treatment in question is not provided for by the legislation" in the patient’s home country. Such treatment would be subject to prior authorisation. The Directive goes back to the European Parliament for plenary vote, scheduled for 18 January 2011. Consult the Parliament press release
Consult the Draft Recommendation for Second Sitting

 
DG Research
 
Transnational rare disease funding programme E-Rare renewed for four more years
 
E-Rare, the ERA-Net for research programmes on Rare Diseases, has had its funding renewed for another four years under the Seventh Framework Programme of the European Commission. E-Rare specifically funds transnational research in rare diseases. Building on the success of the first four-year term, E-Rare-2 will expand to include 16 funding agencies and ministries from twelve countries – Austria, Belgium, France, Germany, Greece, Hungary, Israel, Italy, the Netherlands, Portugal, Spain and Turkey. Aiming to issue an annual call for transnational rare disease research projects, the first E-Rare-2 call (and the third call since the E-Rare project first debuted in June 2006) is anticipated to launch by year’s end.

 


 
National & International Policy Developments
 
WHO resolution targets birth defects
 
At the 63rd World Health Assembly, which earlier this year brought together health ministers and senior health officials from World Health Organization Member States, delegates adopted a variety of global health resolutions, including one to “to help redress the limited focus to date on preventing and managing birth defects, especially in low- and middle-income countries. The resolution calls on Member States to prevent birth defects wherever possible, to implement screening programmes, and to provide ongoing support and care to children with birth defects and their families”. Birth defects encompass a vast spectrum of disorders, the majority of which are rare. Learn more
 
New UK-based network brings professionals and patients together to combat RAS MAPK pathway disorders
 

On 10 September a one hundred and twenty strong delegation of patients, families, healthcare professionals and policy workers descended upon the House of Lords to mark the launch of the RASopathies Network - a patient and clinician partnered initiative. The RASopathies Network is committed to both supporting families and promoting research, with the aim of improving understanding of all aspects of the conditions and ultimately the development of treatment trials. Given the importance of cooperation in achieving these goals, international collaboration is particularly welcome. RASopathies denote a class of developmental syndromes that are caused by germline mutations in genes that encode protein components of the Ras/mitogen activated protein kinase (MAPK) pathway. These conditions - which include Noonan syndrome, LEOPARD syndrome, hereditary gingival fibromatosis type 1, capillary malformation-AV malformation syndrome, neurofibromatosis type 1, Legius syndrome, Costello syndrome, cardio-facio-cutaneous syndrome and autoimmune lymphoproliferative syndrome - are attracting an increasing amount of attention from the medical community particularly due to their link to cancer (in six of the nine syndromes). This event was the first of its kind to be held in the United Kingdom and signified a culmination of two years’ work on behalf of Genetic Alliance UK’s Facilitating Networks project, funded by the Department of Health for three years and through which the development of the Rasopathies Network is supported along with five other networks associated with different genetic conditions. The project team has harnessed the hard work, passion and commitment of patient representatives from the Costello Syndrome Support group, Neurofibromatosis Association, BDF Newlife and CFC Syndrome in the UK. While each of the RASopathy conditions is individually classified as rare, collectively it has been estimated that RASopathies account for one in one thousand births in the UK. The support groups have expressed their commitment to engendering a concerted approach to sharing information, raising awareness and facilitating medical research. This patient-clinician initiative is a critical first step in connecting the dots for collaborative international research efforts.

 
Other European news
 
Classical radio station hits rare note in the Czech Republic
 
The Czech radio station Radio Classic FM is featuring a series of interviews with rare disease experts and patients. Cystic fibrosis, metabolic diseases, rare paediatric cancers, Huntington disease, and lysosomal storage diseases are amongst the conditions to be featured in the series, co-financed by the Ministry of Health as part of the promotional scheme for the newly released Czech National Strategy for Rare Diseases.

