Edition of 05 November 2014

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Editorial

Rare Diseases Clinical Research Network in the US awarded $29 million to study more than 200 rare diseases

Earlier last month, the National Institutes of Health (NIH) announced $29 million towards expanding the National Center for Advancing Translational Sciences (NCATS)' collaborative Rare Diseases Clinical Research Network (RDCRN) which is dedicated to furthering translational research and investigating new treatments for patients with rare diseases. Currently comprising of 2600 researchers, the NIH Office of Rare Diseases established RDCRN in 2003. RDCRN is overseen by NCATS to work towards advancing medical research on rare diseases by facilitating collaboration, study enrollment and data sharing.

RDCRN is made up of 22 distinctive consortia and a Data Management and Coordinating Center that work collaboratively to improve the availability of rare disease information, treatment, clinical studies, and general awareness for both patients and the medical community. The RDCRN also aims to provide up-to-date information for patients and to assist in connecting patients with advocacy groups, expert doctors, and clinical research opportunities.

This new NIH funding will establish six new RDCRN consortia, including bone diseases, lung diseases, food allergy disorders, and three separate neurological diseases concentration areas— amyotrophic lateral sclerosis and related disorders, autism and intellectual disabilities, and frontotemporal lobar degeneration. NIH said researchers at the 22 RDCRN consortia will conduct a minimum of two multisite clinical studies, including one longitudinal natural history study for a group of at least three related rare diseases. Each consortium will partner with relevant patient advocacy groups. According to the NIH press release this award will result in “physician scientists at 22 consortia collaborat(ing) with representatives of 98 patient advocacy groups to advance clinical research and investigate new treatments for patients with rare diseases”.
Read the NIH press release
Go to the NCATS website

EC Expert Group

OrphaNews International: the newsletter for the rare disease community has grown from strength to strength over the years

OrphaNews International, an electronic newsletter published fortnightly, has been a source of comprehensive information for the rare disease community for over 9 years. This newsletter of the European Commission Expert Group on Rare Diseases (formerly the European Union Committee of Experts on Rare Diseases 2009-2014, the European Commission’s Rare Diseases Task Force 2005-2009) has been instrumental in providing up-to-date political, regulatory and scientific news that affect rare disease stakeholders around the world. While OrphaNews International is in English, you can also subscribe to the French and Italian newsletters.

Launched as OrphaNews Europe on the 15th June 2005, the newsletter has seen an extraordinary growth in popularity, currently reaching over 15200 readers internationally. Over 160 issues of the newsletter have been published with ever-increasing subscription numbers with each publication. The graph above shows the steady increase in subscription numbers this year alone, with readers from all around the world. Due to its international reach, OrphaNews Europe was renamed OrphaNews International earlier this year. OrphaNews is supported by the European Commission's DG SANCO (EUCERD Joint Action N° 2011-22-01) and the French Muscular Dystrophy Association (AFM).

OrphaNews France caters exclusively to the French audience, reaching more than 9200 readers. The articles published in this newsletter are central to the experience of rare disease stakeholders in France. The French newsletter, also supported by French Muscular Dystrophy Association (AFM) telethon, precedes the English version as it debuted in 2003. Since its inception, OrphaNews France has provided compelling knowledge about the scientific and regulatory progress in France, in the field of rare diseases.

OrphaNews International is translated into Italian (OrphaNews Italia) by Orphanet Italy, to benefit the Italian readers. This translated version of OrphaNews International was launched in December 2011 and currently has more than 4400 subscribers.
Subscribe to the newsletter in French
Subscribe to the newsletter in Italian

EU Policy News

Swiss Federal Office of Public Health announces the adoption of its national plan: National Concept on Rare Diseases

The Federal Council of Switzerland has approved the “National Concept Rare Diseases”, which is an equivalent of the countries’ national plan for rare diseases. The plan proposes 19 measures, including the establishment of reference centers designed to ensure a quick and safe diagnosis as well as effective treatment. The implementation of this plan is scheduled for the spring of 2015. A meeting was held at the Swiss Ministry of Health with stakeholders on 21 October 2014 to take the first steps in determining the actions needed to implement the measures outlined in the "concept".

The Federal Council of Switzerland recognises that people who suffer from rare diseases and their families face many challenges which involves delay in diagnosis, improper management as well as major hurdles with hospitals and social insurance. They are also confronted with the uncertainty regarding reimbursement of certain drugs and benefits.

