Orphan Drugs For Rare Diseases Research Articles

Development of orphan drugs for rare diseases.

Most rare diseases (orphan diseases) still lack approved treatment options despite major advances in research providing the necessary tools to understand their molecular basis and legislation providing regulatory and economic incentives to expedite the development of specific therapies. Addressing this translational gap is a multifaceted challenge, a key aspect of which is the selection of an optimal therapeutic modality to translate advances in rare disease knowledge to potential medicines known as orphan drugs. There are several strategies for developing orphan drugs for rare genetic disorders, including protein replacement therapies, small-molecule therapies (e.g., substrate reduction, chemical chaperone, cofactor, expression modification, and read-through therapies), monoclonal antibodies, antisense oligonucleotides, small interfering RNA or exon skipping therapies, gene replacement and direct genome-editing therapies, mRNA therapy, cell therapy, and drug repurposing. Each strategy has its own strengths and limitations in orphan drug development. Furthermore, numerous hurdles are present in clinical trials of rare genetic diseases because of difficulty with patient recruitment, unknown molecular physiology, the natural history of the disease, ethical concerns regarding 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 become engaged in discussions about these issues.

Issues, Challenges and Opportunities for Economic Evaluations of Orphan Drugs in Rare Diseases: An Umbrella Review.

There are significant challenges when obtaining clinical and economic evidence for health technology assessments of rare diseases. Many of them have been highlighted in previous systematic reviews but they have not been summarised in a comprehensive manner. For all stakeholders working with rare diseases, it is important to be aware and understand these issues. The objective of this review is to identify the main challenges for the economic evaluation of orphan drugs in rare diseases. An umbrella review of systematic reviews of economic studies concerned with orphan and ultra-orphan drugs was conducted. Studies that were not systematic reviews, or on advanced therapeutic medicinal products, personalised medicines or other interventions that were not considered orphan drugs were excluded. The database searches included publications from 2010 to 2023, and were conducted in MEDLINE, EMBASE and the Cochrane library using filters for systematic reviews, and economic evaluations and models. These filters were combined with search terms for rare diseases and orphan drugs. A hand search supplemented the literature searches. The findings were reported by a compliant Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Two hundred and eighty-two records were identified from the literature searches, of which 64 were duplicates, whereas five reviews were identified from the hand search. A total of 36 reviews were included after screening against inclusion/exclusion criteria, 35 from literature searches and one from hand searching. Of those studies 1, 27 and 8 were low, moderate and high quality, respectively. The reviews highlight the scarcity of evidence for health economic parameters, for example, clinical effectiveness, costs, quality of life and the natural history of disease. Health economic evaluations such as cost-effectiveness and budget-impact analyses were scarce, and generally low-to-moderate quality. The causes were limited health economic parameters, together with publications bias, especially for cost-effectiveness analyses. The results highlighted issues around a considerable paucity of evidence for economic evaluations and few cost-effectiveness analyses, supporting the notion that a paucity of evidence makes economic evaluations of rare diseases more challenging compared with more prevalent diseases. Furthermore, we provide recommendations for more sustainable approaches in economic evaluations of rare diseases.

Recent landscape and trends for industry-sponsored pediatric clinical trials in China from 2013 to 2022.

Pediatric medication is a challenging issue globally. Promoting trials of medications for children and implementing measures to encourage innovation for addressing unmet medical and health needs are important. To explore the recent landscape of pediatric clinical trials of new investigational drugs conducted by pharmaceutical enterprises in China from 2013 to 2022 to provide insight into pediatric drug development in the pharmaceutical industry and regulatory policy formulation. We performed a cross-sectional observational investigation of pediatric clinical trials registered from January 1, 2013, to December 31, 2022, on the Registration and Information Disclosure Platform for Drug Clinical Trials, the official registration platform established in 2013 for trials of new investigational drugs initiated by biopharmaceutical enterprises. Trials that included pediatric participants (under 18 years old) were retrieved, and their relevant characteristics were extracted and analyzed. In total, 895 pediatric clinical trials were collected, accounting for 5.1% of the total registered clinical trials initiated prior to January 1, 2023. The overall average annual growth rate for the number of pediatric clinical trials was 12% (P < 0.001). Phase III trials accounted for the highest proportion (49.1%, 439). Of the 895 trials included, 736 (82.2%) were domestic trials, and 159 (17.8%) were international multicenter trials. In terms of tested drugs, investigations of biological products accounted for the largest proportion of trials (67.4%, 603). Among pediatric clinical trials, studies of vaccines accounted for the largest proportion of trials (41.0%, 367), followed by trials for rare diseases (17.2%, 154). Furthermore, geographical distribution analysis revealed that the largest and smallest numbers of trials were conducted in North China (35.7%, 320) and Northeast China (0.8%, 7), respectively. The growth trends for industry-sponsored clinical trials involving children illustrate the progress and increasing capability of pediatric drug development achieved in China since 2013. Current challenges and potential areas of focus for policymakers and stakeholders include investigating orphan drugs for rare diseases according to the unique epidemiological characteristics of Chinese children, expanding the scope of pediatric clinical trials, and improving the uneven geographical distribution of leading research centers.