 
Free web application rapidly evaluates disease-causing potential of DNA sequence alterations
 
MutationTaster, a free, web-based application for the rapid evaluation of the disease-causing potential of DNA sequence alterations, “integrates information from different biomedical databases and uses established analysis tools… Analyses comprise evolutionary conservation, splice-site changes, loss of protein features and changes that might affect the amount of mRNA. Test results are then evaluated by a naive Bayes classifier, which predicts the disease potential. A typical query is completed in less than 0.3 seconds”. MutationTaster speeds up the diagnostic process for inherited conditions while lowering costs. Two other applications created by the same research group could also be particularly helpful to rare disease diagnostics: GeneDistiller is a candidate gene search engine, integrating information from various databases as well as the researchers' background knowledge and the HomozygosityMapper is a tool for mapping disease genes in consanguineous families that is easier to use and much faster than conventional linkage based approaches. The MutationTaster project was developed by researchers at the NeuroCure Clinical Research Centre (Charité-Universitätsmedizin Berlin) and is supported by the Deutsche Forschungsgemeinschaft via the NeuroCure Cluster of Excellence, amongst other sources. Learn more


 
New guide encourages health professionals to involve patients and the public in all aspects of research
 
The London-based Biomedical Research Centre in London of the National Institute for Health Research (NIHR) has developed a guide intended to aid researchers to involve patients, carers, families and patient groups in the various stages of research. These include the development of grant applications, the design/management of research, the undertaking of research, the analysis of the research data, and the dissemination of research findings. The guide outlines ways in which patients and other users can be involved in each of these stages and how researchers can facilitate this involvement. In a press release, Dr David King, Director, NIHR Central Commissioning Facility is quoted as saying that “Patient and Public Involvement (PPI) will increase in importance in the work of all NIHR Biomedical Research Centres and Units as it is increasingly recognised that PPI is a win:win for both patients and researchers. This new guide for research staff will greatly enhance PPI across the NIHR, especially in the area of experimental medicine.” Experimental medicine is an important area in the field of rare diseases. Learn more
 
Other International News
 
Inherited blood disease expert receives prestigious science award
 

Sir David J. Weatherall, a Liverpuddlian who devoted his professional life to understanding and treating inherited blood disorders – particularly thalassaemia – was awarded the 2010 Lasker-Koshland Special Achievement Award in Medical Science for “fifty years of international statesmanship in biomedical science—exemplified by discoveries concerning genetic diseases of the blood and for leadership in improving clinical care for thousands of children with thalassemia throughout the developing world”. The Lasker Awards are among the most respected science prizes in the world, recognising the contributions of scientists, physicians, and public servants who have made major advances in the understanding, diagnosis, treatment, cure, and prevention of human disease. Dubbed “America’s Nobels”, Lasker Awards “often presage future recognition by the Nobel Committee”. Indeed, eighty Lasker laureates have received the Nobel Prize, including 28 in the last two decades. Learn more about the work of Sir David J. Weatherall

 


 
Orphanet News
 
Orphanet Journal of Rare Diseases supplement focuses on the proceedings of the Fifth European Conference on Rare Diseases
 
The Orphanet Journal of Rare Diseases (OJRD) has published its first supplementary issue, containing the oral and poster presentations from the Fifth European Conference on Rare Diseases that took place in Krakow, Poland in May. Amongst the highlights are discussions on the various national strategies for rare disease patients, including the French and German experiences, as well as presentations on centres of expertise for rare conditions, different research considerations, orphan drugs and health technology assessment, genetic testing, classification, organisation of resources very rare disorders, and registries. The supplement also contains some thirty poster presentations from the conference focusing on a wide assortment of rare disease and orphan drug related topics. The OJRD is an open access electronic publication. Consult the OJRD Supplementary issue

 
New Orphanet Report Series presents the rare disease networks in Europe
 
A new report based on data extracted from the European rare disease and orphan drug information portal Orphanet captures the rare disease networks existing in Europe and surrounding countries. A network is defined as “…a group of coordinated activities with financing or an official designation” and can include patient organisations, clinics, laboratories, research, clinical trials, and technological platforms. This new Orphanet Report Series yields data on the rare disease research and clinical networks, providing statistics such as country distribution (number of networks for which a country is coordinator or participant), the diseases included in a particular network, geographical coverage of networks, distribution of networks by type of call, and funding mechanisms (including the EC DG-Research Framework Programmes, DG-Sanco, and E-Rare).

