Embracing Diversity, Equity, Inclusion, and Accessibility in Eosinophilic Gastrointestinal Diseases.

Eosinophilic gastrointestinal diseases (EGIDs) including eosinophilic esophagitis (EoE) are rare diseases in which eosinophils abnormally infiltrate the gastrointestinal tract. Because these are rare diseases, there is limited information regarding race and ethnicity in EGIDs and even less is known about the impact of socioeconomic factors. There is some evidence that access to care in rural settings may be affecting epidemiologic understanding of EGIDs in the pediatric populations. Future work should try to evaluate bias in research and strive for representation in clinical trials and medicine.

Institutional Priority-Setting for Novel Drugs and Therapeutics: A Qualitative Systematic Review.

BACKGROUND: There is a lack of guidance on approaches to formulary management and funding for high-cost drugs and therapeutics by individual healthcare institutions. The objective of this review was to assess institutional approaches to resource allocation for such therapeutics, with a particular focus on paediatric and rare disease populations. METHODS: A search of Embase and MEDLINE was conducted for studies relevant to decision-making for off-formulary, high-cost drugs and therapeutics. Abstracts were evaluated for inclusion based on the Simple Multiple-Attribute Rating Techniques (SMART) criteria. A framework of 30 topics across 4 categories was used to guide data extraction and was based on findings from the initial abstract review and previous health technology assessment (HTA) publications. Reflexive thematic analysis was conducted using QSR NVivo 12 software. RESULTS: A total of 168 studies were included for analysis. Only 4 (2%) focused on paediatrics, while 21 (12%) centred on adults and the remainder (85%) did not specify. Thirty-two (19%) studies discussed the importance of high-cost therapeutics and 34 (23%) focused on rare/orphan drugs. Five themes were identified as being relevant to institutional decision-making for high-cost therapeutics: institutional strategy, substantive criteria, procedural considerations, guiding principles and frameworks, and operational activities. Each of these themes encompassed several sub-themes and was complemented by a sixth category specific to paediatrics and rare diseases. CONCLUSION: The rising cost of novel drugs and therapeutics underscores the need for robust, evidence-based, and ethically defensible decision-making processes for health technology funding, particularly at the hospital level. Our study highlights practices and themes to aid decision-makers in thinking critically about institutional, substantive, procedural, and operational considerations in support of legitimate decisions about institutional funding of high-cost drugs and therapeutics, as well as opportunities and challenges that exist for paediatric and rare disease populations.

Analysis of affordability differences for rare diseases in China: a comparison across disease types and regions.

BACKGROUND: China has implemented policies to make rare diseases more affordable. While previous studies evaluated overall affordability, few have examined affordability differences across regions and disease types. Given the vastness of China and varying medical policies across cities, this study assesses the affordability of rare diseases based on China's First List of Rare Diseases (CFLRD), National Reimbursement Drug List (NRDL), and outpatient chronic and special disease policies in each prefecture. METHOD: Six rare diseases were selected and the average annual treatment cost of all relevant drugs in NRDL was calculated for each disease. Based on the WHO/HAI standardized approach, the study analyzed 289 cities with outpatient chronic and special disease policies, measured the security levels by the actual reimbursement ratio of Basic Medical Insurance (BMI) and affordability by the ratio of individual expenses after reimbursement to the annual disposable income of urban residents in the province. The security levels and affordability differences across disease types and provinces were analyzed using the Mann-Whitney U test and the K-W test. RESULT: The affordability of rare diseases varied significantly on the disease types and annual treatment cost. Diseases with an annual treatment cost below 100 000 yuan are affordable to all prefectures even with low reimbursement rates, while those with a higher treatment cost were not affordable in at least 80% of prefectures even though the reimbursement ratio is high. The affordability of the same disease varies significantly across provinces and municipalities. Outpatient chronic and special diseases insurance and critical illness insurance, and the inconsistencies between them, result in regional differences. CONCLUSION: Although China has made progress in improving the affordability of rare diseases, significant differences persist between cities and diseases. The study suggests the optimization of the BMI system and explores independent funds and innovative insurance models to enhance the affordability of rare diseases, particularly those with extremely high treatment costs.

