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Article En | MEDLINE | ID: mdl-33800980

Scientific knowledge on depression and anxiety in patients with rare diseases during the COVID-19 pandemic is scarce; however, it is essential to perform comprehensive management of these patients. The aim of this study was to research how the situation caused by the SARS-CoV-2 pandemic has influenced the lives of patients with rare diseases regarding depression and anxiety. This Spanish study considered a heterogeneous population sample of 86 patients with confirmed diagnosis of different rare diseases. Participants took part in a cross-sectional online study by completing specific questionnaires on the study topic. Depression was measured using the Patient Health Questionnaire (PHQ-9), and the General Anxiety Disorder Scale (GAD-7) was used for evaluating anxiety. Data collection through an online questionnaire allowed for a greater population scope and therefore the inclusion patients of other nationalities in the study sample. Finally, as a general result, this study found that, in the face of the pandemic, anxiety and depression remained at a higher level in this group than in the general population, making these patients a vulnerable population group.

Pandemics , Anxiety/epidemiology , Anxiety Disorders/epidemiology , Cross-Sectional Studies , Depression/epidemiology , Humans , Mental Health , Rare Diseases/epidemiology , Surveys and Questionnaires
Article En | MEDLINE | ID: mdl-33530652

In the field of rare diseases (RDs), the evidence standard is often lower than that required by health technology assessment (HTA) and payer authorities. In this commentary, we propose that appropriate economic evaluation for rare disease treatments should be initially informed by cost-of-illness (COI) studies conducted using a societal perspective. Such an approach contributes to improving countries' understanding of RDs in their entirety as societal and not merely clinical, or product-specific issues. In order to exemplify how the disease burden's distribution has changed over the last fifteen years, key COI studies for Hemophilia, Fragile X Syndrome, Cystic Fibrosis, and Juvenile Idiopathic Arthritis are examined. Evidence shows that, besides methodological variability and cross-country differences, the disease burden's share represented by direct costs generally grows over time as novel treatments become available. Hence, to support effective decision-making processes, it seems necessary to assess the re-allocation of the burden produced by new medicinal products, and this approach requires identifying cost drivers through COI studies with robust design and standardized methodology.

Cost of Illness , Cystic Fibrosis , Cost-Benefit Analysis , Humans , Rare Diseases/epidemiology , Technology Assessment, Biomedical
Medicina (Kaunas) ; 57(2)2021 Jan 28.
Article En | MEDLINE | ID: mdl-33525390

Uncertainty analysis is the process of identifying limitations in knowledge and evaluating their implications for scientific conclusions. Uncertainty analysis is a stable component of risk assessment and is increasingly used in decision making on complex health issues. Uncertainties should be identified in a structured way and prioritized according to their likely impact on the outcome of scientific conclusions. Uncertainty is inherent to the rare diseases (RD) area, where research and healthcare have to cope with knowledge gaps due to the rarity of the conditions; yet a systematic approach toward uncertainties is not usually undertaken. The uncertainty issue is particularly relevant to multifactorial RD, whose etiopathogenesis involves environmental factors and genetic predisposition. Three case studies are presented: the newly recognized acute multisystem inflammatory syndrome in children and adolescents associated with SARS-CoV-2 infection; the assessment of risk factors for neural tube defects; and the genotype-phenotype correlation in familial Mediterranean fever. Each case study proposes the initial identification of the main epistemic and sampling uncertainties and their impacts. Uncertainty analysis in RD may present aspects similar to those encountered when conducting risk assessment in data-poor scenarios; therefore, approaches such as expert knowledge elicitation may be considered. The RD community has a main strength in managing uncertainty, as it proactively develops stakeholder involvement, data sharing and open science. The open science approaches can be profitably integrated by structured uncertainty analysis, especially when dealing with multifactorial RD involving environmental and genetic risk factors.

