Nature. 2024 Dec;636(8042):404-411. doi: 10.1038/s41586-024-08217-y. Epub 2024 Nov 20.

ABSTRACT

Although rare neurodevelopmental conditions have a large Mendelian component1, common genetic variants also contribute to risk2,3. However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents nor its interplay with rare variants. It is also unclear whether polygenic background affects risk directly through alleles transmitted from parents to children, or whether indirect genetic effects mediated through the family environment4 also play a role. Here we addressed these questions using genetic data from 11,573 patients with rare neurodevelopmental conditions, 9,128 of their parents and 26,869 controls. Common variants explained around 10% of variance in risk. Patients with a monogenic diagnosis had significantly less polygenic risk than those without, supporting a liability threshold model5. A polygenic score for neurodevelopmental conditions showed only a direct genetic effect. By contrast, polygenic scores for educational attainment and cognitive performance showed no direct genetic effect, but the non-transmitted alleles in the parents were correlated with the child's risk, potentially due to indirect genetic effects and/or parental assortment for these traits4. Indeed, as expected under parental assortment, we show that common variant predisposition for neurodevelopmental conditions is correlated with the rare variant component of risk. These findings indicate that future studies should investigate the possible role and nature of indirect genetic effects on rare neurodevelopmental conditions, and consider the contribution of common and rare variants simultaneously when studying cognition-related phenotypes.

PMID:39567701 | DOI:10.1038/s41586-024-08217-y

Sci Rep. 2024 Nov 20;14(1):28780. doi: 10.1038/s41598-024-79872-4.

ABSTRACT

In the last decade, undiagnosed disease programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases. In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. This study was prospectively conducted at the Department of Pediatrics at University Hospital Brno between 2020 and 2023. A total of 58 Czech patients with undiagnosed diseases were enrolled in the study. All children underwent singleton WES with targeted phenotype-driven analysis. We identified 28 variants, including 11 pathogenic, 13 likely pathogenic, and 4 VUS according to ACMG guidelines, as diagnostic of genetic diseases in 25 patients, resulting in an overall diagnostic yield of 43%. Eleven variants were novel and had not been previously reported in any public database. The overall clinical utility (actionability) enabling at least one type of change in the medical care of the patient was 76%, whereas the average number of clinical implications to individual patient care was two. Singleton WES facilitated the diagnostic process in the Czech undiagnosed pediatric population. We believe it is an effective approach to enable appropriate counseling, surveillance, and personalized clinical management.

PMID:39567597 | DOI:10.1038/s41598-024-79872-4

Soc Sci Med. 2024 Dec;363:117380. doi: 10.1016/j.socscimed.2024.117380. Epub 2024 Nov 18.

ABSTRACT

This article sets out to explore the dilemmas present in the reproductive practices of people affected by rare hereditary diseases, focusing on the use of diagnostic tests and the practice of genetic counselling in Brazil. The development of technologies capable of mapping 'genetic flaws' prior to conception or in prenatal consultations has led researchers to consider how these technologies may be shaping contemporary subjectivities related to kinship and guiding reproductive decisions based on knowledge of our 'genetic heritage.' Genetic counselling has emerged in this setting as a modality of health knowledge and information capable of assisting people, especially women, in their reproductive choices. In Brazil, access to these technologies and their use has proven to be unequal and heterogeneous. I argue that the idea of 'choice' that permeates genetic counselling needs to be problematized by considering the social, cultural, economic, affective and moral frameworks in which women are inserted and that inform and/or determine their reproductive decisions. Based on this premise, I analyse how families 'at risk' of rare hereditary diseases deal with the idea of 'genetic inheritance' in relation to the 'wish to have children', and the impasses surrounding the idea of 'informed choice' when we evaluate this rhetoric in the context of the shortfalls in access to healthcare and the limits to reproductive justice in Brazil.

PMID:39561432 | DOI:10.1016/j.socscimed.2024.117380

Neurology. 2024 Dec 24;103(12):e210070. doi: 10.1212/WNL.0000000000210070. Epub 2024 Nov 19.