A systematic review of the assessment of the clinical utility of genomic sequencing: Implications of the lack of standard definitions and measures of clinical utility.

PURPOSE: Exome sequencing (ES) and genome sequencing (GS) are diagnostic tests for rare genetic diseases. Studies report clinical utility of ES/GS. The goal of this systematic review is to establish how clinical utility is defined and measured in studies evaluating the impacts of ES/GS results for pediatric patients. METHODS: Relevant articles were identified in PubMed, Medline, Embase, and Web of Science. Eligible studies assessed clinical utility of ES/GS for pediatric patients published before 2021. Other relevant articles were added based on articles' references. Articles were coded to assess definitions and measures of clinical utility. RESULTS: Of 1346 articles, 83 articles met eligibility criteria. Clinical utility was not clearly defined in 19% of studies and 92% did not use an explicit measure of clinical utility. When present, definitions of clinical utility diverged from recommended definitions and varied greatly, from narrow (diagnostic yield of ES/GS) to broad (including decisions about withdrawal of care/palliative care and/or impacts on other family members). CONCLUSION: Clinical utility is used to guide policy and practice decisions about test use. The lack of a standard definition of clinical utility of ES/GS may lead to under- or overestimations of clinical utility, complicating policymaking and raising ethical issues.

The experiences and perceptions of people with chronic and rare diseases during political-economic sanctions in Iran: a qualitative study.

BACKGROUND: Economic sanctions aim to exert pressure on political and economic foundations. Hypothesizing that sanctions might affect various aspects of population health, this study, as a component of a broader investigation to ascertain the trend effects of sanctions on selected health outcomes in Iran, seeks to explore the experiences of Iranian citizens associated with the imposed sanctions. METHODS: This is a qualitative study. We conducted 31 semi-structured interviews with randomly selected patients diagnosed with at least one chronic and rare disease from diverse backgrounds across four provinces in Iran. We analyzed data using an inductive content analysis approach, facilitated by the MAXQDA10 software. RESULTS: We identified three primary themes: direct effects, side effects, and coping strategies. The immediate effects were perceived to be manifested through the restriction of healthcare service availability and affordability for citizens. The side effects included the economic hardships experienced in individuals' lives and the perceived devastation caused by these difficulties. Some coping mechanisms adopted by patients or their families/relatives included prioritizing comorbidities, prioritizing health needs within families with multiple ill members, and readjusting health/illness requirements in light of daily living needs. CONCLUSION: In addition to the inherent burden of their illness, patients faced substantial healthcare costs as a result of sanctions, restricted access to medications, and availability of low-quality medications. We advocate considering these challenges within the healthcare system resilience framework as a crucial first step for policymakers, aiming to determine actionable measures and mitigate the adverse effects of sanctions on citizens, particularly the most vulnerable groups.

Recommendations for optimal interdisciplinary management and healthcare settings for patients with rare neurological diseases.

BACKGROUND: In 2017, the German Academy for Rare Neurological Diseases (Deutsche Akademie für Seltene Neurologische Erkrankungen; DASNE) was founded to pave the way for an optimized personalized management of patients with rare neurological diseases (RND) in all age groups. Since then a dynamic national network for rare neurological disorders has been established comprising renowned experts in neurology, pediatric neurology, (neuro-) genetics and neuroradiology. DASNE has successfully implemented case presentations and multidisciplinary discussions both at yearly symposia and monthly virtual case conferences, as well as further educational activities covering a broad spectrum of interdisciplinary expertise associated with RND. Here, we present recommendation statements for optimized personalized management of patients with RND, which have been developed and reviewed in a structured Delphi process by a group of experts. METHODS: An interdisciplinary group of 37 RND experts comprising DASNE experts, patient representatives, as well as healthcare professionals and managers was involved in the Delphi process. First, an online collection was performed of topics considered relevant for optimal patient care by the expert group. Second, a two-step Delphi process was carried out to rank the importance of the selected topics. Small interdisciplinary working groups then drafted recommendations. In two consensus meetings and one online review round these recommendations were finally consented. RESULTS: 38 statements were consented and grouped into 11 topics: health care structure, core neurological expertise and core mission, interdisciplinary team composition, diagnostics, continuous care and therapy development, case conferences, exchange / cooperation between Centers for Rare Diseases and other healthcare partners, patient advocacy group, databases, translation and health policy. CONCLUSIONS: This German interdisciplinary Delphi expert panel developed consented recommendations for optimal care of patients with RND in a structured Delphi process. These represent a basis for further developments and adjustments in the health care system to improve care for patients with RND and their families.

