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The interaction between Nitisinone (NTBC) and bovine serum albumin (BSA) as the transport protein in a circulating system was investigated for the first time utilizing various analytical (UV-Vis spectrophotometry, fluorescence spectroscopy, dynamic light scattering, and differential scanning calorimetry) and computational (molecular docking and molecular dynamics simulations) methods. The BSA fluorescence intensity was quenched upon interaction with NTBC, and the quenching mechanism was observed as static. The interaction between NTBC and BSA was examined at 288 K, 298 K, and 308 K where the binding constants were found to be 1.44 × 105 ± 0.22 M-1, 5.18 × 104 ± 0.20 M-1, and 3.02 × 104 ± 0.22 M-1 respectively, suggesting an intermediate binding affinity between NTBC and BSA. Changes in the microenvironment surrounding tryptophan and tyrosine residues of BSA were elucidated using 3-D fluorescence spectroscopy. Thermodynamic studies revealed the calculated values of ΔH =  - 54.34 ± 5 kJ/mol and ΔS =  - 0.0908 ± 0.24 kJ/mol K-1, indicating the involvement of van der Waals forces and hydrogen bonds in the interaction between NTBC and BSA. Moreover, the interaction's spontaneous nature was evidenced by negative ΔG values across all temperatures. Using dynamic light scattering, it was observed that higher NTBC concentrations led to a gradual rise in hydrodynamic diameter and notable aggregation of the NTBC-BSA complex. Moreover, changing signal values and shifted peaks of BSA, NTBC, and complex in differential scanning calorimetry curves, meant there were molecular interactions between the NTBC and BSA. In silico approaches also elucidated how NTBC binds to active sites on BSA, further supporting other findings. Moreover, molecular docking studies offer a more profound insight into the changing dynamics of hydrophobic, hydrogen, and halogen bonding involved in stabilizing the NTBC-BSA complex.

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The recent introduction of the innovative therapy, onasemnogene abeparvovec (Zolgensma®), has revolutionized the spinal muscular atrophy (SMA) therapeutic landscape. Although Zolgensma® therapy has proven to lead to functional improvements in SMA children, some gaps in its safety profile still need to be investigated. To better characterize the Zolgensma® safety profile, we conducted a retrospective observational study, analyzing all the Individual Case Safety Reports (ICSRs) referred to it and collected in the European pharmacovigilance database between 1 January 2019 and 22 September 2023. We found 661 ICSRs related to Zolgensma®, with a growing trend in the annual reporting. The majority of the reports were sent by healthcare professionals and referred to infant females. In more than 90% of the cases, Zolgensma® was the only reported suspected drug. Out of a total of 2744 reported ADRs, increased hepatic enzymes, pyrexia, vomiting, and thrombocytopenia were the most commonly reported adverse reactions. Of these adverse reactions (ADRs), 56.9% were serious, causing or prolonging the patient's hospitalization. A total of 39 ICSRs related to cases with a fatal outcome. Alterations in the heart rhythm, acute hepatic failure, and hepatic cytolysis emerged among the cardiac and hepatic disorders, respectively.

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Introduction: Clinical trials location is determined by many factors, including the availability of patient populations, regulatory environment, scientific expertise, and cost considerations. In clinical drug development of amyotrophic lateral sclerosis (ALS), where genetic differences have been described and may be related to geographic setting, this could have implications for the clinical interpretation of results in underrepresented geographic settings. Objective: The aim of this study was to review country participation in ALS clinical research based on available data from clinical trial registries and databases. Methods: We performed a scoping review with available information about clinical trials on ALS in ClinicalTrials.gov (CT), EU clinical trials register (EudraCT), WHO International Clinical Trials Registry Platform (ICTRP) and Web of Science (WOS). Inclusion criteria were clinical trials in phase 2 and 3 to treat ALS, recruiting or active not recruiting, from 23/06/2018 to 23/06/2023. Results: The total number of clinical trials identified were 188; 54 studies in CT, 38 in EudraCT, 47 in ICTRP and 49 in WOS. We identified 77 clinical trials after deleting duplicates and applying exclusion criteria. The countries with most studies conducted were the US with 35 studies (10.9%), followed by the United Kingdom, Belgium, France and Germany with 21 studies each one of them (6.5%). Conclusion: The data obtained in our review showed a non-homogeneous distribution in clinical trials at the international level, which may influence the interpretation of the results obtained.