/epidemiology , Familial Mediterranean Fever/epidemiology , Neural Tube Defects/epidemiology , Rare Diseases/epidemiology , Systemic Inflammatory Response Syndrome/epidemiology , Uncertainty , Causality , Familial Mediterranean Fever/genetics , Genotype , Humans , Knowledge , Phenotype , Rare Diseases/etiology , Risk Assessment , Risk Factors
Cancer Radiother ; 25(2): 114-118, 2021 Apr.
Article En | MEDLINE | ID: mdl-33487559

PURPOSE: The breast sarcoma induced by radiation therapy is rare but increasing, given the increased long-term survival of patients receiving radiation therapy. Fibrosarcoma, histiocytofibroma and angiosarcoma are the most common breast sarcoma. Angiosarcoma is the most common after breast cancer treated by radiation therapy, often diagnosed too late, with a severe prognosis and a high rate of recurrence. However, because of the low incidence of angiosarcoma associated with radiation therapy (AAR), the benefit of radiation therapy in breast cancer treatment outweighs the risk to develop angiosarcoma. The aim of this study is to evaluate these rare cases of AAR diagnosed in eastern Belgium in comparison to the data from the literature. PATIENTS AND METHODS: Nine cases of AAR after radiation for breast ductal carcinoma were included in this retrospective study. AAR was diagnosed according to Cahan criteria between January 2007 and December 2016. Latency, incidence, management and prognosis are comparable to the literature. RESULTS, CONCLUSION: The median latency was 10 (4-24) years, the incidence of AAR in the East Belgian area was 0.09% of the patients irradiated on the same period. Patients were treated by surgery with wide local excision with or without reconstructive surgery, without radiotherapy and chemotherapy treatment. Kaplan-Meier analysis showed median overall survival of 61.8 months, patient survival of 55.6% at one year and 29.6% at five years. With the constant progress of medicine and its technologies, it would be possible to limit the occurrence of AAR or to diagnose it at an earlier stage.

Breast Neoplasms/etiology , Breast Neoplasms/radiotherapy , Carcinoma, Ductal, Breast/radiotherapy , Hemangiosarcoma/etiology , Neoplasms, Radiation-Induced/etiology , Neoplasms, Second Primary/etiology , Aged , Aged, 80 and over , Belgium/epidemiology , Breast Neoplasms/epidemiology , Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/epidemiology , Carcinoma, Ductal, Breast/mortality , Female , Hemangiosarcoma/epidemiology , Hemangiosarcoma/mortality , Hemangiosarcoma/surgery , Humans , Incidence , Kaplan-Meier Estimate , Mastectomy , Middle Aged , Neoplasms, Radiation-Induced/epidemiology , Neoplasms, Radiation-Induced/mortality , Neoplasms, Radiation-Induced/surgery , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/mortality , Neoplasms, Second Primary/surgery , Rare Diseases/epidemiology , Rare Diseases/etiology , Rare Diseases/mortality , Rare Diseases/surgery , Retrospective Studies , Survival Analysis , Time Factors , Unilateral Breast Neoplasms/epidemiology , Unilateral Breast Neoplasms/etiology , Unilateral Breast Neoplasms/mortality
Article Ru | MEDLINE | ID: mdl-33161658

The study was carried out to analyze detection of rare diseases that are not included into listings of rare (orphan) diseases to be treated at the expense of budget resources of the Russian Federation Russian Federation (hereinafter referred as rare diseases out of reimbursement). The analysis of detection of patients with rare diseases out of reimbursement in Russian Federation was carried out. The information was collected and summarized on the basis of open sources by the way of formalized personal request to the heads of patient and public organizations providing care of patients with rare diseases out of reimbursement. It is established that in the Russian Federation (85 subjects) reside patients with more than 250 forms and groups of rare diseases and only 28 out of them are included into the Federal registries of patients. Actually, there are more than 8 000 nosologic forms of rare diseases that are known thus far. The monitoring permitted to collect data concerning 30 particular nosological forms and groups of rare diseases out of reimbursement. Among them, 23 out of 30 analyzed pathologies have genetic nature. And only for 24 out of 30 diseases the registration of patients is applied. It is necessary to organize modern system of registration of patients within the framework of the Federal registry that includes full and actual data about patients, course of disease, therapeutic interventions that will permit to determine prevalence, disability, mortality, lethality, necessary medicinal maintenance and also to establish spectrum of diseases that are to be included into drug reimbursement programs.