Real-world evidence for coverage determination of treatments for rare diseases.

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making.

Navigating the unknown: how to best 'reflect' standard of care in indications without a dedicated treatment pathway in health technology assessment submissions.

There is an urgent need for expedited approval and access for new health technologies targeting rare and very rare diseases, some of which are associated with high unmet treatment needs. Once a new technology achieves regulatory approval, the technology needs to be assessed by health technology assessment (HTA) bodies to inform coverage and reimbursement decisions. This assessment quantitatively examines the clinical effectiveness, safety and/or economic impact of the new technology relative to standard of care (SoC) in a specific market. However, in rare and very rare diseases, the patient populations are small and there is often no established treatment pathway available to define 'SoC'. In these situations, several challenges arise to assess the added benefit of a new technology - both clinically and economically - due to lack of established SoC to guide an appropriate comparator selection. These challenges include: How should 'SoC' be defined and characterized in HTA submissions for new technologies aiming to establish new treatment standards? What is usual care without an established clinical pathway? How should the evidence for the comparator 'SoC' (i.e., usual care) arm be collected in situations with low patient representation and, sometimes, limited disease-specific clinical knowledge in certain geographies? This commentary outlines the evidence generation challenges in designing clinical comparative effectiveness for a new technology when there is a lack of established SoC. The commentary also proposes considerations to facilitate the reliable integration of real-world evidence into HTA and decision-making based on the collective experience of the authors.

The cost of proband and trio exome and genome analysis in rare disease: A micro-costing study.

PURPOSE: Rare disease genomic testing is a complex process involving various resources. Accurate resource estimation is required for informed prioritization and reimbursement decisions. This study aims to analyze the costs and cost drivers of clinical genomic testing. METHODS: Based on genomic sequencing workflows we microcosted limited virtual panel analysis on exome sequencing backbone, proband and trio exome, and genome testing for proband and trio analysis in 2023 Australian Dollars ($). Deterministic and probabilistic sensitivity analyses were undertaken. RESULTS: Panel testing costs AUD $2373 ($733-$6166), and exome sequencing costs $2823 ($802-$7206) and $5670 ($2006-$11,539) for proband and trio analysis, respectively. Genome sequencing costs $4840 ($2153-$9890) and $11,589 ($5842-$16,562) for proband and trio analysis. The most expensive cost component of genomic testing was sequencing (36.9%-69.4% of total cost), with labor accounting for 27.1%-63.2% of total cost. CONCLUSION: We provide a comprehensive analysis of rare disease genomic testing costs, for a range of clinical testing types and contexts. This information will accurately inform economic evaluations of rare disease genomic testing and decision making on policy settings that assist with implementation, such as genomic testing reimbursement.

Using automated text classification to explore uncertainty in NICE appraisals for drugs for rare diseases.

