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Edition of 27 November 2020

International News

Canada: The diagnostic odyssey of children with rare genetic disorders

In Alberta, Canada, at the Alberta Children’s Hospital (ACH), a genetics clinic, an observation of 299 children living with a rare genetic disorder, who had undergone a gene test (58%), gene panel (11%), or chromosome microarray analysis (79%), was conducted during a mean observational period of 898 days. The observation aimed at outlining the diagnostic odyssey of the mentioned patients, from the initial consultation to the time of receiving the diagnosis, or at the time of the last visit. 30% (90) of the 299 received a diagnosis during the observation period. The observation concluded that the nature of the odyssey diagnosis will change due to the evolution of genomic technologies.

Hong Kong, China: Impact of COVID-19 pandemic on patients with rare disease

A study was conducted through an online survey conducted between April 10 and April 29, 2020 on 272 rare diseases patients living in Hong Kong and who had Covid-19. It revealed that the patients were impacted in many ways, including their medical and rehabilitation services use patterns (71%), mental health (79%), health status (46%), financial status (81%), or social life (92%). Patients with a given dependency on a caregiver were more affected in terms of their medical, rehabilitation, mental health and health status.

Switzerland: Asylum-Seeking Children with Medical Complexity and Rare Diseases in a Tertiary Hospital

In Switzerland, in a tertiary hospital, a study was conducted between January 2016 and December 2017 on 462 patients, all asylum-seeking children, following 811 visits to the hospital. The children had medical complexity, such as genetic diseases, including rare genetic diseases, for example Laron syndrome, a growth hormone insensitivity condition. Rare and complex diseases had already been reported, but no study has already been conducted. Other complex diseases reported were common, for example orthopedic disease, nutritional and mental health problems.

The asylum-seeking children were identified from administrative and electronic health records following frequent visits to the hospital. The mentioned visits were hospital admissions, emergency department visits and outpatient department visits. The children are aged from 2 to 16.7 years. New strategies are needed to manage this category of patients by improving coordination between hospital and non-hospital facilities for more integrated care.

European News

The Executive Summary of the 10th European Conference on Rare Diseases and Orphan Products published

EURORDIS, the rare diseases organisation in Europe, in collaboration with Orphanet, and with the support of the AFTM Téléthon, and the Health Programme of the European Union published the Executive Summary on the 10th European Conference on Rare Diseases and Orphan Products (ECRD), the largest, patient-led rare disease event. The ECRD event is the platform for collaborative dialogue, learning, and conversation which aims at shaping the future of RD policies. The Executive Summary on the 10th ECRD comprises amongst other parts keys facts and figures, the ECRD and the Rare2030 Foresight Study, keynote speeches, conference schemes, partners, or committees’ details.

A supplement on the ECRD was published in the Orphanet Journal of Rare Diseases (OJRD), with the kind support of INSERM. The OJRD supplement on ECRD focuses amongst other topics on the first effective treatment for alkaptonuria, on patient journeys (personal experiences shaping clinical priorities), and on the quality for life for people living with rare diseases (recruitment challenges and consequences in a study pilot).

EURaDMoG: A study on the potential creation of a European Reference Network for rare communicable diseases and other rare diseases linked to mobility and globalisation

The European Expert Network for rare communicable diseases and other rare pathologies in the context of Mobility and Globalisation (EURaDMoG) conducted a study on the possibility to create a European Reference Network (ERN) on rare communicable diseases and other rare conditions in connection of mobility, globalisation and health care provision.

The study aims at identifying changes regarding the population movement within the European Union (EU) and the European Economic Area (EEA) for an adequate diagnosis and treatment. Amongst the findings of the survey is the need to differentiate communicable and non-communicable rare diseases in the context of mobility and globalisation in line with areas that the new ERN should cover. It was also decided not to include non-communicable rare diseases linked to mobility and globalisation in the new ERN, as they are already covered by existing ERNs.

Three following options were proposed: the possibility of not creating a new ERN on communicable rare diseases, the creation of a European expert network, and the creation of a new ERN on communicable rare diseases linked to mobility and globalisation, and which will be focusing on health care provision. The new ERN would make greater use of online platforms and technological tools for a better exchange of data and quality of care. The new ERN will also have to work closely with other ERNs in the search of complementarity.