Orphan Drug Production , Rare Diseases , Humans , Prevalence , Rare Diseases/diagnosis , Rare Diseases/drug therapy , Rare Diseases/epidemiology , Registries , Russia/epidemiology
Jpn J Clin Oncol ; 50(9): 970-975, 2020 Sep 05.
Article En | MEDLINE | ID: mdl-32719865

This review introduces the definition, epidemiology and therapeutic challenges of rare cancers and describes the establishment of the Rare Cancer Center at the National Cancer Center, Japan. Rare cancers are defined as malignant tumors with an incidence rate of less than 6 cases per 100 000 individuals. Due to their low incidence rate, medical treatment for rare cancers is more challenging than for more common cancer types. Specifically, 190 types of cancers, including bone and soft tissue sarcomas, gastrointestinal stromal tumors (GISTs), neuroendocrine tumors and gliomas, are classified as rare cancers. Individually, each of the rare cancers accounts for less than 1% of all cancers, but collectively they account for 15% of all cancers. On the basis of their medical management, rare cancers can be subclassified into two types: Type I (rare cancers within cancer-rare organs) and Type II (rare cancers within cancer-common organs). Most importantly, the outcomes for rare cancers are poorer compared to those of common cancers. In 2014, the Rare Cancer Center was established at the National Cancer Center to address the various challenges related to rare cancers. The Rare Cancer Center has adopted a multifaceted approach for overcoming these challenges, including active sharing of information through a dedicated website and an online seminar series 'Rare Cancer Meet the Expert', providing medical support through telephone consultations via a 'Rare Cancer Hotline', supporting basic research and establishing the 'MASTER KEY Project' aimed at developing new treatments.

Neoplasms/epidemiology , Rare Diseases/epidemiology , Humans , Japan
Ann Hematol ; 99(9): 1967-1977, 2020 Sep.
Article En | MEDLINE | ID: mdl-32621178

Thalassemia is characterized by a defect in the synthesis of one or more of the globin subunits of hemoglobin. This defect results in imbalance in the α/ß-globin chain ratio, ineffective erythropoiesis, chronic hemolytic anemia, and iron overload. With advances in diagnosis, treatment, and transfusion support, the prognosis of patients with thalassemia has improved over the past few decades. An increasing number of patients with thalassemia is living with long-term complications, including cardiomyopathy, chronic liver disease, endocrinopathy, and infections. In this paper, we review common complications that bring the patient with thalassemia to urgent or emergent medical attention. We also discuss the aspects of emergency care that are most relevant while caring for the patient with thalassemia in the emergency department.

Emergency Medical Services/trends , Emergency Service, Hospital/trends , Rare Diseases/diagnostic imaging , Rare Diseases/therapy , Thalassemia/diagnostic imaging , Thalassemia/therapy , Betacoronavirus , Blood Transfusion/methods , Blood Transfusion/trends , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/epidemiology , Cardiomyopathies/therapy , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Diagnosis, Differential , Emergency Medical Services/methods , Humans , Liver Diseases/diagnostic imaging , Liver Diseases/epidemiology , Liver Diseases/therapy , Pandemics , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Rare Diseases/epidemiology , Thalassemia/epidemiology
Eur J Epidemiol ; 35(10): 937-948, 2020 Oct.
Article En | MEDLINE | ID: mdl-32681390

Rare cancers together constitute one fourth of cancers. As some rare cancers are caused by occupational exposures, a systematic search for further associations might contribute to future prevention. We undertook a European, multi-center case-control study of occupational risks for cancers of small intestine, bone sarcoma, uveal melanoma, mycosis fungoides, thymus, male biliary tract and breast. Incident cases aged 35-69 years and sex-and age-matched population/colon cancer controls were interviewed, including a complete list of jobs. Associations between occupational exposure and cancer were assessed with unconditional logistic regression controlled for sex, age, country, and known confounders, and reported as odds ratios (OR) with 95% confidence intervals (CI). Interviewed were 1053 cases, 2062 population, and 1084 colon cancer controls. Male biliary tract cancer was associated with exposure to oils with polychlorinated biphenyls; OR 2.8 (95% CI 1.3-5.9); male breast cancer with exposure to trichloroethylene; OR 1.9 (95% CI 1.1-3.3); bone sarcoma with job as a carpenter/joiner; OR 4.3 (95% CI 1.7-10.5); and uveal melanoma with job as a welder/sheet metal worker; OR 1.95 (95% CI 1.08-3.52); and cook; OR 2.4 (95% CI 1.4-4.3). A confirmatory study of printers enhanced suspicion of 1,2-dichloropropane as a risk for biliary tract cancer. Results contributed to evidence for classification of welding and 1,2-dichloropronane as human carcinogens. However, despite efforts across nine countries, for some cancer sites only about 100 cases were interviewed. The Rare Cancer Study illustrated both the strengths and limitations of explorative studies for identification of etiological leads.