OBJECTIVE: This study examined the application, feasibility, and validity of supervised learning models for text classification in appraisals for rare disease treatments (RDTs) in relation to uncertainty, and analyzed differences between appraisals based on the classification results. METHODS: We analyzed appraisals for RDTs (n = 94) published by the National Institute for Health and Care Excellence (NICE) between January 2011 and May 2023. We used Naïve Bayes, Lasso, and Support Vector Machine models in a binary text classification task (classifying paragraphs as either referencing uncertainty in the evidence base or not). To illustrate the results, we tested hypotheses in relation to the appraisal guidance, advanced therapy medicinal product (ATMP) status, disease area, and age group. RESULTS: The best performing (Lasso) model achieved 83.6 percent classification accuracy (sensitivity = 74.4 percent, specificity = 92.6 percent). Paragraphs classified as referencing uncertainty were significantly more likely to arise in highly specialized technology (HST) appraisals compared to appraisals from the technology appraisal (TA) guidance (adjusted odds ratio = 1.44, 95 percent CI 1.09, 1.90, p = 0.004). There was no significant association between paragraphs classified as referencing uncertainty and appraisals for ATMPs, non-oncology RDTs, and RDTs indicated for children only or adults and children. These results were robust to the threshold value used for classifying paragraphs but were sensitive to the choice of classification model. CONCLUSION: Using supervised learning models for text classification in NICE appraisals for RDTs is feasible, but the results of downstream analyses may be sensitive to the choice of classification model.

Rare paediatric disorders in Indian healthcare settings with focus on neuromuscular disorders: Diagnostic and management challenges.

Rare diseases form the bulk of the financial expenditure of any developing or developed economy. Among the various rare diseases, paediatric neuromuscular disorders form a major portion, with a worldwide survey estimating a prevalence of 1 in 3500 individuals. In a lower middle-income country (LMIC) like India, malnutrition still accounts for most of the under-5 mortality. However, the economic burden of rare paediatric neuromuscular disorders cannot be underestimated. The treating physician should have a basic understanding of how to approach a child presenting with weakness and how to utilise the available tests which are affordable in an LMIC setting. History and examination still form the core, and with new diagnostic methods like nextgeneration sequencing, more and more rare disorders are getting diagnosed. It is important for the treating physician to know about basic supportive care, recent advancements, and available treatment options for these conditions. With exciting new treatment options being available for these disorders, the perception of these diseases as being not treatable is gradually changing. This review aims to be of guidance to clinicians from an LMIC setting like India and to empower them to manage such rare paediatric neuromuscular disorders.

VOLY: The Monetary Value of a Life-Year at the End of Patients' Lives.

OBJECTIVE: We explored the monetary value of the end-of-life (EoL) health gains, that is, the value of a life-year (VOLY) gained at the end of a patient's life in Croatia. We tested whether the nature of the illness under valuation (cancer and/or rare disease) is a factor in the valuation of EoL-VOLYs. The aim was for our results to contribute to the health and longevity valuation literature and more particularly to the debate on the appropriate cost-effectiveness threshold for EoL treatments as well as to provide input into the debate on the justifiability of a cancer and/or a rare disease premium when evaluating therapies. METHODS: A contingent valuation was conducted in an online survey using a representative sample of the Croatian population (n = 1500) to calculate the willingness to pay for gains in the remaining life expectancy at the EoL, from the social-inclusive-individual perspective, using payment scales and an open-ended payment vehicle. Our approach mimics the actual decision-making problem of deciding whether to reimburse therapies targeting EoL conditions such as metastatic cancer whose main purpose is to extend life (and not add quality to life). RESULTS: Average EoL-VOLY across all scenarios was estimated at €67,000 (median €40,000). In scenarios that offered respondents 1 full year of life extension, EoL-VOLY was estimated at €33,000 (median €22,000). Our results show that the type of illness is irrelevant for EoL-VOLY evaluations. CONCLUSIONS: The pressure to reimburse expensive therapies targeting EoL conditions will continue to increase. Delivering "value for money" in healthcare, both in countries with relatively higher and lower budget restrictions, requires the valuation of different types of health gains, which should, in turn, affect our ability to evaluate their cost effectiveness.

Cost of Exempting Sole Orphan Drugs From Medicare Negotiation.

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.

Modeling the multi-state natural history of rare diseases with heterogeneous individual patient data: A simulation study.