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Policy Points The Orphan Drug Act (ODA) was the result of patient advocacy and by many measures has been strikingly successful. However, approximately 95% of the more than 7,000 known rare diseases still have no US Food and Drug Administration-approved treatment. The ODA's success led to sustained criticism of high drug prices, often for products that have orphan drug indications. Critics misconstrue the ODA's intent and propose reducing its incentives instead of pursuing policies focused on addressing broader prescription drug price challenges that exist in both the orphan and nonorphan drug market. Patients and their families will continue to defend the purpose and integrity of the ODA and to drive investments into rare disease research and clinical development.

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The pricing and reimbursement of orphan drugs are related to the accessibility of patients,and are of great significance to the prevention and guarantee of rare diseases.European countries have formed special standards and paths for health technology evaluation,and established special payment funds and diversified risk-sharing agreements,which have effectively improved the accessibility of orphan drugs.Based on this,it selected typical European countries to compare the orphan drug pricing and reimbursement methods.Then,it put forward some suggestions"building orphan drug health technology evaluation accelerated program,exploring the health of orphan drug classification security mechanism,and attaining supply incentives and development incentives through orphan drug pricing and adjustment",to optimize the basis for the orphan drug market access mechanism to provide reference.

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Because genetic alterations including mutations, overexpression, translocations, and dysregulation of protein kinases are involved in the pathogenesis of many illnesses, this enzyme family is the target of many drug discovery programs worldwide. The FDA has approved 80 small molecule protein kinase inhibitors with 77 drugs orally bioavailable. The data indicate that 69 of these medicinals are approved for the management of neoplasms including solid tumors such as breast and lung cancer as well as non-solid tumors such as leukemia. Moreover, the remaining 11 drugs target non-neoplastic diseases including psoriasis, rheumatoid arthritis, and ulcerative colitis. The cost of drugs was obtained from www.pharmacychecker.com using the FDA label to determine the dosage and number of tablets required per day. This methodology excludes any private or governmental insurance coverage, which would cover the entire cost or more likely a fraction of the stated price. The average monthly cost for the treatment of neoplastic diseases was $17,900 with a price of $44,000 for futibatinib (used to treat cholangiocarcinomas with FGFR2 fusions) and minimum of $5100 for binimetinib (melanoma). The average monthly cost for the treatment of non-neoplastic diseases was $6800 with a maximum of $17,000 for belumosudil (graft vs. host disease) and a minimum of $200 for netarsudil eye drops (glaucoma). There is a negative correlation of the cost of the drugs and the incidence of the targeted disease. Many of these agents are or were designated as orphan drugs meaning that there are fewer than 200,000 potential patients in the United States.

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Quinacrine, the main antimalarial drug during World War II, has had a chequered history that included the successful repurposing as an intrapleural sclerosant for the treatment of malignant pleural effusions, a non-surgical method of female sterilisation, and the use as an immunomodulatory drug in lupus erythematosus. While no longer used for these former indications, quinacrine (re)emerged as an indispensable second-line drug for the treatment of nitroimidazole-refractory Giardia duodenalis infections, and thus depicts an indispensable "orphan drug".

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Las enfermedades raras son aquellas que tienen baja prevalencia y que, por lo tanto, el desarrollo de medicamentos para tratarlas no es rentable para las empresas farmacéuticas debido a la baja demanda. A pesar de que ya se cuenta con diferentes políticas públicas alrededor del mundo para incentivar a las industrias farmacéuticas a investigar estos medicamentos, conocidos como medicamentos huérfanos, su desarrollo conlleva muchas dificultades en las evaluaciones clínicas y el precio final para el público es muy elevado. Si bien en años recientes se ha planteado el uso de tecnología de impresión en 3D para producir estos medicamentos o incluso recurrir a otros medicamentos previamente aprobados para tratar enfermedades raras, existe un historial de mal uso de las legislaciones por parte de las empresas con el fin de generar beneficios comerciales, por lo que estas políticas deben reforzarse para que cumplan su propósito; ayudar a una población muy vulnerable. El objetivo del presente texto es exponer los resultados de una revisión documental sobre el panorama científico y sociopolítico en el que se encuentra el problema de las enfermedades raras y los medicamentos huérfanos, así como las posibles soluciones que se están desplegando para abordarlo. Deriva de un estudio que se desarrolla en el momento actual en la Universidad Autónoma Metropolitana, de Ciudad de México.