Data on any network registered with Orphanet can also be retrieved by clicking on the “Networks” sub-tab of the “Research and trials” tab located on the Orphanet homepage. It is possible to search a network by name, disease, gene, type of network, name of a professional or institution, substance, trade name, or sponsor/funding body. Consult the Rare Diseases Networks in Europe report
View all the titles of the Orphanet Report Series

 
New emergency guidelines in Italian for paroxysmal nocturnal haemoglobinuria and in French for myasthenia gravis
 
Orphanet has published one new emergency guideline in Italian for the rare disease “emoglobinuria parossistica notturna” (paroxysmal nocturnal haemoglobinuria) and another in French for ”myasthénie auto-immune” (autoimmune myasthenia gravis). The emergency guidelines are expert-authored and peer-reviewed articles intended to guide health care professionals in emergency situations.

 


 
New Syndromes
 

 
15q25.2 microdeletions associated with risk of congenital diaphragmatic hernia, cognitive deficits and Diamond-Blackfan anaemia
 
The authors describe three individuals - two of whom had congenital diaphragmatic hernia (CDH) - with deletions involving a ∼2.3 Mb region on chromosome 15q25.2. Two additional patients with deletions of this region have been reported, including a foetus with CDH. Clinical data from these patients suggest that recurrent deletions of 15q25.2 are associated with an increased risk of developing CDH, cognitive deficits, cryptorchidism, short stature and possibly Diamond-Blackfan anaemia.
Read the PubMed abstract

 
J Med Genet ; 777-781 ; November 2010
 


 
New Genes
 

 
Primary autosomal recessive microcephaly: two new articles show that WDR62 is mutated
 
Read the first PubMed abstract
Read the second PubMed abstract

 
To read more about "Primary autosomal recessive microcephaly"

 
Nat Genet ; 1010-1014 ; November 2010
Nat Genet ; 1015-1020 ; November 2010

 
Arrhythmogenic right ventricular cardiomyopathy: de novo desmin-mutation N116S is associated
 
Read the PubMed abstract
 
To read more about "Arrhythmogenic right ventricular dysplasia"

 
Hum Mol Genet ; 4595-4607 ; 1 December 2010
 
Metachondromatosis: PTPN11, involved in Noonan and LEOPARD syndromes, identified
 
Read the PubMed abstract
 
To read more about "Metachondromatosis"

 
PLoS Genet ; e1000991 ; 17 June 2010
 
Tracheal agenesis: 5q11.2 deletion in a patient
 
Read the PubMed abstract
 
To read more about "Tracheal agenesis"

 
Eur J Hum Genet ; 1265-1268 ; November 2010
 


 
Research in Action
 

 
Fundamental Research
 
Epidermolysis bullosa simplex type Dowling-Meara: K14 mRNA reprogramming looks promising
 
Read the PubMed abstract
 
To read more about "Epidermolysis bullosa simplex, Dowling-Meara type"

 
Hum Mol Genet ; 4715-4725 ; 1 December 2010
 
Titinopathies: removal of the calpain 3 protease reverses the myopathology in a mouse model
 
Read the PubMed abstract
 
To read more about "Autosomal recessive limb-girdle muscular dystrophy type 2J"
To read more about "Tibial muscular dystrophy"

 
Hum Mol Genet ; 1608-4624 ; 1 December 2010
 
Clinical Research
 
Dyskeratosis congenita, poikiloderma with neutropenia and Rothmund-Thomson syndrome unified by C16orf57 mutations
 
Read the PubMed abstract
 
To read more about "Dyskeratosis congenita"
To read more about "Poikiloderma with neutropenia"
To read more about "Rothmund-Thomson syndrome"

 
Hum Mol Genet ; 4453-4461 ; 15 November 2010
 
Silver-Russell syndrome: epigenotype-phenotype correlations
 
Read the PubMed abstract
 
To read more about "Silver-Russell syndrome"

 
J Med Genet ; 760-768 ; November 2010
 
Congenital disorders of glycosylation type Ik: disease presents at the severe end of the CDG I clinical spectrum
 