Multi-state survival models are used to represent the natural history of a disease, forming the basis of a health technology assessment comparing a novel treatment to current practice. Constructing such models for rare diseases is problematic, since evidence sources are typically much sparser and more heterogeneous. This simulation study investigated different one-stage and two-stage approaches to meta-analyzing individual patient data (IPD) in a multi-state survival setting when the number and size of studies being meta-analyzed are small. The objective was to assess methods of different complexity to see when they are accurate, when they are inaccurate and when they struggle to converge due to the sparsity of data. Biologically plausible multi-state IPD were simulated from study- and transition-specific hazard functions. One-stage frailty and two-stage stratified models were estimated, and compared to a base case model that did not account for study heterogeneity. Convergence and the bias/coverage of population-level transition probabilities to, and lengths of stay in, each state were used to assess model performance. A real-world application to Duchenne Muscular Dystrophy, a neuromuscular rare disease, was conducted, and a software demonstration is provided. Models not accounting for study heterogeneity were consistently out-performed by two-stage models. Frailty models struggled to converge, particularly in scenarios of low heterogeneity, and predictions from models that did converge were also subject to bias. Stratified models may be better suited to meta-analyzing disparate sources of IPD in rare disease natural history/economic modeling, as they converge more consistently and produce less biased predictions of lengths of stay.

High-cost drugs for rare diseases: their expenditure and value based on a regional area-based study.

Background: in the field of rare diseases (RDs) most of the European studies on budget impact analysis of drugs that have been conducted often lay on theoretical assumptions and focus only on Orphan drugs (ODs). Objectives: we aimed to estimate the budget impact of specific drugs for non-oncological RDs, both ODs and non-ODs, using real-world data about patients residing in Veneto Region (Italy) and to describe its expenditure structure and dynamics. Methods: a population-based multi-source observational study was conducted using data from Regional administrative databases; an ad-hoc drugs' list specific for RDs including both ODs and non-ODs and classifying them by ATC codes has been created. Results: In 2019, the total expenditure for drugs specific for RDs was EUR 97.2 million (6.6% of the total Regional budget). The RD drug list included 58 ATC codes, of which 15 ATC had an annual budget impact over EUR 1 million ("blockbuster drugs"). The most expensive treatment was a non-OD drug (Coagulation factor VIII). The two most represented therapeutical areas were the metabolic and the hematological ones. Conclusions: Cost analyses on RD high-cost drugs expenditure should consider any specific RD drug, not only ODs. Expenditure dynamics for RD drugs are peculiar showing "blockbuster drugs". Some therapeutical areas seem to be lacking in the drug research field.

Healthcare costs for patients with rare diseases: Evidence from China.

OBJECTIVE: Rare diseases cause a huge financial burden to countless patients and families. It is an important public health issue that requires widespread attention. This study analyzes medical expenses composition and the change in trends of out-of-pocket (OOP) expenses for patients with Amyotrophic lateral sclerosis (ALS) and explores the factors influencing these changes. METHODS: Data were obtained from the Chinese Medical Insurance Department database from 2018 to 2020, including 857 patients with ALS in 60 cities across 30 provinces. We used descriptive methods to analyse the baseline characteristics and medical expenses of outpatients and inpatients with ALS. And we used quantile regression to analyse the differences in patient OOP ratio and the factors influencing them. RESULTS: In China, 80.3% of ALS patients chose tertiary hospitals, with an annual direct medical cost of 11,339.7 RMB per patient and an OOP ratio of 41.6%. The annual medical cost for outpatients was 345.1 RMB per patient, with an OOP ratio of 36.7%. The annual medical cost for inpatients was 28,139.8 RMB per patient, with an OOP ratio of 41.7%. Compared to outpatients, inpatients had higher medical costs but lower actual reimbursement rates. The OOP ratio of ALS patients decreased, then increased over time. And the OOP ratio was influenced by medical institution, medical insurance, and age (p < 0.05). Patients who chose tertiary hospitals, those who were covered by the urban resident basic medical insurance and younger patients had relatively higher OOP ratio. CONCLUSION: In recent years, although China has begun to pay attention to the rights and interests of patients with rare diseases, the government has provided some healthcare security to patients with rare diseases. However, the level of medical insurance coverage was still low, the equity of protection was still insufficient and the financial burden on patients was high. Therefore, the government should further improve the healthcare system to provide full life-cycle and affordable healthcare services to patients with rare diseases.

Healthcare access and health equity: intricate challenges for rare diseases.

No abstract available.