Neoplasms/etiology , Occupational Diseases/etiology , Occupational Exposure/adverse effects , Rare Diseases/etiology , Adult , Aged , Case-Control Studies , Europe/epidemiology , Female , Humans , Incidence , Male , Middle Aged , Neoplasms/epidemiology , Occupational Diseases/epidemiology , Rare Diseases/epidemiology , Risk Factors
Eur J Endocrinol ; 183(2): 141-148, 2020 Aug.
Article En | MEDLINE | ID: mdl-32413847

Objective: Given that volumes of patients and interventions are important criteria to qualify as a reference centre (RC) for the European Reference Network on Rare Endocrine Conditions (Endo-ERN), the present study aimed to evaluate the data that were reported in the original application against subsequent assessments of activity and review the criteria that may define RCs using two main thematic groups (MTGs): Pituitary and Thyroid, as examples. Methods: Review of content in application forms and continuous monitoring data and of a survey distributed to RCs. A list of 'key procedures' for the assessment of performance of RCs was composed with the help of the Pituitary and Thyroid MTG chairs. Results: In the original application, the number of undefined procedures ranged from 20 to 5500/year (Pituitary) and from 10 to 2700/year (phyroid) between applicants. In the survey, the number of key procedures per centre ranged from 18 to 150/year (Pituitary) and from 20 to 1376/year (Thyroid). The median numbers of new patients reported in the continuous monitoring program were comparable with the application and survey; however, some centres reported large variations. Conclusions: Monitoring of clinical activity in an ERN requires clear definitions that are optimally aligned with clinical practice, diagnosis registration, and hospital IT systems. This is a particular challenge in the rare disease field where the centre may also provide expert input in collaboration with local hospitals. Application of uniform definitions, in addition to condition-specific clinical benchmarks, which can include patient-reported- as well as clinician-reported outcome measures, is urgently needed to allow benchmarking of care across Endo-ERN.

Endocrine System Diseases/therapy , Rare Diseases/therapy , Data Interpretation, Statistical , Endocrine System Diseases/epidemiology , Europe/epidemiology , Humans , Outcome Assessment, Health Care , Pituitary Diseases/epidemiology , Pituitary Diseases/therapy , Rare Diseases/epidemiology , Reference Standards , Surveys and Questionnaires , Thyroid Diseases/epidemiology , Thyroid Diseases/therapy
Article En | MEDLINE | ID: mdl-32365682

Introduction: Studies on the epidemiology of primary sclerosing cholangitis (PSC) are mainly based on tertiary referral centers; and are retrospective case series susceptible to selection bias. The aim of this study was to estimate incidence; survival and cause of mortality of PSC in Italy; using population-based data. Methods: Data collected from the National Rare Diseases Registry (RNMR) and the National Mortality Database (NMD) were integrated and analyzed. Results: We identified 502 PSC incident cases. The crude incidence rate between 2012 and 2014 was 0.10 per 100,000 individuals. Sixty percent were male; mean age at disease onset and at diagnosis were 33 and 37 years; respectively; highlighting a mean diagnostic delay of 4 years. The rate of interregional mobility was 12%. Ten-year survival was 92%. In 32% of cases the cause of death was biliary-related; 12% died of biliary or gallbladder cancer. Conclusions: For rare diseases such as PSC; population-based cohort's studies are of paramount importance. Incidence rates of PSC in Italy are markedly lower and survival much longer than the ones reported from tertiary; single-centre series. Moreover; the diagnostic delay and the patient interregional mobility highlights the need for increasing awareness on the disease and for resource reallocation among Italian regions within the National Health Service.

Cholangitis, Sclerosing , Adolescent , Adult , Aged , Child , Child, Preschool , Cholangitis, Sclerosing/epidemiology , Cholangitis, Sclerosing/mortality , Cost of Illness , Delayed Diagnosis , Female , Humans , Infant , Infant, Newborn , Italy/epidemiology , Male , Middle Aged , Rare Diseases/epidemiology , Rare Diseases/mortality , Registries , Retrospective Studies , State Medicine , Young Adult
Ned Tijdschr Geneeskd ; 1642020 04 30.
Article Nl | MEDLINE | ID: mdl-32395952

According to the European definition, rare diseases are life-threatening or chronically debilitating conditions that affect only 5 out of 10,000 people in the European Union. It is estimated that there are around 6000-8000 different rare diseases, affecting 6-8% of the population in the course of their lives. For the Netherlands, this means that about 1 million people are affected by a rare disease, or one in 17 people. Patients with rare diseases indicate that they often have a long and uncertain diagnostic journey behind them, while the first symptoms present in childhood in 75% of the rare diseases. In this perspective, we discuss some of the results from the research report 'Scherperzicht op diagnostischevertragingbijzeldzameaandoeningen' in which the diagnostic journey for patients with rare diseases is mapped out with figures. We also make recommendations to speed up the diagnostic process for patients with rare diseases.

