Treatment Of Rare Diseases Research Articles

A study of Regulatory aspects on Registration of Orphan Drugs in US and EU

The medicinal products used in the treatment, prevention, and diagnosis of rare disease like Myoclonus disease, Huntington's disease, Tourette syndrome are called as Orphan drugs, when it comes to defining rare disease and approving them as “Orphan designations.” The Criteria varies from country to country based on severity, prevalence of the disease and alternative therapies available.
 In 1983, the US government brought the Orphan Drug Act to facilitate and encourage pharmaceutical company to develop orphan drugs without which they show reduced interest in the research and development of these drugs. The reason being their low market value and sales of orphan a drug is so miniscule that it will not enable them to even recover a fraction of the investment made in them.
 After the inception of “Orphan Drugs” act 4500 orphan designations have been approved, 730 biologic drug products have been approved to treat 250 Orphan designations.
 In the past decades, orphan designations have doubled in number when compared to its preceding decade but only 1/5th of the developed medications to treat them and received regulatory approval.

Improving Access to Rare Disease Treatments: Subsidy, Pricing, and Payment Schemes

There are more than 7,000 known rare diseases, but pharmaceutical manufacturers developed treatments for only 500 of them. To improve the availability and accessibility of treatments for rare diseases, governments have introduced several programs including subsidies, exogenous pricing, and outcome-based payment schemes in recent years. What kind of subsidy programs and pricing mechanisms can improve patient access? Inspired by various pilot programs, we present a multistage game theoretic model to analyze different subsidy schemes proposed for rare diseases. In addition to the traditional setting in which the manufacturer sets the price, we consider an “exogenous pricing scheme” under which an independent consortium sets the price. We also examine an outcome-based payment scheme, which offers the drug for free if it is not efficacious. We formulate a four-stage Stackelberg game to determine whether it is optimal to subsidize the pharmaceutical manufacturer, the patients, or both. Our results offer several insights. First, we find that government subsidies are crucial to entice new drug development for rare diseases. Also, we find that the pricing scheme matters: The exogenous pricing scheme can improve patient welfare, but it reduces the manufacturer’s expected profit. We find that this result is robust even when an outcome-based payment scheme is used. This paper was accepted by Jayashankar Swaminathan, operations management. Funding: This work was supported by the Dutch Science Foundation [Nederlandse Organisatie voor Wetenschappelijk Onderzoek VENI Talent Scheme]. Supplemental Material: The data files and online appendices are available at https://doi.org/10.1287/mnsc.2022.4634 .

HPR48 Reimbursement Policies Regarding Rare Diseases in Central and Eastern European Countries

The purpose of this study is to gather information on reimbursement policies regarding rare diseases in Central and Eastern European (CEE) countries. The aim is also to demonstrate whether there are separate reimbursement requirements for therapies used in the treatment of rare diseases.

Regulatory Framework for Drug Development in Rare Diseases.

Drug development is a highly regulated industry. Therapeutic options for rare diseases must meet the same high standards for the demonstration of safety and efficacy as do those for more common diseases. The approval of the Orphan Drug Act in 1983 has resulted in many more resources for preclinical research, the standardization of patient registries, and the use of real-world data, among other measures, that, along with the advances in drug development, has resulted in the approval of therapies for some of the most unusual diseases. Increased attention to the diagnosis and treatment of rare diseases has also accelerated the development of gene therapies that may offer significant amelioration and even cures for such diseases in the near future. Rare diseases disproportionately affect children, with severe and debilitating effects. Few effective treatments are available for most rare diseases. To avoid the unnecessary waste of data collected in studies of these patients, and to promote efficient drug development, there is a growing collaboration among patient communities, investigators, clinicians, sponsors, and regulatory authorities. All interested parties are working together to identify the most appropriate research questions and move quickly to make available safe and effective treatments. This article is a survey of the most commonly used regulatory remedies that have been put in place to serve as a framework for drug development in rare diseases.

Recent Advances in Lipid Nanoparticles for Delivery of mRNA.