Read the PubMed abstract
 
To read more about "CDG syndrome type Ik"

 
J Med Genet ; 729-735 ; November 2010
 
Congenital hyperinsulinism: ABCC8 and KCNJ11 molecular spectrum of 109 diazoxide-unresponsive patients
 
Read the PubMed abstract
 
To read more about "Congenital hyperinsulinism"

 
J Med Genet ; 752-759 ; November 2010
 
Congenital adrenal hyperplasia: a health status cohort study of 203 adult patients
 
Read the PubMed abstract
 
To read more about "Congenital adrenal hyperplasia"

 
J Clin Endocrinol Metab ; 5110-5121 ; November 2010
 
Dystrophic epidermolysis bullosa: revertant mosaicism due to a second-site COL7A1 mutation
 
Read the PubMed abstract
 
To read more about "Dystrophic epidermolysis bullosa"

 
J Invest Dermatol ; 2407-2411 ; October 2010
 
Wilson disease: characterization of alternative splice variants of gene ATP7B
 
Read the PubMed abstract
 
To read more about "Wilson disease"

 
Hepatology ; 1662-1670 ; November 2010
 
Acute lymphoblastic leukaemia: reimplantation of cryopreserved ovarian tissue from patients is potentially unsafe
 
Read the PubMed abstract
 
To read more about "Acute lymphoblastic leukemia"

 
Blood ; 2908-2914 ; 21 October 2010
 
Immune thrombocytopenic purpura: health-related quality of life outcomes
 
Read the PubMed abstract
 
To read more about "Immune thrombocytopenic purpura"

 
Annals of Hematology ; 51-54 ; Vol 89 (Supplement 1) 2010
 
Amyotrophic lateral sclerosis, myasthenia gravis and facioscapulohumeral muscular dystrophy: health-related quality of life
 
Read the PubMed abstract
 
To read more about "Amyotrophic lateral sclerosis"
To read more about "Myasthenia gravis"
To read more about "Facioscapulohumeral dystrophy"

 
J Neurol ; 1473-1481 ; September 2010
 
Gene Therapy
 
Haemophilia B: hyperactive sleeping beauty transposase enables persistent phenotypic correction in mice and canine model
 
Sleeping Beauty (SB) transposase enables somatic integration of exogenous DNA in mammalian cells, but potency as a gene transfer vector especially in large mammals has been lacking. The authors show that hyperactive transposase system delivered by high-capacity adenoviral vectors (HC-AdVs) can result in somatic integration of a canine factor IX (cFIX) expression-cassette in canine liver, facilitating stabilised transgene expression and persistent haemostatic correction of canine haemophilia B with negligible toxicity. Stabilised cFIX expression levels during rapid cell cycling in mice and phenotypic correction of the bleeding diathesis in haemophilia B dogs for up to 960 days was observed. Read the PubMed abstract
 
To read more about "Hemophilia B"

 
Mol Ther ; 1896-1906 ; November 2010
 
Beta-thalassaemia: transfusion independence and HMGA2 activation after gene therapy
 
Gene therapy of beta-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. The authors report that, 33 months after lentiviral beta-globin gene transfer, an adult patient with severe beta(E)/beta(0)-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells. Read the PubMed abstract
 
To read more about "Beta-thalassemia"

 
Nature ; 318-322 ; 16 September 2010
 
Therapeutic Approaches
 
Leber congenital amaurosis: flow-sorted embryonic-stage Crx-positive donor cells have potential to replace lost cones and rods
 
Read the PubMed abstract
 
To read more about "Congenital Leber amaurosis"

 
Hum Mol Genet ; 4545-4559 ; 1 December 2010
 
Collagen VI muscular dystrophies: reactivation of defective autophagy rescues myofiber degeneration
 
Read the PubMed abstract
 
To read more about "Qualitative or quantitative defects of collagen 6"

 
Nat Med ; 1313-1320 ; November 2010
 


 
Patient Management and Therapy
 

 
Prader-Willi syndrome: one year of growth hormone treatment in adults improves body composition
 