ABSTRACT

Macroglossia can be seen in multiple conditions, but its evaluation becomes more challenging when approached as an isolated presenting symptom. This is a case of a 65-year-old patient with isolated progressive tongue hypertrophy of unclear etiology for 5 years. We navigate the causes of macroglossia and discuss the clinical and diagnostic procedures that helped us narrow the differential diagnoses for our patient. We emphasize searching for evidence of more systemic involvement and the use of appropriate genetic testing to change the course of the disease and avoid therapeutic delay.

PMID:39561306 | DOI:10.1212/WNL.0000000000210070

Support Care Cancer. 2024 Nov 19;32(12):807. doi: 10.1007/s00520-024-08998-y.

ABSTRACT

Diagnosing rare cancers is challenging and often leads to prolonged diagnostic trajectories. This study investigated the diagnostic trajectory of patients with rare cancers in The Netherlands. Data from 1541 patients were recruited via patient advocacy in a national online survey on their diagnostic trajectory, such as first general practitioner (GP) consultation to hospital referral and number of hospital visits before final diagnosis. Differences between solid vs. non-solid tumours and EURACAN domains were explored. Diagnostic timelines varied from less than 3 months to over 12 months. Most patients (76.0%) first consulted their GP before going to a hospital. 76.3% of all patients were referred to a hospital within less than 3 months. 32.1% reported receiving an incorrect diagnosis, and 44.6% of them underwent treatment or medication for the (perceived) incorrect diagnosis. Patients with solid vs. non-solid rare cancers trajectories differed significantly for treatment hospital, route to diagnosis, correctness of initial diagnosis, and number of hospital visits before correct diagnosis (all p < 0.001). Patients with neuroendocrine (NET; 21.7%) and endocrine tumours (17.5%) experienced longer GP-to-hospital visit waiting times. Patients with non-solid cancers often received a correct diagnosis after one hospital visit (75%) when compared with patients with solid cancer (2+ = 57.7%). Those with rare skin cancer and non-cutaneous melanoma, head and neck, and thoracic cancer visited multiple hospitals before an accurate diagnosis (56.7%, 53.8%, and 50.0%). Patients with rare cancers face significant challenges with diagnostic delays and inaccuracies. Researching symptom signatures and investing in regional clinical networks might improve diagnostic timelines.

PMID:39560783 | DOI:10.1007/s00520-024-08998-y

Int J Pharm. 2025 Jan 5;668:124964. doi: 10.1016/j.ijpharm.2024.124964. Epub 2024 Nov 16.

ABSTRACT

Biotinidase deficiency is a rare inherited disorder characterized by biotin metabolism issues, leading to neurological and cutaneous symptoms that can be alleviated through biotin administration. Three-dimensional (3D) printing (3DP) offers potential for personalized medicine production for rare diseases, due to its flexibility in designing dosage forms and controlling release profiles. For such point-of-care applications, rigorous quality control (QC) measures are essential to ensure precise dosing, optimal performance, and product safety, especially for low personalized doses in preclinical and clinical studies. In this work, we addressed QC challenges by integrating a precision balance into a direct powder extrusion pharmaceutical 3D printer (M3DIMAKER™) for real-time, in-line mass uniformity testing, a critical quality control step. Small and large capsule-shaped biotin printlets (3D printed tablets) for immediate- and extended-release were printed. The integrated balance monitored and registered each printlet's weight, identifying any deviations from acceptable limits. While all large printlet batches met mass uniformity criteria, some small printlet batches exhibited weight deviations. In vitro release studies showed large immediate-release printlets releasing 82% of biotin within 45 min, compared to 100% for small immediate-release printlets. For extended-release formulations, 35% of the drug was released from small printlets, whereas 24% was released from large printlets at the same time point. The integration of process analytical technology tools in 3DP shows promise in enhancing QC and scalability of personalized dosing at the point-of-care, demonstrating successful integration of a balance into a direct powder extrusion 3D printer for in-line mass uniformity testing across different sizes of capsule-shaped printlets.