The strange illnesses are those that have low prevalence and that, therefore, the development of medications to treat them is not profitable for the pharmaceutical companies due to the drop demands. Although it is already counted with different political public around the world to motivate to the pharmaceutical industries to investigate these medications, well-known as orphan medications, their development bears many difficulties in the clinical evaluations and the final price for the public it is very high. Although in recent years he/she has thought about the use of impression technology in 3D to produce these medications or even to appeal to other medications previously approved to treat strange illnesses, a record of wrong use of the legislations exists on the part of the companies with the purpose of generating commercial benefits, for what these politicians should be reinforced so that they complete its purpose; to help a very vulnerable population. The objective of the present text is to expose the results of a documental revision on the scientific and sociopolitical panorama in which is the problem of the strange illnesses and the orphan medications, as well as the possible solutions that they are spreading to approach it. It derives of a study that is developed in the current moment in the Metropolitan Autonomous University, of Mexico City.

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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.

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This analysis explores the impact of the FDA's orphan drug designation (ODD) on biotechnology companies' share prices in the short and long term. Our analysis reveals that there is a significant immediate increase in share prices following an ODD announcement, which underscores its potential as a robust indicator of short-term investor returns. However, the long-term findings present a more complex picture, with a sustained impact within the biotech industry but a significant depreciation against the broader market over time. These findings elucidate the nuanced effects of regulatory milestones on the financial performance of pharmaceutical companies and highlight the need for more comprehensive studies to further unravel these complex dynamics.

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Prussian blue insoluble (PB) is an antidote for decorporation of radioactive and non-radioactive isotopes of thallium and cesium. Its dosage in the form of capsules, Radiogardase-Cs, is a United States Food and Drug Administration approved formulation since 2003. In India and many other countries, this drug is not available and in case of requirement it is imported from US or Europe. The author has worked extensively to make PB capsules available in India. The drug was recently approved by the Indian drug regulatory agency, Central Drugs Standard Control Organisation and is now available commercially in India. However this drug needs special attention as it is an orphan drug with limited requirement. The post-approval phase of this drug poses a different set of challenges and the author has highlighted some key issues with probable approaches for post-approval product management.

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INTRODUCTION: Hereditary factor X deficiency is a rare bleeding disorder, with limited treatment options. This paper describes the approach to pre-clinical development and characterization of a high-purity plasma-derived factor X concentrate, to achieve orphan drug marketing authorization for the treatment of hereditary factor X deficiency. METHODS: A chromatographic process was developed, to purify factor X from human plasma for fractionation. The product was characterized using in vitro, in vivo and ex vivo tests for potency, purity, thrombogenicity, immunogenicity, toxicity and stability. RESULTS: The production process complied with good pharmaceutical manufacturing practice. It achieved 6000-fold purification and 100-fold concentration of the factor X protein compared to human plasma. The factor X protein was 94%-96% pure. Other residual plasma proteins were well below levels in plasma, minimizing potential interference in hemostasis after therapeutic administration. Effective virus-reduction during manufacture, and the absence of thrombogenicity, toxicity and immunogenic potential were confirmed, addressing the main safety concerns historically associated with plasma-derived therapeutics. The freeze-dried product remained stable between +2°C and +30°C for at least three years. After reconstitution with water for injections, the factor X activity was maintained for at least 48 h at +18°C to +22°C. CONCLUSION: Targeted pre-clinical development of the first highly-purified concentrate to treat hereditary factor X deficiency is described. Following international guidelines for nonclinical safety testing, particular strategies were adopted for unmodified products derived from human blood plasma. This approach may also be relevant to the development of other ultra-orphan medicinal products.

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The European Medicines Agency (EMA) fosters access to innovative medicines through accelerated procedures and flexibility in the authorization requirements for diseases with unmet medical needs, such as many rare diseases as well as oncological diseases. However, the resulting increase of medicines being marketed with conditional authorizations and in exceptional circumstances has lead to higher clinical uncertainty about their efficacy and safety than when the standard authorizations are applied. This uncertainty has significant implications for clinical practice and the negotiation of pricing and reimbursement, particularly as high prices are based on assumptions of high value, supported by regulatory prioritization. The burden of clinical development is often shifted towards public healthcare systems, resulting in increased spending budgets and opportunity costs. Effective management of uncertainty, through appropriate testing and evaluation, and fair reflection of costs and risks in prices, is crucial. However, it is important not to sacrifice essential elements of evidence-based healthcare for the sake of access to new treatments. Balancing sensitive and rational access to new treatments, ensuring their safety, efficacy, and affordability to healthcare systems requires thoughtful decision-making. Ultimately, a responsible approach to timely access to innovative medicines that balances the needs of patients with healthcare systems' concerns is necessary. This approach emphasizes the importance of evidence-based decision-making and fair pricing and reimbursement.

