OBJECTIVE: To examine ultra-orphan drugs in terms of incremental health, costs, and cost-effectiveness compared to more prevalent disease drugs.
METHODS: We identified FDA drug approvals from 1999-2019. For drugs approved for multiple indications, we considered each drug-indication pair separately. Utilizing FDA\'s orphan drug designation and US disease prevalence, we categorized drug-indication pairs as: ultra-orphan (<10,000 patients), \'other\' orphan (≥10,000 and <200,000), and non-orphan (≥200,000). We searched the PubMed database for cost-effectiveness and cost-utility studies. We excluded manufacturer-funded studies. We extracted estimates of incremental health gains in terms of quality-adjusted life-years (QALYs) and incremental costs associated with drug-indication pairs compared to the standard of care at the time of their approval. We compared QALY gains, added costs, and incremental cost-effectiveness ratios (ICERs) using the Kruskal-Wallis (KW), Mann-Whitney U (MWU), and Kolmogorov-Smirnov (KS) tests.
RESULTS: Median incremental QALYs, costs, and ICERs differed across non-orphan, \'other\' orphan, and ultra-orphan categories (KW p<0.01). Compared to non-orphan drugs, ultra-orphan drugs had larger QALY gains (0.700 vs. 0.050, MWU p<0.01, KS p<0.01), larger costs ($172,231 vs. $3,360, MWU p<0.01, KS p<0.01), and larger ICERs ($1,216,184/QALY vs. $114,061/QALY, MWU p<0.01, KS p<0.01). Compared to \'other\' orphan drugs, ultra-orphan drugs had larger QALY gains (0.700 vs. 0.310, MWU p=0.65, KS p=0.32), larger costs ($172,231 vs. $69,308, MWU p=0.03, KS p=0.03), and larger ICERs ($1,216,184/QALY vs. $223,472/QALY, MWU p<0.01, KS p<0.01).
CONCLUSIONS: Novel ultra-orphan drugs typically offer larger incremental health gains than drugs for more prevalent diseases, but due to their substantial added costs, are typically less cost-effective.

BACKGROUND: Clinical development for orphan drugs presents significant difficulties and challenges. There is no unique or standard design, conduct, and outcome assessment methodology and it is sometimes impractical to fit design models of rare disease trials in any practiced and well-known framework. In the European Union (EU) these challenges encompass a broad array of subjects, including trial design, study outcomes, patient recruitment, trial conduct ethics, trial cost, and chances of success. This literature-based review study aims to provide a thorough overview of the critical aspects of rare disease trials in the EU by analyzing the current landscape of rare disease trials, highlighting key challenges, delving into regulatory and research initiatives and innovation in trial designs, and proposing multi-faceted solutions to implement effective rare disease clinical trials in the region.
CONCLUSIONS: Traditional clinical trial designs, validation, and evaluation methodologies used for nonorphan drugs often prove unsuitable for orphan drugs, given the small patient populations, sometimes fewer than 1000 cases. There is an increasing need for accessible therapies and both regulators as well as industry are trying to develop affordable and effective drugs to address this need. Despite several steps that have been taken, the timely development of drugs remains a challenge. One of the reasons behind the long development timeline is the recruitment, retention, and conduct of rare disease trials. To optimize the development timelines of orphan drugs in the EU, it is important to ensure that the safety and efficacy of the product is not compromised. Industry and regulatory agencies must implement innovative trial designs, devise flexible policies, and incorporate real-world data for assessing clinical outcomes.
CONCLUSIONS: Collaboration among academic institutions, pharmaceutical companies (both small and major), patient groups, and health authorities is crucial in overcoming obstacles related to clinical trials and providing assistance and creative ideas. The ultimate objective of granting rare disease patients timely and affordable access to medications with a positive balance between benefits and risks is to be met.

OBJECTIVE: The accessibility issue of orphan drugs in China is prominent. Based on real-world data from a tier-one city in Northeast China, this study aims to analyze the current usage and affordability of orphan drugs for rare diseases.
METHODS: The data was sourced from the health insurance claims data of a certain city from 2018 to 2021, including a total of 16 orphan drugs. The utilization of orphan drugs is assessed using four indicators: frequency of medical insurance claims, medication cost, defined daily doses (DDDs), and defined daily drug cost (DDDc). Affordability is measured using the concept of catastrophic health expenditure (CHE).
RESULTS: Between January 2018 and December 2021, there were a total of 2,851 medical insurance claims in the city, with a total medication costs of $3.08 million. Overall, during the study, there was a year-on-year increase in the utilization frequency of individual rare disease drugs in the city, with DDDs rising from 140.22 in 2018 to 3983.63 in 2021. Additionally, the annual medication costs of individual drugs showed a consistent upward trend, increasing from $10,953.53 in 2018 to $120,491.36 in 2021. However, the DDDc of individual drugs decreased from $398.12 in 2018 to $96.65 in 2021.The number of sales and the amount of sales for orphan drugs in community pharmacies have significantly increased. Prior to medical insurance coverage, out of the 16 orphan drugs, 9 drugs had annual treatment costs exceeding CHE for urban residents, and 15 drugs had annual treatment costs exceeding CHE for rural residents. After medical insurance coverage, there were no drugs with out-of-pocket costs exceeding CHE for urban residents, while 8 drugs had out-of-pocket costs exceeding CHE for rural residents. Furthermore, both before and after medical insurance coverage, the four treatment drugs for idiopathic pulmonary arterial hypertension were more affordable compared to the four treatment drugs for multiple sclerosis.
CONCLUSIONS: The usage frequency of orphan drugs in a certain city increased gradually, but the disease burden remained heavy. More policy support should be provided to the priority rare disease populations, and the rare disease medical security and diagnosis and treatment systems should be improved.