PMID:39557179 | DOI:10.1016/j.ijpharm.2024.124964

Med Sci (Paris). 2024 Nov;40 Hors série n° 1:6-8. doi: 10.1051/medsci/2024128. Epub 2024 Nov 18.

ABSTRACT

High-throughput sequencing has introduced the concept of "actionable genes". These genes are linked to diseases for which specific treatments or care exist. Accurate genetic diagnosis is therefore crucial for initiating interventions that can prevent or delay the progression of rare diseases. High-throughput sequencing has considerably increased the capacities of genetic analyses, but it has also led to an increase in requests for analyses, lengthening the time taken to obtain results. It is becoming necessary to prioritize analyses, especially when "actionable genes" are suspected to be implicated. In the case of myopathies, a French national study has identified 63 actionable genes, implicated in diseases for which a targeted treatment and/or priority care can be initiated, thereby improving the patient's prognosis. Despite advances, many rare diseases remain without specific treatments, underlining the continuing importance of research and innovation in medical genetics.

PMID:39555868 | DOI:10.1051/medsci/2024128

Methods Mol Biol. 2025;2866:45-57. doi: 10.1007/978-1-0716-4192-7_3.

ABSTRACT

Targeted next-generation sequencing (NGS) in rare disease focuses on genetic analysis of specific regions in genome that are linked to a rare disease. In addition to library preparation, sequencing, and data analysis, targeted NGS includes an additional step of target enrichment of selected genes and regions. It allows for more sensitive and profound sequencing, as it is a fast and cost-effective approach with less data burden and is therefore often a method of choice for identifying rare variants in known genes, especially in diagnostics of rare diseases. Several in silico tools address the pathogenicity predictions of rare variants of unknown significance (VUS) and can therefore facilitate clinical interpretation.

PMID:39546196 | DOI:10.1007/978-1-0716-4192-7_3

Dermatologie (Heidelb). 2024 Dec;75(12):967-971. doi: 10.1007/s00105-024-05432-6. Epub 2024 Nov 14.

ABSTRACT

We report on two cases of nail tumors associated with onychorrhexis, distal V‑shaped onycholysis, and subungual keratosis. Surgical exposure was performed in each case to confirm the diagnosis. Histopathological examination revealed skin changes consistent with onychopapilloma. We describe two common surgical techniques in the treatment of onychopapilloma: classical longitudinal excision and alternative tangential excision with corresponding follow-up.

PMID:39542881 | DOI:10.1007/s00105-024-05432-6

Eur J Pediatr. 2024 Nov 14;184(1):9. doi: 10.1007/s00431-024-05851-6.

ABSTRACT

Cystinosis metabolic bone disease (CMBD) is an emerging concept in infantile nephropathic cystinosis, patients presenting with bone pains, fractures, and deformations during teenage or early adulthood. The underlying mechanisms remain unclear. Our aim was to explore the pro-inflammatory profile of osteoclastic lineage in cystinotic patients. We obtained blood samples from 14 cystinotic patients and 10 pediatric healthy controls. Peripheral blood mononuclear cells (PBMCs) were isolated and used to explore by RT-qPCR the transcript expression of 8 inflammatory markers (Il-6, Il-8, Il-1β, CXCL1, CCL2/MCP-1, CXCR3, Il-1 Receptor, Il-6 Receptor). In addition, when possible, PBMCs were differentiated into osteoclasts for further experiments. The expression of Il-6, IL-8, CXCR3, and CCL2/MCP-1 was significantly increased in PBMCs from cystinotic patients. We also explored the expression of Il-1 Receptor and Il-6 Receptor, two major pro-osteoclastic signal inducers, in osteoclasts differentiated from PBMCs from controls (N = 3) and patients (N = 4). The expression of IL-1 Receptor (but not IL-6 receptor) was increased in osteoclasts obtained from cystinotic patients.