Delayed Diagnosis/trends , Rare Diseases/diagnosis , Adult , Child , European Union , Female , Humans , Male , Netherlands/epidemiology , Rare Diseases/epidemiology
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(3): 400-405, 2020 Mar 10.
Article Zh | MEDLINE | ID: mdl-32294843

Objective: To understand the characteristics of 24 388 inpatients with rare diseases in Zhejiang province during 2007-2017 and provide evidence for rare disease prevention and control. Methods: Inpatient data of rare diseases and the number of hospitalization in each year were collected in 10 hospitals of class Ⅲ (A) in Zhejiang province from 2007 to 2017, and descriptive statistical analysis was used. Results: A total of 24 388 cases of rare diseases were found, accounting for 2.69‰ (24 388/9 054 201) of total hospitalized cases. The top 3 types of rare diseases were "diseases of blood and blood-forming organs and certain disorders involving immune mechanism" (32.81%, 8 001/24 388), "congenital malformations, deformations and chromosomal abnormalities" (24.87%, 6 065/24 388) and "diseases of the nervous system" (19.01%, 4 635/24 388). The number of rare disease cases increased year by year from 2007 to 2017 with an average annual growth of 19.69%, however, the proportion of rare disease cases in the annual number of hospitalized cases only showed upward trend during 2016-2017, the time distribution of different types of rare diseases had different characteristics. The male to female ratio of rare diseases cases was 1.35∶1(13 990/10 398), "diseases of the digestive system" (4.45∶1, 1 180/265), "consequences of injury, poisoning and other external causes" (3.51∶1, 281/80) and "diseases of the nervous system" (2.26∶1, 3 213/1 422) had the highest male to female ratio. The distributions of rare disease types and diseases of different types in different age groups varied. The top 10 rare diseases accounted for 53.55% (13 060/24 388) of the total cases, and the top 3 diseases were adult idiopathic neutropenia (14.41%, 3 515/24 388), corticobasal degeneration (7.60%, 1 854/24 388) and henock-schoenlein purpura (6.01%, 1 466/24 388). Conclusion: The analysis on the characteristics of 24 388 rare disease cases in Zhejiang during 2007-2017 provided reference evidence for the promotion of rare disease research, monitoring, building registration database, and development of the prevention and control strategy for rare diseases in China.

Rare Diseases/epidemiology , Rare Diseases/therapy , Adult , China/epidemiology , Databases, Factual , Female , Hospitalization/statistics & numerical data , Humans , Inpatients/statistics & numerical data , Male , Rare Diseases/prevention & control
PLoS One ; 15(4): e0230587, 2020.
Article En | MEDLINE | ID: mdl-32271766

As high-throughput sequencing is increasingly applied to the molecular diagnosis of rare Mendelian disorders, a large number of patients with diverse phenotypes have their genetic and phenotypic data pooled together to uncover new gene-phenotype relations. We introduce Phenogenon, a statistical tool that combines, Human Phenotype Ontology (HPO) annotated patient phenotypes, gnomAD allele population frequency, and Combined Annotation Dependent Depletion (CADD) score for variant pathogenicity, in order to jointly predict the mode of inheritance and gene-phenotype associations. We ran Phenogenon on our cohort of 3,290 patients who had undergone whole exome sequencing. Among the top associations, we recapitulated previously known, such as "SRD5A3-Abnormal full-field electroretinogram-recessive" and "GRHL2 -Nail dystrophy-recessive", and discovered one potentially novel, "RRAGA-Abnormality of the skin-dominant". We also developed an interactive web interface available at to visualise and explore the results.