A French survey on COVID-19 infection in NMO/SD patients

A French survey conducted on 117 patients with neuromyelitis optica spectrum disorders (NMO/SD), a rare disabling disease which needs immunosuppressive therapy, and who had also Covid-19, outlined the prevalence and characteristics of Covid-19 in the case of NMO/SD. The survey used NOMADMUS cohort, gathering data from French expert NMO/SD centers, and data was collected for example in the department of neurology of Pitié Salpêtrière Hospital. Comorbidities, demographics, neurological history, COVID-19 characteristics and outcome were collected.

For 75 patients, 6.7% of suspected or confirmed cases of Covid-19 were confirmed. No severe infection was noticed. A similar Iranian survey reported 3.8% of Covid-19 prevalence, and a Chinese one, -19.2%. The French survey helped in reporting out Covid-19 prevalence in the immunosuppressed population, and the necessity of treatment maintenance for the mentioned population. The studies were conducted during Covid-19 outbreak and in the context of difficulty in accessing Covid-19 testing.

The Italian Undiagnosed Rare Diseases network: Review of 3 years of activity

The Italian Undiagnosed Rare Diseases Network (IURDN) is one of undiagnosed RD programs developed recently these years to address the complexity of undiagnosed RD cases. IURDN was created in 2016 and is composed of six centres that are working to improvement RD cases’ diagnosis. From March 2016 to June 2019, one hundred and ten cases were analysed by the IURDN. PhenoTips software was used to collect the clinical information. Reported results mentioned a molecular diagnostic yield of 53,8%. One hundred and ten cases were analysed between March 2016 and June 2019.

Health Economics

One orphan drug to treat many diseases to unlock the rare diseases economic trap

A literature review has helped form a hypothesis that the use of one drug to treat many RD may help resolve the economic trap presented by RDs. High biomedical, pharmaceutical and technological potential are the economic reality in the area of the development of new orphan drugs. The hypothesis refers to a drug suitable for a therapy that will treat 10 or 100 different RD. To make this hypothesis became a reality supposes that there will be an increase in both market demand (a high number of RD patients) and market supply (lower prices applied by manufacturers). This kind of situation could encourage insurance and governmental agencies in fostering innovation, by reassuring them that investment is less risky. Further preclinical and clinical studies are needed to verify the feasibility of the hypothesis.

Orphan Drugs

The European Orphan Drug Experts Group established

In line with the new European Union Pharmaceutical Strategy and the evaluation of the Orphan Medicinal Products Regulation, the European Orphan Drug Experts Group has been launched. The mission of the Group of Experts is to bring innovative proposals regarding innovation and research for the development of new orphan drugs and rare diseases therapies. The Expert Group is composed of RD cross-functional experts including researchers, patient representatives, rare disease companies or trade association.

Organisation members of the RD community are part of this project, such as EURORDIS, the European association for small to medium-sized companies in the field of pharmaceuticals and medical technologies (EUCOPE), and the European Reference Networks Board of Coordinators (ERN-BC).

Central and Eastern Europe and health technology assessment and reimbursement policy for oncology orphan drugs

An article in the Orphanet Journal of Rare Diseases (OJRD) highlights a study of country-specific health technology assessment (HTA) policies and on the decisions regarding recommendations and reimbursement of 36 orphan drugs (OD) in Central and Eastern Europe (Hungary, Bulgaria, Croatia, Lithuania, Estonia, Poland, Czechia, Romania, Latvia, and Slovakia). The study also stresses on the impact of reimbursement of OD on the public budget. For reimbursement, the rating in Latvia is 11.11%, and Poland 41.67%. Regarding positive recommendations, it was noted the highest rate for Bulgaria and Estonia (36.11%), and for Latvia (11.11%).

The three countries, Slovakia, Hungary, and Latvia, had a positive recommendation along with a reimbursement, and also a negative recommendation, and the absence of reimbursement. The oncology OD reimbursement is seen as a growing burden for public budgets.