CONCLUSION: There is an inflammatory profile in PBMCs and osteoclastic lineage in cells obtained from cystinotic patients. CXCR3 and MCP-1 stimulate migration and activation of macrophages, that may explain the previously reported local increased osteoclastogenesis. The osteoclastic overexpression of IL-1 Receptor is a relevant observation in the field since blocking Il-1β signaling has recently been proposed as a novel therapeutic approach to improve muscular wasting in this orphan disease.

WHAT IS KNOWN: • Cystinosis metabolic bone disease (CMBD), an emerging concept with unclear underlying mechanisms, induces bone pains, fractures and deformations in patients with cystinosis. • Blocking Il-1β signaling may be a novel therapeutic approach to improve muscular wasting in cystinosis.

WHAT IS NEW: • There is an inflammatory profile in PBMCs and osteoclastic lineage in cells obtained from cystinotic patients, with an over-expression of IL-1 Receptor in osteoclasts. • We provide another experimental rationale to propose targeted anti-inflammatory therapies in cystinotic patients with severe bone disease.

PMID:39540998 | DOI:10.1007/s00431-024-05851-6

Infect Dis Poverty. 2024 Nov 13;13(1):85. doi: 10.1186/s40249-024-01249-6.

ABSTRACT

BACKGROUND: Rare infectious diseases of poverty (rIDPs) involve more than hundreds of tropical diseases, which dominantly affect people living in impoverished and marginalized regions and fail to be prioritized in the global health agenda. The neglect of rIDPs could impede the progress toward sustainable development. This study aimed to estimate the disease burden of rIDPs in 2021, which would be pivotal for setting intervention priorities and mobilizing resources globally.

METHODS: Leveraging data from the Global Burden of Disease Study 2021, the study reported both numbers and age-standardized rates of prevalence, mortality, disability-adjusted life-years (DALYs), years lived with disability, and years of life lost of rIDPs with corresponding 95% uncertainty intervals (UIs) at global, regional, and national levels. The temporal trends between 1990 and 2021 were assessed by the joinpoint regression analysis. A Bayesian age-period-cohort model was used to project the disease burden for 2050.

RESULTS: In 2021, there were 103.76 million (95% UI: 102.13, 105.44 million) global population suffered from rIDPs with an age-standardized DALY rate of 58.44 per 100,000 population (95% UI: 42.92, 77.26 per 100,000 population). From 1990 to 2021, the age-standardized DALY rates showed an average annual percentage change of - 0.16% (95% confidence interval: - 0.22, - 0.11%). Higher age-standardized DALY rates were dominated in sub-Saharan Africa (126.35 per 100,000 population, 95% UI: 91.04, 161.73 per 100,000 population), South Asia (80.80 per 100,000 population, 95% UI: 57.31, 114.10 per 100,000 population), and countries with a low socio-demographic index. There was age heterogeneity in the DALY rates of rIDPs, with the population aged under 15 years being the most predominant. Females aged 15-49 years had four-times higher age-standardized DALY rates of rIDPs than males in the same age. The projections indicated a slight reduction in the disease burden of rIDPs by 2050.

CONCLUSIONS: There has been a slight reduction in the disease burden of rIDPs over the past three decades. Given that rIDPs mainly affect populations in impoverished regions, targeted health strategies and resource allocation are in great demand for these populations to further control rIDPs and end poverty in all its forms everywhere.

PMID:39538351 | DOI:10.1186/s40249-024-01249-6

Inn Med (Heidelb). 2024 Dec;65(12):1283-1292. doi: 10.1007/s00108-024-01810-3. Epub 2024 Nov 13.

