Health Qual Life Outcomes. 2023 Dec 12;21(1):132. doi: 10.1186/s12955-023-02216-9.

ABSTRACT

BACKGROUND: Genomic testing transforms the diagnosis and management of rare conditions. However, uncertainty exists on how to best measure genomic outcomes for informing healthcare priorities. Using the HTA-preferred method should be the starting point to improve the evidence-base. This study explores the responsiveness of SF-6D, EQ-5D-5L and AQoL-8D following genomic testing across childhood and adult-onset genetic conditions.

METHOD: Self-reported patient-reported outcomes (PRO) were obtained from: primary caregivers of children with suspected neurodevelopmental disorders (NDs) or genetic kidney diseases (GKDs) (carers' own PRO), adults with suspected GKDs using SF-12v2; adults with suspected complex neurological disorders (CNDs) using EQ-5D-5L; and adults with dilated cardiomyopathy (DCM) using AQol-8D. Responsiveness was assessed using the standardised response mean effect-size based on diagnostic (having a confirmed genomic diagnosis), personal (usefulness of genomic information to individuals or families), and clinical (clinical usefulness of genomic information) utility anchors.

RESULTS: In total, 254 people completed PRO measures before genomic testing and after receiving results. For diagnostic utility, a nearly moderate positive effect size was identified by the AQoL-8D in adult DCM patients. Declines in physical health domains masked any improvements in mental or psychosocial domains in parents of children affected by NDs and adult CNDs and DCM patients with confirmed diagnosis. However, the magnitude of the changes was small and we did not find statistically significant evidence of these changes. No other responsiveness evidence related to diagnostic, clinical, and personal utility of genomic testing was identified.

CONCLUSION: Generic PRO measures may lack responsiveness to the diagnostic, clinical and personal outcomes of genomics, but further research is needed to establish their measurement properties and relevant evaluative space in the context of rare conditions. Expected declines in the physical health of people experiencing rare conditions may further challenge the conventional application of quality of life assessments.

PMID:38087302 | PMC:PMC10717517 | DOI:10.1186/s12955-023-02216-9

Annu Int Conf IEEE Eng Med Biol Soc. 2023 Jul;2023:1-4. doi: 10.1109/EMBC40787.2023.10340908.

ABSTRACT

Spinal muscular atrophy (SMA) is a rare neuromuscular disease which may cause impairments in oro-facial musculature. Most of the individuals with SMA present bulbar signs such as flaccid dysarthria which mines their abilities to speak and, as consequence, their psychic balance. To support clinicians, recent work has demonstrated the feasibility of video-based techniques for assessing the oro-facial functions in patients with neurological disorders such as amyotrophic lateral sclerosis. However, no work has so far focused on automatic and quantitative monitoring of dysarthria in SMA. To overcome limitations this work's aim is to propose a cloud-based store-and-forward telemonitoring system for automatic and quantitative evaluation of oro-facial muscles in individuals with SMA. The system integrates a convolutional neural network (CNN) aimed at identifying the position of facial landmarks from video recordings acquired via a web application by an SMA patient.Clinical relevance- The proposed work is in the preliminary stage, but it represents the first step towards a better understanding of the bulbar-functions' evolution in patients with SMA.

PMID:38083694 | DOI:10.1109/EMBC40787.2023.10340908

Annu Int Conf IEEE Eng Med Biol Soc. 2023 Jul;2023:1-4. doi: 10.1109/EMBC40787.2023.10341070.

ABSTRACT

Recent studies have illuminated the potential of harnessing the power of Deep Learning (DL) and the Internet of Health Things (IoHT) to detect a variety of disorders, particularly among patients in the middle to later stages of the disease. The utilization of time series data has proven to be a valuable asset in this endeavour. However, the development of effective DL architectures for time series classification with limited data remains a critical gap in the field. Although some studies have explored this area, it is still an understudied and undervalued topic. Thus, there is a crucial need to address this gap and provide insights into designing effective architectures for time series classification with limited data, specifically in the context of healthcare-related time series data for rare diseases. The goal of this study is to investigate the possibility of making accurate predictions with a smaller time series dataset by using an Ensemble DL architecture. This framework is composed of a deep CNN model and transfer learning approaches like ResNet and MobileNet. The ensemble model proposed in this study was supplied with 3D images that were generated from time series data by using Recurrence Plot (RP), Gramian Angular Field (GAF), and Fuzzy Recurrence Plot (FRP) as the transformation techniques. The proposed method has shown promising classification accuracy, even when applied to a small dataset, and surpassed the performance of other state-of-the-art methods when tested on the ECG5000 dataset.Clinical relevance- The proposed deep learning architecture is capable of effectively handling limited clinical time series datasets, enabling the construction of robust models and accurate predictions.