US and Europe: Pivotal trial endpoints of drugs for rare and non-rare cancers

Rare Cancers Europe (RCE) highlights that surrogate endpoints in the case of rare cancers may be the only way to show improvements on time. It is mentioned that surrogate endpoints (progression-free survival or overall response rate) may somehow constitute misleading information. Pivotal trial endpoints for approved cancer drugs by the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) were categorised (OS vs. OS surrogates). The new cancers orphan drugs (treatment of solid and haematologic tumors in adults) approved between 2009 and 2019 by FDA were considered. The same treatments were approved by EMA in December 2019. An evaluation of the RCE definition of rare cancers was carried out, as well as the correlation of FDA and EMA orphan drug designations.

During the study period, on the total of 76 drugs approved by the FDA and EMA, 39 (51%) were approved In the US (OS) and 49 (64%) in the EU. 50 (66%) drugs were granted orphan drug status (FDA), and 17 (22%) by the EMA. However, no association was made between rare cancers (RCE definition) and FDA and EMA drug indications with orphan status. Also, no association was made between pivotal trial endpoints (OS vs. non-OS) and orphan drug designation (FDA), and there was as well no association between rare cancers (RCE definition) and pivotal trial endpoints. It was concluded that approval of drugs for non-rare cancers should be better aligned with OS as pivotal trial endpoints.

Orphan drug development: Opportunities and barriers for innovation and entrepreneurship

The authors write that orphan drugs (OD) are a challenge for the RD community and present an opportunity to focus on innovation and global engineering. The study was based on a literature review taking into consideration existing knowledge of the orphan drug development process. Possible tensions were explored for entrepreneurship and innovation. Social systems theories were also taken into account, as they allow solutions to be linked from different disciplines. The authors pointed out the gaps in research. They emphasised a different way of thinking by including in the debate on OD development other stakeholders’ voices and other aspects apart from economic logic.

Screening and prenatal diagnosis

Neonatal and carrier screening for rare diseases and the way innovation challenges screening criteria worldwide

Neonatal bloodspot screening (NBS) is helping children with screened diseases obtain better health outcomes, and carrier screening allows autonomous reproductive choice. NBS for phenylketonuria, and carrier screening for Tay-Sachs disease, sickle cell anaemia and β-thalassaemia, started 50 years ago. With technological developments, NBS and carrier screening areas are being expanded in some countries, and they have challenged both areas with test, target population, treatment, programme evaluation, and the decision-making.

The two areas have even opened debate, with carrier screening more driven by disease prevention, than reproductive autonomy, and questions arising about potential beneficiaries and diseases to consider. NBS belongs to the public health programme, and carrier screening is available through medical professionals. Stakeholders of both areas were called to exchange visions and knowledge, as applications and interpretation of screening principles are quickly evolving.

Ethical Legal and Social

Parents’ and professionals’ views, experiences and challenges on delivering genome sequencing for rapid genetic diagnosis in critically ill children

An article in the European Journal of Human Genetics focuses on a qualitative study on parents’ and healthcare professionals’ views on rapid genomic sequencing (RGS) tests, and the challenges of wider clinical implementation. RGS is widely used in case of care of critically children. Interviews were carried out with parents and professionals who reported their positive views about RGS, mainly for the rapid diagnosis. For parents, their child’s illness may in some cases complicated their decision making. Pre-test counselling is needed to help parents in the decision making. The need for a multidisciplinary team for a rapid service and for efficient delivery was also raised.

Rare neurological diseases, a challenge for policy makers, patients and healthcare professionals

A report highlighting rare diseases policy challenges, especially in the case of rare neurological diseases (RNDs), such Duchenne muscular dystrophy or Prader-willi syndrome, has been published. RNDs are most of the time undiagnosed or misdiagnosed. RNDs patients can spent 5 to 30 years without a diagnosis. Other challenges are related to treatment and management, policy responses for RD and RNDs, and the creation of orphan drug legislation (availability of new approved treatments), or public funding from government and national research councils.

The report proposed some solutions to these challenges, including collaboration and coordination of all stakeholders, sharing knowledge, and improving and linking disease registries for more research support in population-limited.