Prader-Willi syndrome (PWS) is a multisymptomatic disease that shares many similarities with the growth hormone (GH) deficiency syndrome, including altered body composition with more body fat than lean body mass. Forty-six adults with PWS were randomised to GH or placebo treatment for 12 months in a double-blind trial. The results showed that long-term treatment with GH effectively improved body composition and represents a safe, potential treatment option, relieving some of the negative consequences of PWS.
Read the PubMed abstract

 
To read more about "Prader-Willi syndrome"

 
J Clin Endocrinol Metab ; 4943-4950 ; November 2010
 
Spinocerebellar ataxia: best practice guidelines for molecular genetic testing
 
The European Molecular Quality Genetics Network has put forward best practice guidelines for the spinocerebellar ataxias.
Read the PubMed abstract

 
To read more about "Spinocerebellar ataxia type 1"

 
Eur J Hum Genet ; 1173-1176 ; November 2010
 
Eosinophilic esophagitis: budesonide is effective in adolescent and adult patients
 
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus characterised by dense tissue eosinophilia; it is refractory to proton pump inhibitor therapy. This study shows that a 15-day course of treatment with budesonide is well tolerated and highly effective in inducing a histologic and clinical remission in adolescent and adult patients with active EoE.
Read the PubMed abstract

 
To read more about "Eosinophilic esophagitis"

 
Gastroenterology ; 1526-1537 ; November 2010
 


 
Orphan Drugs
 

 
Comparative study shows that more orphan drugs are approved for reimbursement when cost assessment is not required
 
An article recently published in the journal Clinical Therapeutics compares the pharmacoeconomic evaluations of orphan drugs in the Netherlands and Scotland. These evaluations are frequently required in order to determine reimbursement policy but differ from country to country. The authors point out that in the Netherlands, where sponsors are exempt from furnishing a full evaluation, some 95% of the 38 orphan drugs submitted received reimbursement approval during the period studied. The authors also revealed that seven orphan medicines were “… reimbursed by the Policy Rule for Expensive Hospital and Orphan Drugs” in the Netherlands. Scotland does not have a similar policy rule. Scotland does require pharmacoeconomic evaluation, and the Scottish Medicines Consortium approved 51% of 37 orphan products (24 of which underwent a full pharmacoeconomic evaluation). Some 73% of the submissions in Scotland that had an unfavourable cost-effective ratio (defined as more than €34,000 per QALY gained) received a negative recommendation for reimbursement. Consult the PubMed abstract
 
More research needed to determine a satisfactory framework for orphan drugs reimbursement decision-making
 
With more and more medicinal products for rare diseases becoming available, the issue of reimbursement is becoming increasingly important – who, what, where – and how much? An article published in Health Policy looks at how priority is determined for orphan drugs. Priority Setting for Orphan Drugs: An international Comparison looks at the products Fabrazyme and Cerezyme and how reimbursement policy is determined in specific countries (Canada, Australia and Israel). The authors conclude that “Drug funding decisions which provide some benefit to only some patients is highly contentious and morally controversial. …This study has shown the importance of the Rule of Rescue to key stakeholders (i.e., industry and patients) in drug reimbursement, the advantages of establishing a mechanism for orphan drug reimbursement decisions (i.e., Australia), and the challenges in access associated with the absence of a national orphan drug system (i.e., Canada)”. This study also demonstrates that “an economic approach to reimbursement decisions is not always possible or even appropriate for all drugs. More research is necessary to determine the framework on which to base such decisions”. Consult the PubMed abstract
 
Twelve new orphan designations from the COMP in November
 
The European Medicines Agency Committee for Orphan Medicinal Products (COMP) adopted 12 positive opinions issued at the November 2010 COMP meeting for the treatment of:

- sickle cell disease
- squamous cell carcinoma of the head and neck in patients undergoing radiotherapy
- systemic sclerosis
- acute lymphoblastic leukaemia
- non-24-hour sleep-wake disorder in blind people with no light perception
- mantle cell lymphoma
- hepatocellular carcinoma
- acute peripheral arterial occlusion
- multiple myeloma
- primary myelofibrosis
- post-polycythaemia vera myelofibrosis
- post-essential thrombocythaemia myelofibrosis