PMID:38083542 | DOI:10.1109/EMBC40787.2023.10341070

EBioMedicine. 2023 Dec 11;99:104894. doi: 10.1016/j.ebiom.2023.104894. Online ahead of print.

ABSTRACT

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated.

METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed.

FINDINGS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants.

INTERPRETATION: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study.

FUNDING: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).

PMID:38086156 | DOI:10.1016/j.ebiom.2023.104894

bioRxiv. 2023 Dec 1:2023.11.30.569436. doi: 10.1101/2023.11.30.569436. Preprint.

ABSTRACT

Although mutations in dozens of genes have been implicated in familial forms of amyotrophic lateral sclerosis (fALS) and frontotemporal degeneration (fFTD), most cases of these conditions are sporadic (sALS and sFTD), with no family history, and their etiology remains obscure. We tested the hypothesis that somatic mosaic mutations, present in some but not all cells, might contribute in these cases, by performing ultra-deep, targeted sequencing of 88 genes associated with neurodegenerative diseases in postmortem brain and spinal cord samples from 404 individuals with sALS or sFTD and 144 controls. Known pathogenic germline mutations were found in 20.6% of ALS, and 26.5% of FTD cases. Predicted pathogenic somatic mutations in ALS/FTD genes were observed in 2.7% of sALS and sFTD cases that did not carry known pathogenic or novel germline mutations. Somatic mutations showed low variant allele fraction (typically <2%) and were often restricted to the region of initial discovery, preventing detection through genetic screening in peripheral tissues. Damaging somatic mutations were preferentially enriched in primary motor cortex of sALS and prefrontal cortex of sFTD, mirroring regions most severely affected in each disease. Somatic mutation analysis of bulk RNA-seq data from brain and spinal cord from an additional 143 sALS cases and 23 controls confirmed an overall enrichment of somatic mutations in sALS. Two adult sALS cases were identified bearing pathogenic somatic mutations in DYNC1H1 and LMNA, two genes associated with pediatric motor neuron degeneration. Our study suggests that somatic mutations in fALS/fFTD genes, and in genes associated with more severe diseases in the germline state, contribute to sALS and sFTD, and that mosaic mutations in a small fraction of cells in focal regions of the nervous system can ultimately result in widespread degeneration.

PMID:38077003 | PMC:PMC10705414 | DOI:10.1101/2023.11.30.569436

Ann Surg. 2023 Dec 11. doi: 10.1097/SLA.0000000000006164. Online ahead of print.

ABSTRACT

OBJECTIVE: We aimed to investigate if ex vivo plasma from injured patients causes endothelial calcium (Ca2+) influx as a mechanism of trauma-induced endothelial permeability.

SUMMARY BACKGROUND DATA: Endothelial permeability after trauma contributes to post-injury organ dysfunction. While the mechanisms remain unclear, emerging evidence suggests intracellular Ca2+ signaling may play a role.

METHODS: Ex vivo plasma from injured patients with "Low Injury/Low Shock" (injury severity score [ISS]<15, base excess [BE])≥-6mEq/L) and "High Injury/High Shock" (ISS≥15, BE<-6mEq/L) were used to treat endothelial cells. Experimental conditions included Ca2+ removal from the extracellular buffer, cyclopiazonic acid pre-treatment to deplete intracellular Ca2+ stores, and GSK2193874 pre-treatment to block the TRPV4 Ca2+ channel. Live cell fluorescence microscopy and ECIS were used to assess cytosolic Ca2+ increases and permeability, respectively. Western blot and live cell actin staining were used to assess myosin light chain (MLC) phosphorylation and actomyosin contraction.

RESULTS: Compared to Low Injury/Low Shock plasma, High Injury/High Shock induced greater cytosolic Ca2+ increase. Cytosolic Ca2+ increase, MLC phosphorylation, and actin cytoskeletal contraction were lower without extracellular Ca2+ present. High Injury/High Shock plasma did not induce endothelial permeability without extracellular Ca2+ present. TRPV4 inhibition lowered trauma plasma-induced endothelial Ca2+ influx and permeability.