Messenger RNA (mRNA), which is composed of ribonucleotides that carry genetic information and direct protein synthesis, is transcribed from a strand of DNA as a template. On this basis, mRNA technology can take advantage of the body's own translation system to express proteins with multiple functions for the treatment of various diseases. Due to the advancement of mRNA synthesis and purification, modification and sequence optimization technologies, and the emerging lipid nanomaterials and other delivery systems, mRNA therapeutic regimens are becoming clinically feasible and exhibit significant reliability in mRNA stability, translation efficiency, and controlled immunogenicity. Lipid nanoparticles (LNPs), currently the leading non-viral delivery vehicles, have made many exciting advances in clinical translation as part of the COVID-19 vaccines and therefore have the potential to accelerate the clinical translation of gene drugs. Additionally, due to their small size, biocompatibility, and biodegradability, LNPs can effectively deliver nucleic acids into cells, which is particularly important for the current mRNA regimens. Therefore, the cutting-edge LNP@mRNA regimens hold great promise for cancer vaccines, infectious disease prevention, protein replacement therapy, gene editing, and rare disease treatment. To shed more lights on LNP@mRNA, this paper mainly discusses the rational of choosing LNPs as the non-viral vectors to deliver mRNA, the general rules for mRNA optimization and LNP preparation, and the various parameters affecting the delivery efficiency of LNP@mRNA, and finally summarizes the current research status as well as the current challenges. The latest research progress of LNPs in the treatment of other diseases such as oncological, cardiovascular, and infectious diseases is also given. Finally, the future applications and perspectives for LNP@mRNA are generally introduced.

HTA36 Value of Real-World Evidence for Treatments for Ultra Orphan or Rare Diseases: Lessons and Insights From Review of NICE Highly Specialized Technology Assessment Reports (2016-2022)

HTA36 Value of Real-World Evidence for Treatments for Ultra Orphan or Rare Diseases: Lessons and Insights From Review of NICE Highly Specialized Technology Assessment Reports (2016-2022)

OP38 Managed (Early) Access In England: The ‘Ins And Outs’

IntroductionManaged access approaches have been used by The National Institute for Health and Care Excellence (NICE) in partnership with NHS England since 2015. The Cancer Drugs Fund is an exemplar of this approach which enables earlier patient access to promising new treatments while further real-world data is collected to address evidential uncertainties. Increasingly, this approach is being applied to rare diseases and other conditions to address unmet clinical need with extensive involvement from patient organizations and clinicians.MethodsAll Managed Access Agreements (MAAs) in development or published in England were reviewed to present data on the number of technologies (i) entering, (ii) in active monitoring, and (iii) exiting managed access, for both cancer and other disease areas.ResultsAfter six years since the first MAA (at December 2021), over 73,000 patients have benefited from earlier access to promising new treatments for cancer, genetic and rare diseases, including cystic fibrosis, spinal muscular atrophy and sickle cell disease via managed access. Fifty-eight technologies were commissioned via managed access: thirty technologies in active data collection, eleven technologies being re-evaluated, and seventeen technologies have exited managed access. Patient and clinical engagement have been essential to the successful real-world data collections delivered and underway.ConclusionsManaged access is an approach for providing earlier patient access to promising new technologies that would not otherwise be recommended for use in England. The approach to managed access in England is maturing at the same time the volume of topics entering and exiting managed access in England is expected to grow throughout 2022 with the introduction of the Innovative Medicines Fund.

HTA260 Informal Carer Disutility: How Many Caregivers Are Captured in Cost-Utility Analyses of Treatments for Rare Diseases Submitted for NICE Highly Specialised Technology Appraisals?

The latest National Institute for Health and Care Excellence (NICE) health technology assessment (HTA) methods permit the inclusion of caregiver disutility data, where appropriate, in technology appraisals. In the context of rare diseases, the impact on the health-related quality of life of a patients’ parents, partner, and other family members can be substantial. This research reviewed how carer disutility and the number of impacted carers have been considered within previous NICE highly specialised technology (HST) appraisals.