ABSTRACT

Rare kidney diseases encompass a wide range of congenital, inherited and acquired conditions. Two million Europeans are affected by rare kidney diseases. The European Rare Kidney Disease Reference Network (ERKNet) aims to improve the clinical management of patients with these diseases. ERKNet encompasses 95 highly specialized adult and pediatric nephrology units at 72 sites in 24 European Union (EU) member states, as well as a group of patient advocates (European Patient Advocacy Group, ePAG). ERKNet centers care for more than 65,000 rare kidney disease patients and pursues a variety of activities. An online consultation service helps improve the management of complex cases. Expert working groups develop clinical practice guidelines for individual groups of rare kidney diseases. In a 3-year postgraduate program, junior physicians at ERKNet centers are trained by experts in the diagnosis and treatment of rare kidney diseases through webinars and case-based eLearning modules. Information brochures and online texts on rare kidney diseases for patients, relatives and the general public are produced and disseminated. Clinical research is supported by a European Registry for Rare Kidney Diseases (ERKReg), which provides important information on demographics and disease progression and facilitates the identification of patient cohorts for therapeutic studies. In addition, the registry provides clinical performance statistics of reference centers and allows benchmarking to promote the harmonization and standardization of care for rare kidney disease patients across Europe.

PMID:39538006 | DOI:10.1007/s00108-024-01810-3

BMC Health Serv Res. 2024 Nov 12;24(1):1388. doi: 10.1186/s12913-024-11763-w.

ABSTRACT

BACKGROUND: It often takes a long time before a rare disease is diagnosed. Without a diagnosis, the right therapy often cannot be carried out and without the right therapy, the patients are denied the opportunity for a cure or relief from their symptoms. In addition, rare diseases can also have economic consequences for those affected. This study aimed to investigate the extent to which a rare disease affects the income and work performance of the patients concerned and whether the use of AI in diagnostics would have the potential to reduce economic losses.

METHODS: The work performance and income of 71 patients of the outpatient clinic for rare inflammatory systemic diseases with renal involvement at Hannover Medical School were analyzed during the course of the disease. The WHO Health and Work Performance Questionnaire (HPQ) was used to collect data. During the patient interviews, the questionnaire was completed four times: at the onset of the first symptoms, when a diagnostic decision support system (DDSS) would have suggested the correct diagnosis, at the time of diagnosis and at the current status.

RESULTS: With the onset of the diagnostic odyssey, the monthly net income of the patients under study dropped by an average of 5.32% due to lower work performance or work absenteeism. With the correct diagnosis, the original or even a better income of 11.92% could be achieved. Loss of income due to illness was more massive in patients with a rare disease with joint, muscle and connective tissue involvement than in patients with rare vasculitides. If a DDSS had been used, the loss of income would have been 2.66% instead of the actual 5.32%.

CONCLUSION: Rare diseases resulted in temporary or existing income losses in 28.17% of the patients. Losses in work performance and income were related to the type of disease and were more pronounced in patients with joint, muscle or connective tissue disease than in patients with rare vasculitides. The use of a DDSS may have the potential to reduce the negative income effects of patients through earlier correct diagnosis.

TRIAL REGISTRATION: Retrospectively registered.

PMID:39533273 | DOI:10.1186/s12913-024-11763-w

Rev Med Inst Mex Seguro Soc. 2024 May 6;62(3):1-8. doi: 10.5281/zenodo.10998859.

ABSTRACT

BACKGROUND: Rare diseases (RD) are those that have a low prevalence in the population; ≈80% have a genetic origin, and to diagnose them it takes from 5 to 10 years, and they require evaluations from ≈10 specialists. There is no international consensus on the definition and number of RDs, which affects the availability of resources for their diagnosis, treatment, and research.

OBJECTIVE: To determine the prevalence of RDs in the Medical Genetics Service of a regional general hospital belonging to the Mexican Institute for Social Security (IMSS), in Puebla, Mexico.

MATERIAL AND METHODS: The patients' records who were evaluated by the above-mentioned service from January 2019 to June 2022 were reviewed. Those patients with a diagnosis of a RD were identified, and the prevalence was obtained by using the formula: total number of cases of the disease/number of people in the population at that moment in time.

RESULTS: A total of 798 medical records were reviewed and a prevalence of RDs of 27% was obtained. Those diseases with a prevalence of 1 case per 2000 inhabitants were considered, being 118 different RD. Considering only the 20 rare diseases registered in Mexico in 2022, 11 of these were detected, distributed in 35 patients, with an estimated prevalence of 4.3%.