Computational Biology/methods , Genetic Association Studies , Genetic Diseases, Inborn , High-Throughput Nucleotide Sequencing , Rare Diseases , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , Cohort Studies , DNA-Binding Proteins/genetics , Databases, Genetic , Gene Frequency , Genetic Association Studies/methods , Genetic Association Studies/statistics & numerical data , Genetic Diseases, Inborn/epidemiology , Genetic Diseases, Inborn/genetics , Genetic Predisposition to Disease , Genotype , High-Throughput Nucleotide Sequencing/methods , High-Throughput Nucleotide Sequencing/statistics & numerical data , Humans , Membrane Proteins/genetics , Monomeric GTP-Binding Proteins/genetics , Nail Diseases/epidemiology , Nail Diseases/genetics , Phenotype , Rare Diseases/epidemiology , Rare Diseases/genetics , Retinal Dystrophies/epidemiology , Retinal Dystrophies/genetics , Skin Diseases/epidemiology , Skin Diseases/genetics , Transcription Factors/genetics , Whole Exome Sequencing
PLoS One ; 15(4): e0230850, 2020.
Article En | MEDLINE | ID: mdl-32240232

OBJECTIVE: Rare diseases are often underdiagnosed, and their management is frequently complicated by a lack of access to treatment and information about the diseases. To allow for better policy planning, we sought to examine the current status of managing rare diseases in Malaysia. METHODS: This study was conducted in two phases. In the first phase, we triangulated information from reviews of journal publications, documents from the Malaysian government and in-depth interviews among selected key healthcare stakeholders in Malaysia. The second phase was designed as a cross-sectional survey to estimate the number of cases and treatment coverage for rare diseases in Malaysia. RESULTS: Malaysia has no official definition of rare disease yet but currently in the process of reviewing them for Malaysia. There are 13 rare disease specialists and a dozen medical doctors in genetic clinics around Malaysia, mainly in public health facilities. From the survey, 1,249 patients were diagnosed with rare diseases in public hospitals. Only 60% received their medications or supplements, and the rest continued with symptomatic treatment. CONCLUSION: Generally, Malaysia has made significant progress in the management of rare diseases, but there are still opportunities for development in critical areas. Ultimately, if all healthcare providers, government, society, and politicians work together to manage rare diseases, we will see an improvement in patient outcomes.

Rare Diseases/diagnosis , Rare Diseases/epidemiology , Adult , Cross-Sectional Studies , Female , Health Personnel , Humans , Malaysia/epidemiology , Male , Middle Aged , Specialization , Surveys and Questionnaires
Gac. sanit. (Barc., Ed. impr.) ; 34(2): 141-149, mar.-abr. 2020. tab, graf
Article Es | IBECS | ID: ibc-196050

OBJETIVO: Evaluar el acceso al mercado de los medicamentos huérfanos en España que a fecha de 31 de diciembre de 2017 tuvieran vigente su designación, y para aquellos comercializados en España estimar los tiempos entre la asignación de código nacional (CN) por parte de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) y la fecha de comercialización efectiva. MÉTODO: La base de datos para identificar los medicamentos huérfanos autorizados por la Agencia Europea de Medicamentos (EMA), a fecha 31 de diciembre de 2017 (n = 142), es su Registro Comunitario publicado por la Comisión Europea. La EMA publica los medicamentos huérfanos que han perdido la designación. Las fechas de asignación de CN provienen de la AEMPS, y las de comercialización, de Bot PLUS. Se llevó a cabo un análisis descriptivo de las variables de estudio. Las variables cuantitativas se describieron utilizando la media y mediana, así como la desviación estándar y su rango. Las variables cualitativas se describieron según frecuencias absolutas y relativas. La comparación de resultados se realizó mediante contrastes paramétricos y no paramétricos en función de la aplicabilidad, con un nivel de significación del 5%. RESULTADOS: Entre 2002 y 2017, la EMA autorizó (con designación vigente a 31 de diciembre de 2017) 100 medicamentos huérfanos. De ellos, 86 tienen CN asignado, y de estos, 54 se han comercializado en España (54% de los medicamentos huérfanos vigentes y 63% de aquellos con CN). Para todos los medicamentos huérfanos con fecha de comercialización (53), el tiempo (mediana) desde la asignación del CN hasta su comercialización en España es de 13,4 meses (desviación estándar: 17,0; mínimo: 2,1; máximo: 91,7). La mediana para los comercializados en 2002-2013 y 2014-2017 es de 12,4 meses y 14,0 meses, respectivamente (p = 0,46). Esta diferencia no es estadísticamente significativa, lo que cabría esperar dado el número limitado de medicamentos huérfanos en nuestra «población». CONCLUSIÓN: Numerosos factores determinan el acceso a los medicamentos huérfanos. La autorización centralizada de comercialización en Europa es un éxito; su acceso es más limitado, dadas las complejidades de evaluación de la evidencia disponible en los procesos de financiación y precio. Es necesario implementar nuevas políticas que reduzcan las desigualdades en el acceso y permitan la sostenibilidad del sistema. Para conseguir estos objetivos, podrían contemplar un proceso acelerado en la decisión de financiación y precio, y el pago por resultados con incertidumbre alta