Consult the European Register of Designated Orphan Medicinal Products
Consult the Orphanet list of orphan drugs authorised for marketing in Europe

 
CHMP adopts positive opinions to extend therapeutic indications of two orphan products
 
At the October meeting for the EMA’s Committee for Medicinal Products for Human Use (CHMP), positive opinions for applications for extensions of the therapeutic indications, adding new treatment options for medicines that are already authorised in the European Union, were given to Sprycel (dasatinib) to include the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukaemia in the chronic phase and to Sutent (sunitinib) to include the treatment of unresectable of metastatic, well-differentiated pancreatic neuroendocrine tumours with disease progression in adults.
 
CHMP recommends that physicians return to prescribing full dose of Fabrazyme
 
Triggered by an increase in reported adverse events in patients treated with a lower dose of Fabrazyme (agalsidase beta) that was introduced during the recent supply shortage, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is now recommending that physicians switch back to prescribing the full dose of Fabrazyme according to the authorised product information, depending on the availability of enzyme replacement therapy and the severity of the disease. Fabrazyme is used to treat the rare, inherited enzyme-deficiency disorder Fabry disease. Temporary treatment recommendations to manage patients relying on this medicine have been in place since the start of the supply shortage and have been regularly updated.
Learn more

 


 
Courses & Educational Initiatives
 

 
Rare Solid Cancers: An Introduction
 
Organised by the European School of Oncology in collaboration with the Rare Care project. This course, being held in Stresa, Italy from 31 March – 1 April 2011, will focus on all the main rare solid cancers of the adult. Rare cancers present particular challenges, such as organisation of care and methodology of clinical studies. Oncologists, epidemiologists and health administrators will particularly find this course useful.
For further details

 
European Advanced Postgraduate Course in Classical and Molecular Cytogenetics
 
This ten-day course held in February/March each year is designed to provide advanced training in constitutional, haematological, and oncological cytogenetics to medical graduates, pharmacists, pathologists, biologists, health professionals and researchers, with an academic qualification. The students will be trained to identify genetic abnormalities for diagnosis and prognosis, and for fundamental and applied research using both classical and molecular cytogenetic techniques. The course is co-organised by the European Cytogeneticists Association and two French Universities, either as a stand-alone course with only the theoretical part or as a University Diploma including both theoretical and practical training.
For further details

 
ESH Enerca Training Course on Haemoglobin disorders: Laboratory diagnosis and Clinical Management
 
In association with the Thalassaemia International Federation, this course, being held from 1-2 April 2011 in Brussels, Belgium, will address: Thalassaemias - Clinical and Molecular Aspects; Laboratory Diagnosis in Thalassaemia Syndromes; Sickle Cell Disease: Clinical Aspects; Abnormal Haemoglobins; Epidemiology of Haemoglobin Disorders; and more.
For further details

 
The Orphan Europe Academy
 
Orphan Academy 2010-2011 programme The Orphan Europe Academy provides healthcare professionals with the opportunity to increase knowledge, develop new ideas and strengthen scientific collaboration by offering training and educational activities for healthcare professionals involved in the diagnosis and management of patients affected by rare diseases.
For further details

 
EuroGentest Quality Management and Accreditation/Certification of Genetic Testing Workshops
 
The European network of excellence for all aspects of genetic testing, EuroGentest, under its Quality Management and Accreditation/Certification of Genetic testing Workgroup, has several training workshops available around Europe in coming months that focus on accreditation and quality assurance.
For further details

 


 
What's on Where?
 

 
Syringomyelia 2010: International Symposium
 
Date: 9-11 December 2010
Venue: Berlin, Germany

Topics will include: pathophysiology of syringomyelia; diagnostics; clinical entities: chiari malformation, dysraphism, tethered cord, posttraumatic syringomyelia, syringomyelia due to spinal arachnopathies; and therapy: surgical, conservative, outcome; rehabilitation.
For further details

 
4th International Meeting on the Congenital Disorders of Glycosylation and Related Disorders
 