CONCLUSIONS: This study illuminates a novel mechanism of post-injury endotheliopathy involving Ca2+ influx via the TRPV4 channel. TRPV4 inhibition mitigates trauma-induced endothelial permeability. Moreover, widespread endothelial Ca2+ influx may contribute to trauma-induced hypocalcemia. This study provides the mechanistic basis for the development of Ca2+-targeted therapies and interventions in the care of severely injured patients.

PMID:38073572 | DOI:10.1097/SLA.0000000000006164

Wien Klin Wochenschr. 2023 Nov;135(Suppl 8):785-798. doi: 10.1007/s00508-023-02298-x. Epub 2023 Dec 8.

ABSTRACT

Hereditary angioedema (HAE) is a rare, painful, disabling and potentially fatal disease, where early diagnosis and effective treatment are critical. These Austrian guidelines for the diagnosis and management of HAE provide instructions and advice on the state of the art management of HAE in Austria in contrast to global guidelines, where the situation of all countries worldwide must be taken into account. Our goal is to help Austrian physicians to consider HAE as a differential diagnosis with corresponding symptoms, to make rational decisions for the diagnosis and management of HAE with C1-inhibitor deficiency (type 1 or type 2). The guidelines provide information on common and important clinical symptoms, diagnostic methods, treatment modalities, available HAE-specific medications in Austria and last but not least to motivate physicians to refer patients to HAE centers for confirmation of the diagnosis and adequate treatment decisions.

PMID:38063938 | DOI:10.1007/s00508-023-02298-x

Nat Rev Drug Discov. 2024 Jan;23(1):10-11. doi: 10.1038/d41573-023-00190-x.

NO ABSTRACT

PMID:38057453 | DOI:10.1038/d41573-023-00190-x

Gan To Kagaku Ryoho. 2023 Nov;50(11):1150-1154.

ABSTRACT

Since 1993, the"R & D Promotion System for Orphan Drugs and Orphan Medical Devices"has been in operation to support the development of orphan drugs in Japan. Various supportive measures are in place for indications that target less than 50,000 patients, have high medical needs and high probability of successful development(which means regulatory approval). However, recently a trend was observed that the designation for orphan drugs occurred most often in late phase of development, because clinical data for late stage clinical studies were required to show the high probability of successful regulatory approval. The Ministry of Health, Labour and Welfare are trying to make efforts to expand the orphan drug designation, and have made the decision to include the related expenses will be included in the FY 2023 budget request. It is expected that the expansion of orphan drug designation will lead to promote drug development in rare disease area. On the other hand, fundamental reform is considered necessary for this system. Among the approved anti-cancer drugs that obtained orphan designation in the U. S. and EU as of 2020, there are 24 drugs that have not been approved in Japan. Of these, there are at least 16 drugs approved in either China, Taiwan, and South Korea. From viewpoint of development pathway of an orphan drug, participation in a multi-regional clinical trial(MRCT)is useful, but there are cases that Japan cannot join MRCT in time due to the requirement of Japanese safety data prior to the participation. In that case, it is impossible to conduct a separate clinical trial to obtain Japan regulatory approval due to very limited patients(eg several to several tens of Ultra-Orphan). A review system that allows earlier patient access is desired.

PMID:38056864

Swiss Med Wkly. 2023 Dec 2;153:3644. doi: 10.57187/s.3644.

ABSTRACT

No abstract available.

PMID:38055917 | DOI:10.57187/s.3644

J Biomed Semantics. 2023 Dec 5;14(1):19. doi: 10.1186/s13326-023-00299-3.

ABSTRACT

INTRODUCTION: Healthcare data and the knowledge gleaned from it play a key role in improving the health of current and future patients. These knowledge sources are regularly represented as 'linked' resources based on the Resource Description Framework (RDF). Making resources 'linkable' to facilitate their interoperability is especially important in the rare-disease domain, where health resources are scattered and scarce. However, to benefit from using RDF, resources need to be of good quality. Based on existing metrics, we aim to assess the quality of RDF resources related to rare diseases and provide recommendations for their improvement.

METHODS: Sixteen resources of relevance for the rare-disease domain were selected: two schemas, three metadatasets, and eleven ontologies. These resources were tested on six objective metrics regarding resolvability, parsability, and consistency. Any URI that failed the test based on any of the six metrics was recorded as an error. The error count and percentage of each tested resource were recorded. The assessment results were represented in RDF, using the Data Quality Vocabulary schema.