CO81 A Bayesian Approach to Increase Evidence of Effectiveness in Health Economic Evaluations of Treatments for Rare Diseases

CO81 A Bayesian Approach to Increase Evidence of Effectiveness in Health Economic Evaluations of Treatments for Rare Diseases

EE341 Economic Evaluations of Technologies for the Treatment of Rare Diseases in Latin America and Southeast Asia: A Scoping Review

Rare diseases, due to their low prevalence, are often overlooked. However, their economic burden can be very significant in low and middle-income countries due to their high-cost treatment. This scenario poses challenges for the elaboration of health technology assessments due to the quantity and quality of information on these diseases and their therapeutic options. The aim of this scoping review is to map out how the economic evaluations of technologies for the treatment of rare diseases are being carried out, in terms of data sources, methods, perspective of analysis and costs used in Latin America and Southeast Asia.

Overview of Clinical Pharmacology Packages of New Drug Applications Approved for the Treatment of Rare Diseases.

There are more than 7000 rare diseases affecting approximately 30million people in the United States. More than 90% of these diseases lack approved therapies. Several challenges face the development of "orphan drugs", such as the small populations of patients, high development costs, and long development timelines. This study evaluates clinical pharmacology assessments conducted during the development of drugs to treat rare diseases approved by the United States Food and Drug Administrationin 2020 and 2021. Thirty-nine new drug applications (NDAs) have been identified and the associated regulatory reviews, approved labels, and approval letters were reviewed. Approximately, 95%, 74%, and 77% of these submissions contained at least one type of drug-drug interaction, the effect of organ impairment (hepatic and renal) on drug exposure, and QT liability assessment, respectively. Modeling and simulation approaches were utilized to address many clinical pharmacology questions, with population pharmacokineticanalyses used extensively in the evaluation of the effect of organ impairment on drug exposure and with physiologically based pharmacokinetic analysesused mainly in assessing drug interaction risks. In general, the clinical pharmacology packages in the NDAs of orphan drugs are not optimal and more work is needed to obtain a complete clinical pharmacology package at the time of initial approval to ensure the safe and effective use of these drugs across the spectrum of the target patient population. This study provides insights into the clinical pharmacology studies needed for drugs to treat rare diseases and would help both the regulators and drug developers to identify challenges and opportunities in conducting clinical pharmacology assessments for drugs developed to treat rare diseases.

Scaling genetic resources: New paradigms for diagnosis and treatment of rare genetic disease.

Development of genetic tests for rare genetic diseases has traditionally focused on individual diseases. Similarly, development of new therapies occurred one disease at a time. With >10,000 rare genetic diseases, this approach is not feasible. Diagnosis of genetic disorders has already transcended old paradigms as whole exome and genome sequencing have allowed expedient interrogation of all relevant genes in a single test. The growth of newborn screening has allowed identification of diseases in presymptomatic babies. Similarly, the ability to develop therapies is rapidly expanding due to technologies that leverage platform technology that address multiple diseases. However, movement from the basic science laboratory to clinical trials is still hampered by a regulatory system rooted in traditional trial design, requiring a fresh assessment of safe ways to obtain approval for new drugs. Ultimately, the number of nucleic acid-based therapies will challenge the ability of clinics focused on rare diseases to deliver them safely with appropriate evaluation and long-term follow-up. This manuscript summarizes discussions arising from a recent National Institutes of Health conference on nucleic acid therapy, with a focus on scaling technologies for diagnosis of rare disorders and provision of therapies across the age and disease spectrum.

New treatments for rare bone diseases: hypophosphatemic rickets/osteomalacia.