Date: 13-14 January 2011
Venue: Leuven, Belgium

The meeting will cover all aspects of these disorders, including the discovery of novel types, the study of fundamental aspects of glycosylation, analytical procedures and diagnostic methods and the analysis of models for the disease. The meeting is organised by EUROGLYCANET, a European network for the advancement of research, diagnosis and treatment of a growing group of rare disorders.
For further details

 
2nd Annual Commercialisation & Market Access Strategies for Orphan & Ultra-Orphan Drugs
 
Date: 17 February 2011
Venue: Barcelona, Spain

The event will be focused on orphan therapies and will guarantee all participants access to today’s most relevant case studies and views which directly affect their future business plans and can assist them to maximise market and patient access.
For further details

 
Third International Symposium on Paediatric Movement Disorders
 
Date: 25-26 February 2011
Venue: Barcelona, Spain

This event aims to continue the collaborative activities between professionals interested in paediatric movement disorders, mainly neurologists and neuropaediatricians. As in the previous symposiums qualified experts in the different aspects involved in paediatric movement disorders will increase knowledge, and serve to establish interesting contacts and develop creative ideas. Some newly recognised and treatable inborn errors of metabolism that may present with movement disorders in childhood (i.e. Glut-1 Deficiency, Cerebral Folate Deficiency and Dopamine Transporter Defects) will be presented. Deadline for abstract submission: 15 December 2010
For further details

 
4th International Symposium on Pulmonary Rare diseases and Orphan Drugs
 
Date: 25-26 February 2011
Venue: Milan, Italy

This event will explore issues in rare lung diseases and the development of orphan medicinal products and other therapeutic options for these disorders.
For further details

 
Genetic Diseases of Children…Advancing Research & Care
 
Date: 7-9 March 2011
Venue: NY, USA

The conference will bring together over 1000 researchers, clinicians, affected families, government and industry leaders for the purpose of advancing research to improve health outcomes for children with genetic diseases.
For further details

 
Second ASID Congress of the African Society for Immunodeficiencies
 
Date: 10-13 March 2011
Venue: Hammamet, Tunisia

This second congress will be an excellent opportunity to strengthen the capacity of colleagues all over the continent to better diagnose and manage patients with PIDs. The commitment and contribution of international experts, societies and associations to this process is highly appreciated.
For further details

 
11th International Congress of the European Society of Magnetic Resonance in Neuropediatrics
 
Date: 24-26 March 2011
Venue: Amsterdam, Netherlands

Bringing together neuroscientists, paediatric neurologists, scientists interested in developmental paediatrics, neonatologists, neuroradiologists, neuropsychologists, neurophysiologists and physicists to discuss the newest developments in advanced neuroimaging and image guided therapeutic approaches in the fields of normal and abnormal brain development and brain functions, which will be presented by internationally recognised experts.
For further details

 
12th International Conference on Thalassaemia and the Haemoglobinopathies
 
Date: 11-14 May 2011
Venue: Antalya, Turkey

The main topics will include epidemiology and prevention; heart and vascular abnormalities; reproduction and pregnancy; quality care for quality of life; other haemoglobin disorders; haemopoietic stem cell transplantation; gene regulation and therapy; and much more. Deadline for abstract submission: 15 February 2011.
For further details

 
Ninth European Paediatric Neurology Society Congress
 
Date: 11-14 May 2011
Venue: Cavtat (Dubrovnik), Croatia

The programme includes basic neuroscience and neurobiology, new treatment approaches in muscular disorders, neuro-othology and neuro-opthalmology, advanced critical care and ethics in paediatric neurology as well as practical clinical knowledge in the skills of electroencephalography and electromyography via comprehensive workshops.
For further details

 
First International Symposium on Childhood, Adolescent and Young Adult Hodgkin Lymphoma
 
Date: 12-14 May 2011
Venue: Arlington, Virginia USA

This event seeks to: provide a platform for global collaboration; establish networks of multidisciplinary caregivers; identify leaders for specific projects; promulgate tools for communication and collaboration; and develop standards of care for children with HL.
For further details

 
VII International Conference on Rare Diseases and Orphan Drugs (ICORD 2011)
 
Date: 21-23 May 2011
Venue: Tokyo, Japan

A global meeting on international cooperation and public health policies focussing on research, diagnosis, development of and access to treatment and care for rare diseases. The programme for this conference will be available shortly.
For further details