CONCLUSION: The prevalence of RDs differs according to the criteria implemented. In Mexico, several diseases that fall within the definition of a RD based on their prevalence were not considered as such until 2022, so the recent recognition of rare diseases included by the World Health Organization will benefit affected patients.

PMID:39528408 | DOI:10.5281/zenodo.10998859

Med Anthropol. 2024 Oct 2;43(7):655-668. doi: 10.1080/01459740.2024.2420117. Epub 2024 Nov 11.

ABSTRACT

Drawing on three years of ethnographic engagement with the rare disease community in the United Kingdom and Europe, this article explores the experiences of families who seek and (sometimes) receive a genomic diagnosis. I trace how families learn to enact unexplained symptoms and common disabilities as rare, genetic disorders, and how they coordinate genomic and non-genomic ways of "doing" disease within and beyond the clinic. These experiences shed light on the socio-material processes through which genomic variants become "diseases" (or fail to do so), and on the implications for those whose lives have become entangled with the genomic agenda.

PMID:39526903 | DOI:10.1080/01459740.2024.2420117

Kardiologiia. 2024 Oct 31;64(10):62-67. doi: 10.18087/cardio.2024.10.n2766.

ABSTRACT

Pericarditis as an inflammatory heart disease is rarely discussed in the cardiology community. The latest European guidelines on pericarditis were published in 2015, and Russian clinical guidelines are dated 2022. However, in recent years, a number of publications have appeared that have forced the scientific community to take a fresh look at this problem. This is mainly due to a change in the paradigm of the treatment of idiopathic recurrent pericarditis (IRP) registered in the Russian Federation as a rare (orphan) disease. According to most experts, IRP is an underestimated cardiac disease, which, due to the lack of specific symptoms and the physicians' alertness regarding the IRP diagnostics, is rarely the subject of scientific discussions. The issues of diagnosis and therapy of IRP in light of the latest reports became the matter under discussion for a group of leading Russian experts chaired by Corresponding Member of the Russian Academy of Sciences, Professor G.P. Arutyunov.

PMID:39526520 | DOI:10.18087/cardio.2024.10.n2766

Pediatr Surg Int. 2024 Nov 9;40(1):300. doi: 10.1007/s00383-024-05865-z.

ABSTRACT

PURPOSE: The purpose of this study was to understand the provision and distribution of esophageal atresia (EA) follow-up (FU) and transition services across European Reference Network for rare Inherited and Congenital Anomalies (ERNICA) member and affiliate centers.

METHODS: A REDCap questionnaire was sent to clinical leads of 18 ERNICA members and 14 affiliate centers.

RESULTS: 29 of 32 centers responded (91%), the majority of which were highly specialized. Two-thirds had a dedicated EA clinic with a specialist multi-disciplinary team (MDT), offered to selected/complex patients only in 40% of centers. ERNICA centers were more likely to offer an MDT FU clinic than affiliates, with lack of resources most cited as a barrier to uptake (67%). Delivery of routine investigations was heterogeneous, particularly provision of three endoscopies over the course of FU (24%). Only 55% had a dedicated transition pathway, more prevalent in ERNICA centers (81% vs. 30%; p < 0.01). Self-reported awareness of ERNICA and European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidance for FU and transition was poor (28%).

CONCLUSION: Despite the existence of European follow-up and transition guidelines, their delivery is not uniform and may be limited by lack of awareness of the guidelines and a lack of resources.

PMID:39521743 | DOI:10.1007/s00383-024-05865-z

Int J Mol Sci. 2024 Oct 29;25(21):11586. doi: 10.3390/ijms252111586.