Phosphorus is one of the most abundant minerals in the human body; it is required to maintain bone integrity and mineralization, in addition to other biological processes. Phosphorus is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and fibroblast growth factor 23 (FGF-23) in a complex set of processes that occur in the gut, skeleton, and kidneys. Different molecular mechanisms - overproduction of FGF-23 by tumors responsible for oncogenic osteomalacia, generation of an FGF-23 mutant that is resistant to cleavage by enzymes, and impaired FGF-23 degradation due to a reduction in or loss of the PHEX gene - can lead to FGF-23-stimulating activity and the consequent waste of urinary phosphate and low levels of 1,25(OH)2D3. Conventional treatment consists of multiple daily doses of oral phosphate salts and vitamin D analogs, which may improve radiographic rickets but do not normalize growth. Complications of the conventional long-term treatment consist of hypercalcemia, hypercalciuria, nephrolithiasis, nephrocalcinosis, impaired renal function, and potentially chronic kidney disease. Recently, burosumab, an antibody against FGF-23, was approved as a novel therapy for children and adults with X-linked hypophosphatemia and patients with tumor-induced osteomalacia. Burosumab showed good performance in different trials in children and adults. It increased and sustained the serum phosphorus levels, decreased the rickets severity and pain scores, and improved mineralization. It offers a new perspective on the treatment of chronic and disabling diseases.

A survey of registered pharmacological clinical trials on rare neurological diseases in children in 2010-2020.

To clarify the current state of methodology of clinical trials for rare neurological diseases in children, and to provide a basis for the further optimization of the trial design. Data of clinical trials for the rare neurological diseases with childhood onset (searched through https://rarediseases.info.nih.gov/diseases and www.Orpha.net) registered on the Clinicaltrils.gov from January 2010 to June 2020 was collected. Analysis on the methodology of the clinical trials were performed, focusing on initiator of the studies, multi or single research center, study design, sample size, and the endpoint using in the trial. A total of 162 clinical trials were included, covering only 7.3% (61/835) of rare neurological diseases in children. 101 (62.3%) were initiated by pharmaceutical companies, and 61 (37.7%) by investigators. Most (95.4%) of global multicenter studies were initiated by pharmaceutical companies, whereas most (70.0%) of single-center studies were initiated by investigators (χ 2 = 61.635, P < 0.001). Of the 162 trials, 74 (45.7%) were open-label single-arm trials, 68 (42.0%) were randomized double-blind parallel controlled trials (RCT), 12 (7.4%) were randomized crossover trials. Most of RCTs (73.5%) and 54.1% of open-label single-arm trials were initiated by pharmaceutical companies. The proportion of RCTs in clinical trials for diseases with a prevalence of ≥1/10,000 (62.5%) was higher than that in diseases with prevalence ≤1/1,000,000 (12.0%) or 1/1,000,000~1/10,000 (43.1%) (χ 2 = 14.790, P = 0.001). The median expected sample size of the studies was 34 (4-500). 132 (132/162, 81.5%) studies enrolled fewer than 100 cases. Diseases with a prevalence of ≥1/10,000 had significantly larger sample sizes than other prevalence classes (P < 0.001, P = 0.003). There were few clinical trials targeting on treatment of rare neurological diseases in children. Trials on rare diseases used fewer participants, and high-quality randomized controlled trials were less common. It is necessary to conduct global multicenter recruitment and choose optimal study designs to improve the level of evidence in clinical trials on rare diseases.

Diagnosis and treatment of rare pediatric neurogenetic diseases enter disease modifying therapy era

随着诊断能力和多学科管理水平的提升，分子生物学和基因工程技术的快速发展，儿童神经遗传罕见病的诊治模式正在发生改变，由基于症状学和综合征诊治的传统模式逐渐进入到靶向病因和致病机制的疾病修正治疗模式。酶替代治疗、造血干细胞移植、反义寡核苷酸技术、基因治疗等技术的临床应用，改变了部分儿童神经遗传罕见病无药可治或严重致残致死的现状。因此，儿童神经专科医生需要改变诊疗的理念和模式，掌握和应用这些新技术，领先的研究团队应积极开展相关机制研究和临床试验，推进创新疗法的研发。.

The Challenge for Orphan Drugs Remains: Three Case Studies Demonstrating the Impact of Changes to NICE Methods and Processes and Alternative Mechanisms to Value Orphan Products.