OBJECTIVE: To assess the access to orphan medicines in Spain, focusing on those with an active "orphan" designation, as of 31st December 2017; and for those orphan medicines in the Spanish market, estimate the time between being assigned a National Code (NC) by the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) and being approved for launch. METHOD: We used the European Commission's Public Register of orphan medicines to identify the orphan medicines authorised by the European Medicines Agency (EMA), as of 31 December 2017, while we sourced expired orphan indications from the EMA's website. Dates when NCs were assigned were sourced from the AEMPS, and commercialisation dates from Bot PLUS. A descriptive analysis of the study variables was done. The quantitative variables were described using means and medians, as well as standard deviations and ranges. The qualitative variables were described according to absolute and relative frequencies. The comparison of results was performed by parametric and non-parametric contrasts according to the applicability, at a 5% significance level. RESULTS: The EMA has approved 100 orphan medicines (with designation as of 31/12/2017) between 2002-2017. Eighty-six have a NC assigned by the AEMPS. Fifty-four have been launched in Spain (representing 54% of the full sample; 63% with NC). For the 53 orphan drugs with launch date in Spain, the median time between receiving its NC and its launch is 13.4 months (standard deviation: 17.0; minimum: 2.1; maximum: 91,7). The median time is 12.4 months and 14.0 months for those medicines launched in Spain between 2002-2013 and 2014-2017 respectively (p = 0.46). This difference is not statistically significant, which is what could be expected given the low numbers of orphan medicines in the "population". CONCLUSION: Complex factors determine the access to orphan drugs in Europe. The centralised procedure to obtain marketing authorisation at European level is a success. However, access is more limited, given the complexities of the evaluation of the available evidence for pricing and reimbursement decisions. It is therefore necessary to implement new policies that reduce inequalities in access and help achieve sustainable healthcare systems. To achieve this, they will need to offer the possibility of allowing earlier access, and using payment by results when there is high uncertainty

Humans , Orphan Drug Production/statistics & numerical data , Access to Essential Medicines and Health Technologies , Drug Approval/organization & administration , Spain , Rare Diseases/epidemiology , Legislation, Drug/trends , Pharmaceutical Trade , National Drug Policy , Databases, Pharmaceutical
Brain ; 143(4): 1099-1105, 2020 04 01.
Article En | MEDLINE | ID: mdl-32168371

A large fraction of rare and severe neurodevelopmental disorders are caused by sporadic de novo variants. Epidemiological disease estimates are not available for the vast majority of these de novo monogenic neurodevelopmental disorders because of phenotypic heterogeneity and the absence of large-scale genomic screens. Yet, knowledge of disease incidence is important for clinicians and researchers to guide health policy planning. Here, we adjusted a statistical method based on genetic data to predict, for the first time, the incidences of 101 known de novo variant-associated neurodevelopmental disorders as well as 3106 putative monogenic disorders. Two corroboration analyses supported the validity of the calculated estimates. First, greater predicted gene-disorder incidences positively correlated with larger numbers of pathogenic variants collected from patient variant databases (Kendall's τ = 0.093, P-value = 6.9 × 10-6). Second, for six of seven (86%) de novo variant associated monogenic disorders for which epidemiological estimates were available (SCN1A, SLC2A1, SALL1, TBX5, KCNQ2, and CDKL5), the predicted incidence estimates matched the reported estimates. We conclude that in the absence of epidemiological data, our catalogue of 3207 incidence estimates for disorders caused by de novo variants can guide patient advocacy groups, clinicians, researchers, and policymakers in strategic decision-making.