 
Eighth European Cytogenetics Conference
 
Date: 2-5 July 2011
Venue: Porto, Portugal

This meeting will provide the participants with an opportunity for not only contributing their knowledge and experience, but also for interacting with each other. Deadline for abstract submission: 28 February 2011.
For further details

 
European Conference on Post Polio Syndrome
 
Date: 31 August – 02 September 2011
Venue: Copenhagen, Denmark

This international conference is being held by the European Polio Union, and The Danish Society of Polio and Accident Victims.
For further details

 
5th International Conference on Birth Defects and Disabilities in the Developing World
 
Date: 24-27 September 2011
Venue: Lodz, Poland

The primary theme of the conference will be economics of healthcare and methods for establishing sustainable financial resources to implement programs of value to health and assure access to care. Other topics include integration of services into national primary health programs for care of neonates and children with birth defects and disabilities; monitoring risk factors for major defects globally; preconception care; and development of networks and partnerships for most efficient utilization of the limited resources.
For further details

 
Treat-NMD Global Conference
 
Date: 8-11 November 2011
Venue: Geneva, Switzerland

The conference will comprise a range of sessions addressing the challenges in the neuromuscular field, including: Delivery of future therapies; Biomarkers; Care considerations; Neuromuscular diseases and society; and Regulatory issues, orphan drugs and the rare disease field.
For further details

 


 
Press & Publications
 
Small Molecule Therapy for Genetic Disease
 

This text summarises the work accomplished in the treatment of inborn errors of metabolism with simple molecules, enabling interested clinician scientists to rapidly survey the field, ascertaining what has been done as well as future directions for therapeutic research. An analysis of the cofactors used to augment the function of defective enzymes and the compounds that are able to utilise an alternative pathway in order to avoid the consequences of the metabolic block present in the patient is presented. Among other therapies, the use of zinc and tetrathiomolybdate to treat Wilson disease and the use of cysteamine to treat nephropathic cystinosis is discussed. A chapter considers the FDA and regulation of small molecules for orphan diseases, and another considers the Office of Rare Diseases research.

Author: JG Thoene -Ed.
Publisher: Cambridge University Press, October 2010
ISBN: 9780521517812

 


 
Orphanews Europe, the newsletter of the European Union Committee of Experts on Rare Diseases
Orphanews Europe is supported by the European Commission's DG SANCO
and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Ségolène Aymé
Editor: Louise Taylor
Contact Us
Editorial Board: Ségolène Aymé, Catherine Berens, Olaf Bodamer, Raphaël Demonchy, Helen Dolk, Anders Fasth, Laura Fregonese, Edmund Jessop, Jordi Llinares-Garcia, Antoni Montserrat, Charlotte Rodwell, Paloma Tejada, Aurélie Vandeputte
National Contact Point: Till Voigtländer (Austria), Jean Jacques Cassiman (Belgium), Rumen Stefanov (Bulgaria), Ana Stavljenic-Rukavina (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), Andres Metspalu (Estonia), Riitta Salonen (Finland), Manfred Stuhrmann (Germany), Michael Petersen (Greece), János Sándor (Hungary), Andrew Green (Ireland), Judith Melki (Israel), Bruno Dallapiccola and Domenica Taruscio (Italy), Andre Megarbane (Lebanon), Vaidutis Kucinskas (Lithuania), Alfred Cuschieri (Malta), Abdelaziz Sefiani (Morocco), Martina Cornel (Netherlands), Stein Are Aksnes (Norway), Jolanta Sykut-Cegielska (Poland), Jorge Sequeiros (Portugal), Dragica Radojkovic (Serbia), Ludovit Kadasi (Slovakia), Borut Peterlin (Slovenia), Miguel del Campo and Manuel Posada de la Paz (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Habiba Chaabouni-Bouhamed (Tunisia), Fatmahan Atalar and Ugur Ozbek (Turkey), Edmund Jessop and Idoia Gomez-Paramio (United Kingdom)
For more information on the European Union Committee of Experts on Rare Diseases
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