Quality of life

Diagnosis of Rare Diseases and clinical decision support systems

An article in the Orphanet Journal of Rare Diseases (OJRD) addressed the delay to diagnosis, one of the main issues in the rare diseases area. A scoping review was conducted on PubMed resulting in 636 English articles on clinical decision support systems (CDSSs) published from December 16, 2008 to December 16, 2018. Data items were used for data charting. 22 articles on 19 different CDSSs were found, and were classified following three types of CDSSs: “Machine learning” “analysis or comparison of genetic and phenotypic data,” and “information retrieval”.

Amongst the 19, twelve CDSSs mentioned phenotypic and genetic data, clinical data, literature databases and patient questionnaires. Fourteen of the nineteen CDSSs were fully developed systems and therefore publicly available. For six CDSSs, it was possible to enter data manually, and for four CDSSs, there is no information for data integration available. In seven other CDSSs, it was also possible to enter data. However, for thirteen CDSSs, it was not possible at all to provide information. For the next step, future research has to be conducted on the CDSSs’ clinical usage, data integration, and possibility to update clinical knowledge. The authors note that the evolution of these tools is of high interest.

Bioinformatics and biotechnology

Phenotype-genotype comorbidity analysis of patients with rare disorders and insight on pathological and molecular bases

A study presents a computational approach (DECIPHER database) which is connecting patient phenotypes (phenotypic co-occurence) and genomic information on patient mutations. The computational approach allowed genetic and molecular analysis, which was initially not possible following small numbers of RD patients affected. In that vein, phenotypic comorbidity analysis is therefore useful, is using information of patients with the same phenotypes, and is as well related to shared genes and functional systems.

The DECIPHER database contains phenotypic and genomic information for thousands of RD patients living with various RD. The DECIPHER database has functional coherence, genes mapping and systems involved in similar pathological processes. The computational approach was implemented as a workflow (PhenCo) that has an implementation code available from GitHub.

Data Management

A preliminary study on phenotypically similar rare disease identification from an integrative knowledge graph for data harmonisation

In the absence of standardised protocol defining and harmonising RD across multiple resources, a study was conducted by researchers at NIH-NCATS, which hosts the Genetic and Rare Diseases information center (GARD) to identify phenotypical similarity among genetic and rare diseases presenting similar clinical manifestations, and for data support harmonisation. Difficulties were reported in developing comprehensive disease resources with RD information aimed at education and clinical decision-making. Due to the absence of a standardised protocol, there were data redundancies, inconsistencies, confusion and difficulties for the use of the mentioned resources.

The evaluation results showed a high precision (94%) and a satisfactory quality (86% F measure). Phenotypically similar RD were identified through GARD diseases and 2 approaches, disease mapping comparison and phenotypical similarity derivation from disease classification systems. The results of the study will direct GARD data harmonisation and expanded translational science research, and will as well accelerate data transparency and consistency through different disease resources and terminologies. This will help to build a robust and up-to-date knowledge resource on RD.

Data Analysis and Rare Disease Diagnostics

An article in the Journal of the Indian Institute of Science provides an overview of data processing taking place during the process of multi-stage of RD diagnosis. One or two changes in the genome cause a high number of RD. It is a challenge to identify the causes of variants from different millions of variants that make the genome different among human beings. Algorithms and methods are used in laboratories to help the diagnosis process. Deep learning and machine learning are also contributing in the improvement of the process.

RaDiOS ontology, an automated generation of decision-tree models for the economic assessment of interventions for rare diseases

An article in the Journal of Biomedical Informatics highlights a method (RadiOS) reusing knowledge collected in an ontology that can generate automatically decision tree models and in various contexts and interventions. From the updated reference ontology RaDiOS, a transformation tool (RaDiOS-MTT) was implemented. The information stored in RaDiOS can be used to automatically generate decision trees for the economic assessment of RD interventions. With RaDiOS-MTT, research groups can reuse the collected knowledge, and this can help the development health economics assessments and ultimately to RD interventions.

Summary of the edition of 27 November 2020

Editorial
Political news
Scientific news
And also...