Neurodevelopmental Disorders/epidemiology , Neurodevelopmental Disorders/genetics , Rare Diseases/epidemiology , Rare Diseases/genetics , Genetic Variation , Humans , Incidence
Article En | MEDLINE | ID: mdl-32182694

Background: To investigate the multidimensional difficulties in accessing a definitive diagnosis of adult rare diseases and the associated impact factors in China. Methods: A total of 1010 adult rare disease patients from the 2018 China Rare Disease Survey were used for analysis. The Structural Equation Models examined the interrelationships among five accessibility indicators and the effects of three sets of impact factors. Results: (1) Accessibility: 72.97% of patients were misdiagnosed; they waited an average of 4.30 years and visited 2.97 hospitals before the definitive diagnosis; 67.13% were diagnosed outside the home city and traveled an average of 562 km. (2) Interrelationships among accessibility indicators: the experience of misdiagnosis significantly increased diagnosis delay and the number of hospitals visited, but had no significant effect on healthcare utilization across cities. (3) Impact factors: the rarity of disease only increased the number of hospitals visited and residence-hospital distance; high-quality healthcare distribution was key in determining accessibility; the older, disabled, poor, and less-educated individuals, and those in Central/West China were disadvantaged. Conclusion: The socioeconomic dimension of difficulties in accessing a definitive diagnosis of rare diseases should be attended, especially the uneven distribution of high-quality healthcare and those disadvantaged patients. More systematic rare disease surveys are needed in the future.

Travel , Adult , China/epidemiology , Cross-Sectional Studies , Female , Health Services Accessibility , Humans , Male , Rare Diseases/epidemiology , Surveys and Questionnaires
Hum Genet ; 139(5): 569-574, 2020 May.
Article En | MEDLINE | ID: mdl-32056000

Extremely rare diseases are increasingly recognized due to wide-spread, inexpensive genomic sequencing. Understanding the incidence of rare disease is important for appreciating its health impact and allocating recourses for research. However, estimating incidence of rare disease is challenging because the individual contributory alleles are, themselves, extremely rare. We propose a new method to determine incidence of rare, severe, recessive disease in non-consanguineous populations that use known allele frequencies, estimate the combined allele frequency of observed alleles and estimate the number of causative alleles that are thus far unobserved in a disease cohort. Experiments on simulated and real data show that this approach is a feasible method to estimate the incidence of rare disease in European populations but due to several limitations in our ability to assess the full spectrum of pathogenic mutations serves as a useful tool to provide a lower threshold on disease incidence.

Genes, Recessive , Genetic Predisposition to Disease , Mutation , Polymorphism, Single Nucleotide , Rare Diseases/epidemiology , Rare Diseases/genetics , Cohort Studies , Gene Frequency , Humans , Incidence , Models, Genetic , United States/epidemiology
PLoS One ; 15(2): e0228417, 2020.
Article En | MEDLINE | ID: mdl-32027664

Congenital hyperinsulinism (CHI) is a significant cause of hypoglycaemia in neonates and infants with the potential for permanent neurologic injury. Accurate calculations of the incidence of rare diseases such as CHI are important as they inform health care planning and can aid interpretation of genetic testing results when assessing the frequency of variants in large-scale, unselected sequencing databases. Whilst minimal incidence rates have been calculated for four European countries, the incidence of CHI in the UK is not known. In this study we have used referral rates to a central laboratory for genetic testing and annual birth rates from census data to calculate the minimal incidence of CHI within the UK from 2007 to 2016. CHI was diagnosed in 278 individuals based on inappropriately detectable insulin and/or C-peptide measurements at the time of hypoglycaemia which persisted beyond 6 months of age. From these data, we have calculated a minimum incidence of 1 in 28,389 live births for CHI in the UK. This is comparable to estimates from other outbred populations and provides an accurate estimate that will aid both health care provision and interpretation of genetic results, which will help advance our understanding of CHI.

Congenital Hyperinsulinism/epidemiology , Genetic Testing/statistics & numerical data , Practice Patterns, Physicians'/statistics & numerical data , Rare Diseases/epidemiology , Referral and Consultation/statistics & numerical data , Child, Preschool , Congenital Hyperinsulinism/diagnosis , Congenital Hyperinsulinism/genetics , Congenital Hyperinsulinism/surgery , Female , Humans , Incidence , Infant , Infant, Newborn , Live Birth/epidemiology , Male , Neonatal Screening/methods , Pancreatectomy/statistics & numerical data , Rare Diseases/diagnosis , Rare Diseases/genetics , United Kingdom/epidemiology