RESULTS: For three out of the six metrics, the assessment revealed quality issues. Eleven resources have non-resolvable URIs with proportion to all URIs ranging from 0.1% (6/6,712) in the Anatomical Therapeutic Chemical Classification to 13.7% (17/124) in the WikiPathways Ontology; seven resources have undefined URIs; and two resources have incorrectly used properties of the 'owl:ObjectProperty' type. Individual errors were examined to generate suggestions for the development of high-quality RDF resources, including the tested resources.

CONCLUSION: We assessed the resolvability, parsability, and consistency of RDF resources in the rare-disease domain, and determined the extent of these types of errors that potentially affect interoperability. The qualitative investigation on these errors reveals how they can be avoided. All findings serve as valuable input for the development of a guideline for creating high-quality RDF resources, thereby enhancing the interoperability of biomedical resources.

PMID:38053130 | DOI:10.1186/s13326-023-00299-3

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2023 Sept 28;48(9):1388-1396. doi: 10.11817/j.issn.1672-7347.2023.220639.

ABSTRACT

Rare pediatric neurogenetic diseases always have early onset, no specific therapy, high mortality, and pose a severe risk to the health and survival of children. Adeno-associated virus (AAV)-mediated gene therapy, a type of disease-modifying therapy, provides a new option for the treatment of rare pediatric neurogenetic diseases and represents a significant advancement in the field. Currently, the US Food and Drug Administration (FDA) and the European Medicines Association (EMA) have approved AAV-mediated gene therapy medications for treating spinal muscular atrophy, aromatic L-amino acid decarboxylase deficiency, and Duchenne muscular dystrophy. Numerous preclinical and clinical trial research findings from recent years indicate that AAV-mediated gene therapy has a promising future in treating genetic disorders. The quick approval process for rare diseases medications may bring hope for the treatment of children with rare neurogenetic diseases. AAV-mediated gene therapy is an emerging technology with certain risks and challenges. It is necessary to establish a standardized regulatory system and a sound long-term follow-up system to evaluate the efficacy and safety of gene therapy.

PMID:38044650 | DOI:10.11817/j.issn.1672-7347.2023.220639

Orphanet J Rare Dis. 2023 Nov 30;18(1):373. doi: 10.1186/s13023-023-02987-w.

ABSTRACT

BACKGROUND: While substantial placebos have been used in herbal medicine (HM) clinical trials for rare diseases, the use and quality of reporting of HM-placebo remain unclear. We aim to describe the use of HM-placebo in clinical trials for rare diseases and determine the quality of reporting in these trials.

METHODS: This is a cross-sectional study. We searched PubMed, Embase, Web of Science, SinoMed, China National Knowledge Infrastructure, WanFang database, China Science and Technology Journal Database, National Institute of Informatics Support Academic Information Services, ClinicalTrials.gov and Chinese Clinical Trials Registry from their inception date to 14 February 2023 to identify registered and published trials that use placebos as a comparator in rare diseases. We collected data on placebo use reporting and the efficacy and safety of placebo. Descriptive statistics, the Chi-square test, and Binary multivariable logistic regression analysis were used to determine the placebo characteristics of the HM trial and its effect on reporting.

RESULTS: Among the 55 studies, we included that with a median administration time of placebo of 84 days (IQR 42-180) and a median placebo sample size of 30 (IQR 24-54). About half of the trials (27, 49.1%) did not provide their ethical approvals, and one trial had details of informed consent. None of the studies were fully reported and more than half of the items reported less than 50%. A total of 10 trials (18.2%) of placebo has active ingredients even though none of them performed pharmacological inert tests. Of the 29 studies with available data on adverse events, 5 (17.2%) trials did not show a better safety profile in the placebo group. Under the context that a relatively high-quality report is defined as a report with more than 9 items, there was a statistically significant difference between the two groups in the rate of relatively high-quality reports of the administration time (p = 0.047, OR 0.10, 95% CI 0.01 to 0.90), but the results are not representative.