The national plan deliberated by the Federal Council of Switzerland has planned to designate reference centers for disease or group of diseases that require special attention, which includes rare diseases. According to the “concept”, these centres must ensure that patients have access to good treatment throughout the duration of the disease. The plan also makes provisions for health care professionals to pursue education to gain further specialised information in the field of rare diseases. The plan pays particular attention for patients that are transitioning from paediatric to adult medicine.

In addition, the “concept” also recommends the use of coordinators in the townships and hospitals who will guide patients in their administrative procedures as well as provide much needed relief to their relatives. Also included in the “concept” are the current procedures for the refund of benefits for sickness and disability which is currently too complex for patients and health professionals in Switzerland. The Federal Office of Public Health (BAG) has examined how to establish standardised procedures to facilitate collaboration between physicians, medical directors and insurance agencies in order to improve the management of certain drugs and genetic analysis.

Rare disease patients and other stakeholders in Switzerland see the announcement of the “National concept on Rare Diseases” a huge step forward for the better diagnoses and treatment of rare diseases and await its implementation.

Read the National Concept Rare Diseases in French
Read the National Concept Rare Diseases in German

DG SANCO

EMA

National & International Policy Developments

Other European news

Other International News

Intricacies in the Affordable Care Act of the United States may fail rare disease patients

The advent of the Affordable Care Act (ACA) in US was one of the most promising news for rare disease patients. Before the implementation of this act, rare disease patients in US patients were vulnerable as often they were unable to access these treatments because of high out-of-pocket costs, particularly if they are not already covered under a health insurance. ACA, promised improved access to healthcare for those who have not had access to insurance coverage through existing public and private sources. However, the authors in an article published in “ Journal of Managed Care & Specialty Pharmacy » mentions that this process can be quite cumbersome. A goal of the ACA was to create a market in which choices in insurance products offered could be easily understood and compared by individuals. The act requires everyone to enrol in 1 of the 4 “metal level” plans - bronze, silver, gold, and platinum – bronze being the one that covers the least, while platinum covers 90% of the plan. These metal levels provided the basis for how plans designed their insurance products, including their drug benefits.

Robinson et al., found that the coverage of drugs and other treatment levels for rare disease patients differs considerably based on many factors such as the state that the patient belongs to, the number of drugs that have been approved by the FDA for the rare disease in question as well as utilisation management. Higher cost medications, such as those for rare disease therapies, may be placed on a plan’s higher formulary tiers (gold and platinum) with higher premiums. The authors analysed 7 rare diseases and the available treatments to examine how the insurance agencies would cover patients with the particular disease. They found that bronze plans were far less likely than silver plans to cover the selected products. Select drugs identified as being the only FDA-approved product indicated for a certain rare disease were robustly covered while when several orphan drugs with FDA-approved indications to treat the same rare disease coverage was generally low and potentially more complex.

The copayment rates across the products ranged from as low as $20 to as high as $250. The authors also found that a gold or platinum plan may prove to be more cost-effective in the long term for patients than a bronze plan, with higher premiums potentially being offset by reduced out-of-pocket maximums and better coverage. The authors reiterate the importance for patients with rare diseases seeking coverage in the exchanges to, at minimum, examine plan formularies prior to enrolling in an exchange plan and managed care pharmacists can play an important role in educating rare disease patients on plans.
Consult the Pubmed abstract

Guidance Documents and Recommendations

Bioinformatics, Registries and Data Management

Algorithm that aids in genetic diagnosis by ranking genes based on the phenotype

Correlating mutated genes with the patient’s phenotype to reach a possible clinical diagnosis is an area of great importance to clinicians and researchers. Masino et al., have published an algorithm that aids in interpreting variant information relative to patient phenotype in BMC Bioinformatics. This algorithm ranks genes by the semantic similarity between patient phenotype features and phenotype features directly associated with each of a patient’s mutated genes. The rank ordered list assigns a score to each gene that indicates the “strength of association” between the gene and the patient’s clinical presentation (or phenotype). When the algorithm presents the ranks of the genes, the ones with very low scores are unlikely to be associated with the patient’s specific phenotype, thus not requiring a detailed review, while the genes that rank highly within the list are likely to aid in a genetic diagnosis.