The National Institute for Health and Care Excellence (NICE) is responsible for ensuring that patients in England and Wales can access clinically and cost-effective treatments. However, NICE's processes pose significant reimbursement challenges for treatments for rare diseases. While some orphan medicines have been appraised via the highly specialised technology route, most are appraised via the single technology appraisal programme, a route that is expected to be increasingly used given new more restrictive highly specialised technology criteria. This often results in delays to access owing to differences in applicable thresholds and the single technology appraisal approach being ill-equipped to deal with the inevitable decision uncertainty. NICE recently published their updated methods and process manual, which includes a new severity-of-disease modifier and an instruction to be more flexible when considering uncertainty in rare diseases. However, as the threshold gap between the single technology appraisal and highly specialised technology programmes remains, it is unlikely that these changes alone will address the problem. We explored the potential impact of quality-adjusted life-year weights in decision making. We explored the impact of NICE's new severity-of-disease modifier weighting and two alternative methods (the use of alternative quality-adjusted life-year weights and the fair rate of return), using three recent single technology appraisals of orphan medicines (caplacizumab, teduglutide and pirfenidone for mild idiopathic pulmonary fibrosis). Our results suggest NICE's severity-of-disease modifier would not have affected the recommendations. Using alternative methods, based upon achievement of an incremental cost-effectiveness ratio below standard thresholds, patients could have received access to caplacizumab approximately 5 months earlier, and the appraisals for teduglutide and pirfenidone would have resulted in a positive recommendation following appraisal consultation meeting 1 when neither of these products was available over 5 years from the initial submission. Ultimately, moving from a restrictive end-of-life modifier to one based on disease severity is a more equitable approach likely to benefit many therapies, including orphan products. However, NICE's single technology appraisal updates are unlikely to result in faster reimbursement of orphan medicines, nor will they address concerns around market access for orphan medicines in the UK.

Improving Understanding and Treatment of Rare Diseases through Real-World Data

Improving Understanding and Treatment of Rare Diseases through Real-World Data

Design of SaCas9-HF for In Vivo Gene Therapy.

Genome alteration results in several diseases for which therapeutics are limited. Gene editing provides a strong and potential alternative for the treatment of rare and genetic diseases. CRISPR-Cas9-based system is now being envisaged as a potential tool for the cure of genetic diseases. The RNA-guided nuclease, SaCas9 enzyme, along with its HF versions is widely employed for in vivo gene editing because of its small size and high efficiency. The current work summarizes the widely used and improved methods for in vivo manipulation of genes. The potential of CRISPR-Cas9-based systems can be harnessed to treat genetic diseases and holds great promise for therapeutic interventions in gene therapy. The in vivo gene editing poses a caveat in the form of delivery systems, the tissue in question, and several other factors. This work describes the methods which have been optimized to offer high efficiency, delivery, and gene editing in vivo.

Rare Types of Spontaneous Liver Ruptures During Pregnancy

This literature review is devoted to the problem of spontaneous liver ruptures in pregnant women. Its goal was to raise awareness among physicians as one of the methods to improve the early diagnosis of the disease, as well as to consider the role of the hepatological surgeon in the surgical treatment of rare obstetric diseases. The main links of the pathogenesis of liver ruptures were considered, the problem of high maternal and perinatal mortality was disclosed. Based on the literature data, the most optimal obstetric and surgical treatment and diagnostic tactics for managing pregnant women with spontaneous liver ruptures were determined.

Research advances in treatment methods and drug development for rare diseases.

As the incidence of rare diseases increases each year, the total number of rare disease patients worldwide is nearly 400 million. Orphan medications are drugs used to treat rare diseases. Orphan drugs, however, are rare and patients often struggle to utilize them and expensive medications during treatment. Orphan drugs have been the focus of new drug research and development for both domestic and international pharmaceutical companies as a result of the substantial investment being made in the field of rare diseases. Clinical breakthroughs have been made in every field, from traditional antibodies and small molecule drugs to gene therapy, stem cell therapy and small nucleic acid drugs. We here review the therapeutic means of rare diseases and drug development of rare diseases to show the progress of treatment of rare diseases in order to provide a reference for clinical use and new drug development of rare diseases in China.