CONCLUSION: The overall situation of HM-placebo in the field of rare diseases was poor. In particular, the placebo is tied to the quality of trials, and poor placebo hinders the generation of high-quality evidence for herbal clinical trials in the field of rare diseases. We summarize the current methods of assessment involved in the use of placebos and propose various considerations for placebos in different contexts. Our study can greatly promote rare disease researchers to review the quality of their placebo and clinical trials. It is imperative to guarantee that meticulously conducted research generates clinical evidence of the highest caliber. We also expect that in the future, more rigorous relevant standards about the reporting and design of HM-placebo will be developed. High-quality clinical trials are the prerequisite for the wide clinical application of herbal medicines for rare diseases.

PMID:38037078 | PMC:PMC10691121 | DOI:10.1186/s13023-023-02987-w

Trop Doct. 2023 Nov 29:494755231217325. doi: 10.1177/00494755231217325. Online ahead of print.

NO ABSTRACT

PMID:38031360 | DOI:10.1177/00494755231217325

BMJ Open. 2023 Nov 29;13(11):e069441. doi: 10.1136/bmjopen-2022-069441.

ABSTRACT

INTRODUCTION: Genomic testing is a relatively new, disruptive and complex health technology with multiple clinical applications in rare diseases, cancer and infection control. Genomic testing is increasingly being implemented into clinical practice, following regulatory approval, funding and adoption in models of care, particularly in the area of rare disease diagnosis. A significant barrier to the adoption and implementation of genomic testing is funding. What remains unclear is what the cost of genomic testing is, what the underlying drivers of cost are and whether policy differences contribute to cost variance in different jurisdictions, such as the requirement to have staff with a medical license involved in testing. This costing study will be useful in future economic evaluations and health technology assessments to inform optimal levels of reimbursement and to support comprehensive and comparable assessment of healthcare resource utilisation in the delivery of genomic testing globally.

METHODS: A framework is presented that focuses on uncovering the process of genomic testing for any given laboratory, evaluating its utilisation and unit costs, and modelling the cost drivers and overall expenses associated with delivering genomic testing. The goal is to aid in refining and implementing policies regarding both the regulation and funding of genomic testing. A process-focused (activity-based) methodology is outlined, which encompasses resources, assesses individual cost components through a combination of bottom-up and top-down microcosting techniques and allows disaggregation of resource type and process step.

ETHICS AND DISSEMINATION: The outputs of the study will be reported at relevant regional genetics and health economics conferences, as well as submitted to a peer-reviewed journal focusing on genomics. Human research ethics committee approval is not required for this microcosting study. This study does not involve research on human subjects, and all data used in the analysis are either publicly available.

PMID:38030253 | DOI:10.1136/bmjopen-2022-069441

Orphanet J Rare Dis. 2023 Nov 28;18(1):368. doi: 10.1186/s13023-023-02978-x.

ABSTRACT

BACKGROUND: Compassionate use is a system that provides patients with expedited access to drugs which has not yet been approved, but currently in clinical trials. The investigational drugs have been authorized for compassionate use in cases involving patients suffered from life-threatening diseases and with no alternative treatments. For instance, patients afflicted with highly heterogeneous rare diseases are eligible for treatment assistance through the compassionate use program. This study aims to investigate the characteristics of compassionate use in the context of rare diseases, evaluate the efficacy and safety of compassionate use for rare diseases, and analyze the marketing approval of investigational drugs.

METHODS: The case reports/case series of compassionate use were collected by conducting searches on Embase, PubMed, Web of Science, CNKI and SinoMed, spanning from January 1991 to December 2022. Subsequently, two independent reviewers evaluated these reports. Case reports/case series that met the inclusion criteria and exclusion criteria were enrolled. Information extracted from these reports and series included patients' basic information, the investigational drug's name, its indication, adverse events, treatment outcomes, and other relevant data.

RESULTS: A total of forty-six studies were included, encompassing 2079 patients with an average age of 38.1 years. Thirty-nine different drugs were involved in 46 studies. Furthermore, neoplasms emerged as the most common therapeutic area for compassionate use in rare disease management (23/46, 50.0%). Regarding the treatment efficacy, four studies reported successful disease resolution, while 35 studies observed symptom improvement among patients. Conversely, four studies documented no significant effects on patients' diseases. Moreover, one study reported worsened results following compassionate use, while the efficacy was not described in 2 studies. Adverse events were reported in 31 studies (67.4%) because of the compassionate use, while no adverse events occurred in 13 studies (28.3%). In other 2 studies, there was no description about whether treatment-emergent adverse events (TEAEs) were happened. 136 patients (6.5%) had Grade 5 adverse events (death), of which 19 deaths (0.9%) were considered to be related to compassionate use. Furthermore, the investigational drugs in 33 studies (33/46, 71.7%) received new drug approval at the end of January 31, 2023.The time lag from the start of the compassionate use to the formal approval of the investigational drug was 790.5 (IQR 359-2199.3) days. We found that in 11 studies, encompassing 9 different drugs, some compassionate use indications had not received regulatory authorities at the end of January 31, 2023.