ABSTRACT

Primary hyperparathyroidism represents the third most prevalent endocrine disease in the general population, consisting of an excessive secretion of parathyroid hormone from one or, more frequently, more of the parathyroid glands, leading to a dysregulation of calcium homeostasis. Schematically, its development occurs primarily by pathophysiological events with genetic mutation, at the germline and/or somatic level, that favor the neoplastic transformation of parathyroid cells and promote their aberrant proliferation, and mutations determining the shift in the PTH "set-point", thus interfering with the normal pathways of PTH secretion and leading to a "resetting" of Ca2+-dependent PTH secretion or to a secretion of PTH insensitive to changes in extracellular Ca2+ levels. Familial syndromic and non-syndromic forms of primary hyperparathyroidism are responsible for approximately 2-5% of primary hyperparathyroidism cases and most of them are inherited forms. The history of the genetic/molecular studies of parathyroid tumorigenesis associated with multiple endocrine neoplasia type 1 syndrome (MEN1) represents an interesting model to understand genetic-epigenetic-molecular aspects underlying the pathophysiology of primary hyperparathyroidism, both in relation to syndromic and non-syndromic forms. This minireview aims to take a quick and simplified look at the MEN1-associated parathyroid tumorigenesis, focusing on the molecular underlying mechanisms. Clinical, epidemiological, and observational studies, as well as specific guidelines, molecular genetics studies, and reviews, have been considered. Only studies submitted to PubMed in the English language were included, without time constraints.

PMID:39519139 | DOI:10.3390/ijms252111586

Cancers (Basel). 2024 Oct 23;16(21):3573. doi: 10.3390/cancers16213573.

ABSTRACT

Solitary fibrous tumor (SFT) is an orphan disease of mesenchymal origin [...].

PMID:39518014 | DOI:10.3390/cancers16213573

Orphanet J Rare Dis. 2024 Nov 8;19(1):418. doi: 10.1186/s13023-024-03398-1.

ABSTRACT

BACKGROUND: In response to activated patient communities' catalyzation, two significant efforts by the FDA to expedite treatments have now been in place for multiple decades. In 1983, the United States Congress passed the Orphan Drug Act to provide financial incentives for development of drugs for rare diseases. In 1992, partly in response to the HIV epidemic, the FDA implemented Accelerated Approval (AA) to expedite access to promising new therapies to treat serious conditions with unmet medical need based on surrogate marker efficacy while additional clinical data is confirmed. The uses of these regulatory approaches over time are assessed in this study.

METHODS: The following U.S. FDA CDER published lists were used in this analysis: 1. all orphan designations and approvals; 2. all AA and their details updated through December 31, 2022; new molecular entities (NMEs).

RESULTS: Orphan drug designations and approvals have increased several-fold over the past four decades. The largest increase recently has been in therapies targeting oncological diseases (comprised of both oncology and malignant hematology). Although orphan drug approvals based on NMEs are the minority of orphan drug designations, the count of approved orphan drug NMEs has increased in recent years. The characteristics of orphan drug approvals show notable differences by disease area with rare diseases and medical genetics (49%) having a relatively large fraction of orphan drug approvals with NMEs compared to the oncological diseases (32%). Similar to the use of orphan drug designation, oncological disease therapies have been the largest utilizers of AA. Many therapies targeting these diseases address unmet medical need and can leverage surrogate markers that have previously been used in similar trials. The timings of conversion of AA (confirmed or withdrawn) were assessed and found to be consistent across decades and to have some dependency upon the broad disease area (when assessed by three large groups: HIV conversions were fastest; followed by oncology; followed by all others). By the end of 2022, 98% of the first 105 (approved in 2010 or earlier) AA had been converted to confirmed or withdrawn.

CONCLUSIONS: Although the typical timings for AA to be confirmed or withdrawn has not changed significantly over the decades, the disease areas utilizing orphan drug designation and AA have changed significantly over time. Both programs have had increases in their use for therapies targeting oncological diseases. The re-use of surrogate markers for oncological diseases has been an advantage in a way that may not be scientifically feasible in many other disease areas that have greater differentiation across disease etiology. For non-oncological diseases, applicability of AA is, in part, dependent upon greater focus on characterization and acceptance of novel surrogate markers.

PMID:39516878 | DOI:10.1186/s13023-024-03398-1