The authors utilised the Human Phenotype Ontology (HPO) to assist in providing the phenotypic descriptor terms, while the information content within the terms aided in providing semantic similarity. The authors tested their algorithm on four actual clinical cases with hearing impairment, which led to ranking a gene that was previously missed by other eminent physicians and researchers. The authors acknowledge that their method is similar to Phenomizer, but while Phenomizer gene-rank is based on HPO term-to-disease annotations, the method presented in this paper provides gene ranks based on HPO term-to-gene annotations. According to the authors, “phenotype rank combined with variant analysis provides significant improvement over the individual approaches (and) expect that a combined prioritisation approach may increase accuracy and decrease effort for clinical genetic diagnosis». The algorithm source code and the resulting data is publicly available at https://github.com/cbmi/phenomantics.
Consult the Pubmed abstract

Ethical, Legal & Social Issues

New Syndromes

New Genes

Research in Action

Clinical Research

Therapeutic Approaches

Patient Management and Therapy

Orphan Drugs

Political and Scientific News

Article illustrates treatment of advice on adaptive clinical trial designs by the EMA

Adaptive designs allow planned modifications based on data accumulating within a study. The promise of greater flexibility and efficiency stimulates increasing interest in adaptive designs from clinical, academic, and regulatory parties. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. Both the European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. In addition the EMA also offers a key service of scientific advice and protocol assistance, which sponsors of medicines, can avail early in the marketing authorisation process.

Whether this service proves to be vital for sponsors is discussed in an article publishes in Trials where Elsäßer et al., analysed 59 scientific advices that address adaptive study designs in Phase II and III clinical trials and discussed 3 case studies submitted to the EMA and analysed by the CHMP/SAWP. The authors found that “most frequently proposed adaptation was sample size reassessment, followed by dropping of treatment arms and population enrichment”. The authors report an increase in submissions in 2011 and while many of the trials were on a rare disease, not all of them had an orphan designation. Promisingly, the authors found that a majority of proposals were accepted “as is” or with conditions attached, however they also reported that Type I error were more frequent than expected. The case studies presented in this paper illustrated how advice on sample size reassessment, interim dose selection and post-hoc adaptations were handled by the CHMP. Although the authors discuss the case studies and the numbers in a fair amount of detail, it is difficult to draw conclusions on marketing authorisation based on them, as the CHMP views applications as a whole. However, the article gives a flavour of how the CHMP tackles issues relating to adaptive clinical trial and what questions the sponsors could ask while planning such a trial.
Consult the Pubmed abstract

Grants

Courses & Educational Initiatives

What's on Where?

OrphaNews, The Newsletter of the Rare Diseases Community.
OrphaNews 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
Editors for Scientific Content: Catherine Pouzat, Sophie Höhn
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Editorial Board: Ségolène Aymé, Paul Boom, Anna Bucsics, Kate Bushby, Barbara Cagniard, Lorenzo Dagna, Adam Heathfield, Lilian Lau, Yann Le Cam, Jordi Llinares-Garcia, Antoni Monserrat, Charlotte Rodwell, Gerhard Steffes, Till Voigtländer, Jaroslaw Waligora

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Editorial

Rare Diseases Clinical Research Network in the US awarded $29 million to study more than 200 rare diseases

EC Expert Group

OrphaNews International: the newsletter for the rare disease community has grown from strength to strength over the years

EU Policy News

Swiss Federal Office of Public Health announces the adoption of its national plan: National Concept on Rare Diseases

DG SANCO

EMA stays with DG SANCO

EMA

EMA announces that the Clinical trial data will be shared: patients prevail

A revised version of the EMA paediatric investigation plans developed ease the application process

EMA pledges continual support of Small and Medium sized enterprises during SME week

National & International Policy Developments

Other European news

Stamina Foundations’ fraudulent stem cell therapy trial is finally brought to a standstill

Rare Cancers Europe recommendations for clinical studies in rare cancers

Other International News

NIH revises its genomic data sharing policy

Call for public consultation: WHO Statement on Public Disclosure of Clinical Trial Results

Catalyst Pharma plans exorbitant price for rare disease drug in the US

PhRMA renews legal battle over big hospital discounts in the US for orphan drugs

Intricacies in the Affordable Care Act of the United States may fail rare disease patients

Guidance Documents and Recommendations

Special issue of ’Annals of Oncology’ on European Society for Medical Oncology updated clinical practice guidelines