CONCLUSION: The current status of compassionate use for rare diseases was clarified systematically in this study. Compassionate use of investigational drug is a significant treatment option for rare disease. In general, compassionate use appears to demonstrate favorable efficacy in the context of rare diseases, with a significant proportion of compassionate use drugs subsequently receiving marketing approval. However, the safety of drugs for compassionate use cannot be fully evaluated due to the safety data were not covered in some enrolled studies. Therefore, the establishment of an adverse event reporting system specific to compassionate use is warranted.

PMID:38017575 | PMC:PMC10685565 | DOI:10.1186/s13023-023-02978-x

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2023 Nov 29. doi: 10.1007/s00103-023-03810-4. Online ahead of print.

ABSTRACT

BACKGROUND: Rare diseases are often characterized by complex symptoms and usually require coordination of multiprofessional treatment during the diagnostic and healthcare processes. In the wake of the COVID-19 pandemic, the healthcare situation and daily life of people with rare diseases and the caregivers of children with rare diseases changed drastically. The aim of the research project RESILIENT-SE-PAN was to assess the situation of people with rare diseases and caregivers during COVID-19 and to develop recommendations based on the findings.

METHODS: We conducted a mixed methods study including the perspective of people with rare diseases, caregivers and representatives from patient organizations and conducted a concluding workshop.

RESULTS: The findings indicate an impact on healthcare and daily life of participants. Moreover, mental burden, supportive needs, COVID-19-specific aspects but also positive aspects were mentioned. Based on the findings from our mixed methods study, we developed 21 recommendations referring to the following topics: medical diagnostics and healthcare of the rare diseases, additional therapies and aids, access to COVID-19 information and vaccination, psychosocial support, participation and activities, patient organisations and others.

DISCUSSION: The recommendations can provide an orientation for the organisation of healthcare in future crises or pandemics in order to adequately take the situations of people with rare diseases into account and consider the needs of this patient group.

PMID:38019314 | DOI:10.1007/s00103-023-03810-4

JAMA Intern Med. 2024 Jan 1;184(1):63-69. doi: 10.1001/jamainternmed.2023.6293.

ABSTRACT

IMPORTANCE: The Inflation Reduction Act (IRA) requires Medicare to negotiate prices for some high-spending drugs but exempts drugs approved solely for the treatment of a single rare disease.

OBJECTIVE: To estimate Medicare spending and global revenues for drugs that might have been exempt from negotiation from 2012 to 2021.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study analyzed drugs that met the IRA threshold for price negotiation (Medicare spending >$200 million/y) in any year from 2012 to 2021 and had an Orphan Drug Act designation. We stratified drugs into 4 mutually exclusive categories: approved for a single rare disease (sole orphan), approved for multiple rare diseases (multiorphan), initially approved for a rare disease and subsequently approved for a nonrare disease (orphan first), and initially approved for a nonrare disease and subsequently approved for a rare disease (non-orphan first).

OUTCOMES: The primary outcomes were the number of sole orphan drugs, estimated Medicare spending on those drugs from 2012 to 2021, and global revenue since launch.

RESULTS: Among 282 drugs, 95 (34%) were approved to treat at least 1 rare disease, including 25 sole orphan drugs (26%), 20 multiorphan drugs (21%), 13 orphan first drugs (14%), and 37 non-orphan first drugs (39%). From 2012 to 2021, Medicare spending on sole orphan drugs increased from $3.4 billion to $10.0 billion. Each year, a median (IQR) of $2.5 ($1.9-$2.6) billion in Medicare spending would have been excluded from price negotiation because of the sole orphan exemption. The cumulative global revenue of the median (IQR) sole orphan drug was $11 ($6.6-$19.2) billion.

CONCLUSIONS AND RELEVANCE: The sole orphan exemption will exclude billions of dollars of Medicare drug spending from price negotiation. The high level of global revenues achieved by these drugs, however, suggests that special exemption is unnecessary for them to achieve financial success. Congress could consider removing the sole orphan exemption to obtain additional savings for patients and taxpayers and to eliminate any potential disincentive for developing additional indications for these drugs.