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For the development of a test treatment or drug product, it is necessary to conduct composite hypothesis testing to test for effectiveness and safety simultaneously, since some approved drug products have been recalled due to safety concerns. One of the major issues in conducting a composite hypothesis testing for effectiveness and safety is the requirement of a huge sample size to achieve the desired power for detecting clinically meaningful differences in both safety and effectiveness. Situation can be much difficult in orphan drug development. In this article, a generalized two-stage innovative approach to test for effectiveness and safety simultaneously is proposed. Additionally, to alleviate the requirement of a large randomized clinical trial (RCT) and revealing effectiveness, real-world data is suggested to use in conjunction with RCT data for orphan drug development. The proposed approach can help investigators test for effectiveness and safety at the same time without worrying about the sample size. It also helps reduce the probability of approving a drug product with safety concerns.

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Background: Rare diseases are chronic, serious, and life-threatening conditions that have not received sufficient attention from drug developers due to their rarity. Policies have been implemented to encourage research and incentivize the development of orphan drugs. However, the implementation of these policies has been inconsistent worldwide. Objective: The primary aim of this study was to compare orphan drug policies in the United States, Europe, and Saudi Arabia (SA) and assess their impact on the number of approved indications. Method: Lists of all drugs granted orphan designations and authorized for marketing in the United States, European Union, and SA were extracted using orphan drug lists available in regulatory body databases. The availability of these drugs, regarding their approval for orphan indication and designation, was assessed and classified using Anatomical Therapeutic Chemical codes. Result: A total of 792 orphan drug designations with at least one authorized indication were identified in this study. Of these, 92% were designated by the Food and Drug Administration (FDA), and 27% were designated by the European Medicine Agency (EMA). The FDA, EMA, and Saudi Food and Drug Authority approved 753, 435, and 253 orphan drugs, respectively. Conclusion: Fewer orphan drug approvals were found in SA than in the United States and Europe. This highlights the need to focus on rare diseases and orphan drugs and for policies to be created in SA to attract pharmaceutical markets and fulfill unmet orphan drug approval needs.

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There are more than 7 000 rare diseases and approximately 475 million individuals with rare diseases globally, with children accounting for two-thirds of this population. Due to a relatively small patient population and limited financial resources allocated for drug research and development in pharmaceutical enterprises, there are still no drugs approved for the treatment of several thousands of these rare diseases. At present, there are no drugs for 95% of the patients with rare diseases, and consequently, the therapeutic drugs for rare diseases have been designated as orphan drugs. In order to guide pharmaceutical enterprises to strengthen the research and development of orphan drugs, various nations have enacted the acts for rare disease drugs, promoted and simplified the patent application process for orphan drugs, and provided scientific recommendations and guidance for the research and development of orphan drugs. Since there is a relatively high incidence rate of rare diseases in children, this article reviews the latest research on pharmacotherapy for children with rare diseases.

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BACKGROUND: In the United States (US) and in Europe, cystic fibrosis (CF) qualifies as a rare disease, thus positioning the field to benefit from regulatory incentives provided by orphan drug designation (ODD) to boost pharmaceutical research and development. In this study, we analyzed the pool of products for the treatment of CF that received such incentives from the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) over the past two decades. We describe the characteristics and trends in ODDs over time and explore factors that might be determinants of successful drug development. METHODS: We collected the products that received the ODD from the registries of the FDA and the EMA from 2000 to 2021, characterizing their nature, development stage, and type of sponsor. We categorized the study drugs according to the therapeutic target addressed and described trends of drug development over the study period. A logistic regression analysis was done to assess how ODD characteristics were associated with the approval for market authorization. RESULTS: From 2000-2021, 107 ODDs were collectively granted by the FDA and the EMA for products developed for the treatment of CF. Although the trends of the number of ODDs granted remained stable over time, those targeting the CF basic protein defect increased from 6 out of 54 (11.1%) in the first half of the study period up to 20 out of 54 (37.7%) in the second half, while those treating symptoms decreased from 48/54 (88.9%) to 33/53 (62.3%). Overall, 10 products obtained marketing approval: 7 in both the US and Europe, 3 only in Europe. All the approved ODDs were chemical products for chronic use. No statistically significant difference was found across the examinated variables, but we observed possible drivers of successful drug development for ODDs targeting CFTR, as well as for those with active substances previously marketed, and for those developed by large companies and companies with experience in developing orphan drugs. By contrast, our findings suggest that financial issues most hamper the development of ODDs sponsored by small-medium enterprises. CONCLUSIONS: Although ODDs for treating infection and other CF sequelae accounted for the majority, we observed a shift of ODDs toward mechanism-based products over the study period. In line with other rare diseases, we found that approximately 1/10 ODDs for CF reached the status of marketing approval. Advances in disease genetics paved the way for a shift in CF drug development; however, we described how the convergence of pharmaceutical technology, the financial environment, and the regulatory ecosystem played a crucial role in successful marketing authorization in CF.