OBJECTIVE: This systematic literature review aimed to explore experiences worldwide of societal preferences integration into health technology assessments (HTAs) for rare diseases (RDs) and orphan drugs (ODs) through the implementation of multicriteria decision analysis (MCDA), discrete choice experiments (DCEs), and person trade-off (PTO) methods, among others.
METHODS: A systematic search of the literature was conducted in April 2021 using PubMed, Cochrane, Embase, and Scopus databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach was used for the review phases. Finally, the Promoting Action on Research Implementation in Health Services framework was used to discuss the implementation of these instruments in the RD context.
RESULTS: A total of 33 articles met the inclusion criteria. The studies measured societal preferences for RD and OD as part of HTA using MCDA (n = 17), DCE (n = 8), and PTO (n = 4), among other methods (n = 4). These found that patients and clinicians do not prioritize funding based on rarity. The public is willing to allocate funds only if the OD demonstrates effectiveness and improves the quality of life, considering as relevant factors disease severity, unmet health needs, and quality of life. Conversely, HTA agency experts preferred their current approach, placing more weight on cost-effectiveness and evidence quality, even though they expressed concern about the fairness of the drug review process.
CONCLUSIONS: MCDA, PTO, and DCE are helpful and transparent methods for assessing societal preferences in HTA for RD and OD. However, their methodological limitations, such as arbitrary criteria selection, subjective scoring methods, framing effects, weighting adaptation, and value measurement models, could make implementation challenging.

Characterization analysis of 87 pivotal clinical trials for 72 novel orphan drugs (76 orphan indications) approved by the FDA from 2017 to 2023 revealed that the clinical trial evidence supporting FDA orphan drug approvals often lacked high-quality designs, which frequently did not incorporate randomization, blinding, placebo or no treatment control, or clinical endpoint-driven methodologies. Additionally, regulatory flexibility was observed in the quantity of clinical trial evidence required, which included choices such as a single trial plus confirmatory evidence, one large multicenter trial or at least two trials. Furthermore, the overall strength of the clinical trial evidence exhibited variations across different orphan drugs and indications, influenced by features such as the therapeutic area and whether the orphan drug was granted accelerated approvals.

OBJECTIVE: To identify and describe potential societal and individual sources of support for orphan drug programs.
METHODS: The Generalized Risk-Adjusted Cost-Effectiveness method shows that acute illness and disability severity increase individuals\' willingness to pay for health gains. We develop a social welfare function (SWF) that incorporates individuals\' own values, combined with politically or ethically determined weights. We introduce the concept of horizontal equity-that individuals in similar situations should be treated similarly-into the SWF. Finally, we introduce anonymous altruism into individuals\' utility functions-the desire to help others, without knowing their identity.
RESULTS: Combined with the empirical link between disease severity and rarity, the Generalized Risk-Adjusted Cost-Effectiveness method demonstrates heightened willingness to pay for health gains for people with rare diseases, leading rational individuals to support orphan drug programs, our first pillar of support. Adding horizontal equity to the SWF further increases societal support for orphan drug programs. Anonymous altruism, focusing most strongly on those in the most-dire circumstances, leads to altruistic support for those with severe disorders. Because innovators\' economic incentives lead them to focus on larger markets, anonymous altruistic individuals will increasingly prefer public investments into rare diseases over time, as private markets systematically produce gains for common diseases.
CONCLUSIONS: We identified 3 supporting pillars for orphan drug programs: (1) individuals\' propensity to prefer treatments for severe diseases; (2) the preference for horizontal equity in our social welfare; (3) anonymous altruism, the desire to help strangers, coupled with market incentives that underserve strangers with rare diseases.