PMID:38010643 | PMC:PMC10682941 | DOI:10.1001/jamainternmed.2023.6293

CMAJ. 2023 Nov 26;195(46):E1565-E1576. doi: 10.1503/cmaj.230841.

ABSTRACT

BACKGROUND: Globally, pharmaceutical companies offer patient support programs in tandem with their products, which aim to enhance medication adherence and patient experience through education, training, support and financial assistance. We sought to identify the proportion and characteristics of such patient support programs in Canada and to describe the nature of supports provided.

METHODS: We conducted a crosssectional study to identify and characterize all marketed prescription drugs available in Canada as of Aug. 23, 2022, using the Health Canada Drug Product and CompuScript databases. To describe the nature of supports provided, we conducted a content analysis of publicly available patient support program websites and Web-based documents. Using logistic regression, we identified characteristics of drugs associated with having a patient support program including brand-name or branded generic (generic medications with a proprietary name), orphan (medications for rare diseases) or biologic drug status; estimated total cost of prescriptions dispensed at retail pharmacies; and price per unit.

RESULTS: Of the 2556 prescription drugs marketed by 89 companies in the study period, 256 (10.0%) had a patient support program in Canada. Many of the 89 drug manufacturers (n = 55, 61.8%) offered at least 1 patient support program, frequently relying on third-party administrators for delivery. Brandname and branded generic medications, biologic agents and drugs with orphan status were more likely to have a patient support program than generic drugs. Compared with drugs priced $1.01-$10.00 per unit, drugs priced $10.01-$100.00 per unit were nearly 8 times more likely to have a patient support program (adjusted odds ratio 7.54, 95% confidence interval 4.07- 14.64). Most sampled patient support programs included reimbursement navigation (n = 231, 90.2%) and clinical case management (n = 223, 87.1%).

INTERPRETATION: About 1 in 10 drugs marketed in Canada has a manufacturersponsored patient support program, but these are concentrated around brand-name, branded generic, biologic and high-cost drugs, often for rare diseases. To understand the impact of patient support programs on health outcomes and sustainable access to cost-effective medicines, greater transparency and independent evaluation of patient support programs is necessary.

PMID:38011930 | DOI:10.1503/cmaj.230841

Farm Hosp. 2024 Jan-Feb;48(1):T3-T8. doi: 10.1016/j.farma.2023.10.004. Epub 2023 Nov 25.

ABSTRACT

OBJECTIVE: To analyse the presence of Good Humanisation Practices in the care of patients with rare diseases in Hospital Pharmacy Services and to identify the strengths and prevalent areas for improvement in the humanisation of healthcare.

METHODS: An online questionnaire structured in 2 parts was developed using Google Form®. The first one was designed to collect identifying data and the second one included questions related to compliance with the 61 standards of the Manual of Good Humanisation Practices in the healthcare of patients with rare diseases in Hospital Pharmacy Services. Access to the questionnaire was sent by email to the Heads of the Hospital Pharmacy Service of 18 hospitals. The study period was from October 2021 to October 2022. The analysed variables were the number of criteria that were considered met, total compliance (percentage of criteria met), by strategic line and by type or level of standard, globally and grouped by regions of Spain.

RESULTS: 18 Hospital Pharmacy Services were included. The overall mean of standards met was 31.1 (95% CI: 24.8-37.6) and mean total compliance was 52.1% (95% CI: 44.4%-59.7%). The mean compliance by strategic line was: Line 1, Humanisation culture: 46.5% (95% CI: 35.3%-57.7%), Line 2, Patient empowerment: 47.4% (95% CI: 37.1%-57.8%), Line 3, Professional care: 49.7% (95% CI: 39.8%-59.1%), Line 4, Physical spaces and comfort: 55.6% (95% CI: 46.3%-64.8%), and Line 5, Organisation of healthcare: 63.8% (95% CI: 55.8%-71.9%).

CONCLUSION: The average compliance with the standards is between 40% and 60%, which indicates that humanisation is present in the Hospital Pharmacy Services, but there is a wide margin for improvement. The main strength in the humanisation of Hospital Pharmacy Services is a patient-centred care organisation, and the area with the greatest room for improvement is the culture of humanisation.

PMID:38008659 | DOI:10.1016/j.farma.2023.10.004