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OBJECTIVES: Rare diseases are a global public health issue with a more pressing situation in China. Unfortunately, the relevant research and development in this country are still in its infancy, leading to limited drug accessibility. In view of this, the Chinese government has taken a series of countermeasures to promote orphan drug R&D in recent years, which has presented encouraging results. This paper aims to review incentive policies and funding initiatives formulated by the Chinese government and examine their implications on orphan drug R&D. METHODS: Policies targeting orphan drug R&D during 2012-2022 were retrieved from the relevant official websites, categorized into different themes and analyzed for the contents. Data on government funding, drug approval, clinical trial approval and orphan drug designation were collected through internet search to analyze the implications of those incentive policies and initiatives on orphan drug R&D in China. RESULTS: A total of 20 relevant policy documents were identified and five major themes were revealed through content analysis, including national strategy, expedited approval, safety and efficacy requirements, data protection and technical support. The government input in orphan drug R&D has witnessed a steady annual increase. Driven by those incentives, the numbers of orphan drugs approved for marketing and drug candidates entering clinical studies are increasing year by year, and more domestic pharmaceutical companies are actively involved in the R&D of orphan drugs. CONCLUSIONS: Orphan drug development in China is growing rapidly under the stimulation of incentive regulatory policies and more investment in researches. China is working toward a more standardized and comprehensive rare disease ecosystem. However, there are still some challenges, such as the lack of sufficient financial support and the call for systematic legislation on rare diseases, to be addressed for future success.

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Background: Failing to provide social support to cover healthcare costs for rare diseases would lead to great financial distress for the patients and their families. People from countries without a well-developed health safety-net are particularly vulnerable. Existing literature on rare diseases in China focuses on the unmet needs for care of the patients and the difficulties of caregivers and physicians. Very few studies examine the state of social safety-net, the unresolved issues and whether the current localized arrangements are sufficient. This study aimed to gain in-depth knowledge of the current policy system and make sense of the local varieties, which would be essential for developing strategies for future policy changes. Methods: This systematic policy review focuses on the provincial level policies on subsidizing the healthcare costs for people with rare diseases in China. The cut-off point for the policies was March 19, 2022. The researchers coded the healthcare cost reimbursement policies and identified the different provincial level models based on the usage of reimbursement components in each provinces reimbursement arrangements. Results: 257 documents were collected. Five provincial level models (Process I, II, III, IV and V) have been identified with the five components across the country: Basic Medical Insurance for Outpatient Special Diseases (OSD), Catastrophic Medical Insurance for Rare Diseases (CMIRD), Medical Assistance for Rare Diseases (MARD), Special Fund for Rare Diseases (SFRD) and Mutual Medical Fund (MMF). The local health safety-net in each region is a combination of one or more of the five processes. Regions vary greatly in their rare diseases coverage and reimbursement policies. Conclusion: In China, the provincial health authorities have developed some level of social protection for rare disease patients. However, there are still gaps regarding coverage and regional inequality; and there is room for a more integrated healthcare safety-net for people suffering from rare diseases at the national level.

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Most rare diseases(orphan diseases) still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to expedite the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. There are several strategies for the development of orphan drugs for rare genetic disorders including protein replacement therapies, small molecule therapies(e.g. substrate reduction therapy, chemical chaperone therapy, cofactor therapy, expression modification therapy, read through therapy), monoclonal antibodies, antisense oligonucleotide, small interfering RNA or exon skipping therapies, gene replacement and direct genome editing therapies, mRNA therapy, and cell therapy as well as drug repurposing. Each strategy has its strength and limitations for orphan drug development. Furthermore, numerous hurdles are present in clinical trials in rare genetic disease because of difficulty in patient recruitment, unknown molecular physiology and natural history of the disease, ethical concerns about pediatric patients, and regulatory challenges. To address these barriers, the rare genetic diseases community including academic institutions, industry, patient advocacy groups, foundations, payers and government regulatory and research organizations, must be engaged as a partnership in discussions about the issues.