Hypertrophic cardiomyopathy: 2014 European Society of Cardiology guidelines on diagnosis and management

Cardiofaciocutaneous syndrome: guidelines on clinical features, diagnosis and management

Bioinformatics, Registries and Data Management

Algorithm that aids in genetic diagnosis by ranking genes based on the phenotype

Disease Manifestation Network: a novel phenotype network database

A free web-based system for Sanger sequencing-based genetic testing data analysis

Creation of a mitochondrial dysfunction transcriptome using publicly shared data

Ethical, Legal & Social Issues

Research agenda discrepancy in dystrophic epidermolysis bullosa affects patients’ wellbeing

Use of the DISCERN tool for evaluating web searches in childhood epilepsy.

New Syndromes

New syndrome of enterocolitis and autoinflammation caused by mutations in NLRC4

Novel syndrome of CTLA4 haploinsufficiency with autoimmune infiltration disease in four unrelated families

Two new syndromes of developmental delay linked to haploinsufficiency of SETBP1 and truncations of ZMYND11

Microcephalic primordial dwarfism compatible with Seckel syndrome caused by mutations in CENPE in two siblings

Intrauterine growth restriction, short stature, and early-adulthood-onset diabetes associated with a variant in CDKN1C

Novel autosomal recessive intellectual disability syndrome identified in six patients from northern Finland

A syndromic form of Pierre Robin sequence is caused by 5q23 deletions encompassing FBN2 and PHAX

New Genes

Early-onset epileptic encephalopathies caused by de novo mutations in synaptic transmission genes including DNM1

Early-onset antibody-negative diabetes due to novel recessive mutations in PCBD1 in a consanguineous family

Increased susceptibility to childhood acute lymphoblastic leukemia and elevated risk for late relapses associated with KIR ligand C2

Autosomal recessive primary ovarian failure linked to SYCE1 nonsense homozygous mutation in an Israeli Arab family with a consanguineous pedigree

Research in Action

Clinical Research

Childhood-onset, complicated, frequently relapsing nephrotic syndrome: rituximab is an effective and safe treatment

Advanced gastric cancer: the combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel

Osteogenesis imperfecta: two years denosumab treatment demonstrates long term benefit and safety

Granulomatosis with polyangiitis: rituximab is an effective remission-inducing agent, and the addition of a conventional maintenance agent decreased the incidence of relapse

long-term efficacy and safety of pegvisomant in combination with somatostatin analogs

Facioscapulohumeral dystrophy: vitamin E, vitamin C, zinc and selenium supplementation may improve skeletal muscle function

Autism spectrum disorders and intellectual disability: the frequency and the penetrance of SHANK3 mutations warrant its consideration for mutation screening in clinical practice

Typical and atypical rolandic epilepsy: 16p11.2 duplications represent a significant genetic risk factor

Therapeutic Approaches

Ebola hemorrhagic fever: reversion of advanced disease in rhesus macaques with ZMapp, a combination of monoclonal antibodies

FGFR3 skeletal dysplasia: statin treatment rescues patient-specific induced pluripotent stem cell models and a mouse model

Kabuki syndrome: AR-42, a histone deacetylase inhibitor, rescues structural and functional brain deficits in a mouse model

Dystrophic epidermolysis bullosa: aminoglycosides restore full-length type VII collagen by overcoming premature termination codons

Amyloidosis: chaperone nanobodies protect gelsolin against MT1-MMP degradation and alleviate amyloid burden in a model mouse

Patient Management and Therapy

Adult T-cell leukemia/lymphoma: a review

Cytomegalovirus retinitis: review on current and future treatments

Sturge-Weber syndrome: overview of current and future treatment options

Desmoid tumor: review on clinical management

Alport syndrome: review on genetic and biological therapies

Marfan syndrome: review on diagnosis and genetics

Pulmonary lymphangioleiomyomatosis: review on therapeutic strategies

Lymphangioleiomyomatosis: all patients should be screened for angiomyolipoma at diagnosis of lung disease

Turner syndrome: review on management in adult life

Acute myeloid leukemia: review on daunorubicin for the treatment

Multiple myeloma: review on pomalidomide for the treatment

Hemophilia A: review on recombinant factor VIII Fc for the treatment

Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

Non-transfusion-dependent thalassemia: review on identification and diagnosis

Pleuropulmonary blastoma: a review