Repurposing drugs for rare diseases is a creative and cost-efficient method for creating new treatment options for certain conditions. This technique entails repurposing existing pharmaceuticals for new uses by utilizing established information regarding pharmacological characteristics, modes of operation, safety profiles, and interactions with biological systems. Creating new treatments for uncommon diseases is frequently difficult because of factors including small patient groups, disease intricacy, and insufficient knowledge of disease pathobiology. Drug repurposing is a more efficient and cost-effective approach compared to developing new drugs from scratch. It typically requires collaboration among academia, pharmaceutical firms, and patient advocacy groups.

Rare diseases have various types, low incidence rates, complex conditions, and are often difficult to diagnose. Due to China\'s large population, there is a significant number of rare disease patients, but there is a shortage of orphan drugs. Consequently, these patients often find themselves in a situation where necessary medications are either unavailable or unaffordable. To address this urgent clinical need, China has implemented a series of orphan drug policies aimed at improving drug accessibility and affordability. In terms of drug accessibility, companies are encouraged to expedite drug development through the implementation of tax incentives, guidance for clinical research on rare diseases, and the provision of data protection periods of 6 years, along with market exclusivity periods limited to a maximum of 7 years. Moreover, exemptions for clinical trials, acceptance of overseas clinical trial data, and the creation of a list prioritizing clinically urgent new drugs from overseas have been introduced to expedite the drug registration application, review, inspection, and approval processes. In terms of drug affordability, the import value-added tax on rare disease drugs has been reduced by 3%, and various provinces and cities have established a representative rare disease protection model, which includes special funds, medical assistance programs, and serious disease insurance. The national medical insurance catalog has been adjusted to reduce the financial burden on rare disease patients, resulting in an increase in the number of orphan drugs covered by the catalog to 95 as of March 2024. By comparing orphan drug policies in the United States, the European Union, Japan, Australia, and other countries (or regions), we will provide relevant suggestions to further improve orphan drug policies in China, thus bringing more treatment options and hope to patients with rare diseases.

UNASSIGNED: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated patients present with extensive xanthomas and premature atherosclerosis. Lipid-lowering therapy is highly efficacious and has dramatically increased life expectancy of patients with HoFH.
UNASSIGNED: The aim of the study was to obtain a comprehensive registry of HoFH in Canada, known to have several founder effect regions, and describe the clinical characteristics and cardiovascular outcomes of this population over time.
UNASSIGNED: Clinical and genetic data on patients with HoFH were collected via a standardized questionnaire sent to academic sites participating in the Familial Hypercholesterolemia Canada network.
UNASSIGNED: A total of 48 patients with HoFH were enrolled. The median age at diagnosis was 12 years (interquartile range [IQR]: 5-24) and untreated LDL-C levels were 15.0 mmol/L (IQR: 10.5-18.6 mmol/L; 580 mg/dL IQR: 404-717 mg/dL). At last follow-up visit, median age was 40 years (IQR: 26-54 years). Treated LDL-C levels were 6.75 mmol/L (IQR: 4.73-9.51 mmol/L; 261 mg/dL IQR: 183-368 mg/dL) with 95.5% of patients on statins, 88.6% on ezetimibe, 34.1% on proprotein convertase subtilisin/kexin type 9 inhibitors, 27.3% on lomitapide, 13.6% on evinacumab, and 56.8% were treated with low-density lipoprotein apheresis or plasmapheresis. Deaths were reported in 7 (14.5%) and major adverse cardiovascular events were observed in 14.6% of patients with the average onset at 30 years (IQR: 20-36 years). Aortic stenosis was reported in one-half the patients (47.9%) and 10 (20.8%) underwent aortic valve replacement.
UNASSIGNED: This HoFH patient registry in Canada will provide important new health-related knowledge about the phenotypic manifestations and determinants of cardiovascular risk in this population, allowing for closer examination of quality of life and burden to the health care system.

Development of an orphan-designated drug has been more challenging and financially less attractive than that of other drugs due to low prevalence of the condition, poorly defined biomarkers and lack of experience of healthcare providers in diagnosing and treating the condition. Guidance and incentives in some countries support the sponsors in developing orphan-designated drugs despite the challenges. Expedited regulatory programs as offered by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) support the development of drugs, provide shorter marketing application review times or provide preliminary approval. In this study, we analyze marketing application review times in the US and in the European Union (EU) and clinical development times for novel, i.e., containing new molecular entity, orphan-designated drugs that were approved in the US between 1 June 2020 and 31 May 2023, and their correlation with expedited regulatory programs. Seventy-three marketing applications for novel orphan-designated drugs were approved by the FDA, and 39 also received a positive opinion from the EMA. The marketing application review time by the FDA for the 73 novel orphan-designated drugs approved in the US was 244 days (n = 73, median), and the marketing application review time by the EMA for the 39 drugs that were also approved in the EU was 353 days (n = 39, median). The typical clinical development time for a novel orphan-designated drug was 7.2 years (n = 72).