Exploring the Potential Challenges for Developing Generic Orphan Drugs for Rare Diseases: A Survey of US and European Markets

ObjectivesThe US Food and Drug Administration in 1983 and the European Union’s European Medicines Agency in 2000 implemented the orphan drug development program for rare diseases. The study aimed to find the potential challenges encountered by generic companies in developing generics for rare diseases. MethodsWe performed a thematic analysis, which consists of qualitative and quantitative research. For data analysis of approved orphan drugs, we used statistical methods, and for the industrial case study, we selected 14 generic companies and conducted semistructured interviews related to 10 critical areas of drug development. ResultsThe orphan drug approvals were classified into 4 categories: the number of orphan approvals, pediatric claims, formulation, and therapeutic areas. We analyzed the approvals from 2001 to 2021; the Food and Drug Administration approved 815 drugs and European Medicines Agency approved 258 drugs. The pediatric orphan approvals were analyzed from 2010 to 2021; the average percentage of orphan drugs claim pediatric exclusivity during this period was found to be 31.8%. In formulation, we found the highest percentage of drugs belong to small molecules at 71%. In the therapeutic class, oncology drugs have a majority of approvals at 25%. The industrial case study responses revealed that the major challenge for drug development is the complexity of the disease at 21%, followed by the limited market at 17%. ConclusionsThere is a high need for generic orphan drugs in the developing countries. The generic companies can use the opportunities provided by health authorities for the benefit of both the company and the patient perspective.

The challenges of pharmacoepidemiology of orphan drugs in rare diseases

Large electronic health records database available at a national level offer great opportunity for research in rare diseases and orphan drugs. Methods and data used in pharmacoepidemiology present a great potential for epidemiology, drug utilization studies, drug safety, drug effectiveness and pharmacoeconomics. This review presents the different sources of data in Europe, with a special focus on the French situation, with the recent implementation of SNDS (système national des données de santé [French national health data wharehouse]). Some examples are given. Development of rigorous and innovative methods must be encouraged in the future.

Eficácia, segurança e aspectos regulatórios dos medicamentos órfãos para doenças raras: o caso Zolgensma®

Objetivo: discutir o processo regulatório de medicamentos para doenças raras no Brasil, com base no caso Zolgensma®, e avaliar criticamente as evidências disponíveis até o momento sobre a eficácia e a segurança do Zolgensma® no tratamento da atrofia muscular espinhal (AME). Metodologia: estudo descritivo realizado no Núcleo de Avaliação de Tecnologias em Saúde do Hospital Sírio-Libanês (NATS-HSL) em junho de 2019. Resultados: em abril de 2019, o uso do Zolgensma® para AME foi regulamentado nos Estados Unidos com base em dois estudos clínicos abertos (sem mascaramento), sem grupo comparador paralelo (e, portanto, não randomizados). Essas limitações metodológicas aumentam a incerteza nos resultados encontrados. A Agência Nacional de Vigilância Sanitária (Anvisa) aprovou estratégias para regulamentar o processo e os prazos de análise das submissões de registro de novos medicamentos para doenças raras, caso do Zolgensma®. Conclusão: faz-se necessário ampliar o debate em torno do processo de regulamentação e de incorporação de medicamentos órfãos para doenças raras no Brasil. O debate deve incluir as evidências relacionadas aos efeitos – benefícios e riscos – desses medicamentos, e maior clareza nos critérios para concessão de registro e recomendação de incorporação em sistemas de saúde.

Using a stated preference discrete choice experiment to assess societal value from the perspective of patients with rare diseases in Italy

BackgroundDecision makers have huge problems when attempting to attribute social value to the improvements achieved by new drugs, especially when considering the use of orphan drugs for rare diseases. We present the results of a pilot study aimed to investigate patient preferences regarding public funding for drugs used to treat rare diseases.MethodsAn online questionnaire was used as a discrete choice experiment (DCE) survey to explore the preferences of patients with cystic fibrosis and haemophilia in Italy. The questionnaire focused on relevant issues that were defined in a review of the literature. A conditional logistic model showed preferences for specific attributes.ResultsA total of 54 questionnaires (20% response rate) were completed. The issues that received the greatest attention were improvement in health, treatment cost and value for money. However, disease severity and the availability of other treatments were important social values that could not be ignored.ConclusionsThe findings presented here provide evidence as to what patients with cystic fibrosis or haemophilia think are the most important considerations on which to base decisions in health technology scenarios, and regarding the priorities for funding.

Network established to collaborate on diagnosis and treatment of rare diseases in China: A strategic alliance backed by tiered healthcare is the key to the future.

Rare diseases are an important public health issue and a challenge to healthcare. Over the past few years, China has actively worked to improv rare disease care and orphan drugs for rare diseases, but many challenges still remain. In order to further promote measures to combat rare diseases, the "National Network to Collaborate on Diagnosis and Treatment of Rare Diseases" was established by the National Health Commission of the People's Republic of China on February 12, 2019. This network for collaboration consists of 324 hospitals nationwide, and its aim is to set up a practical mechanism for an effective alliance by different tiers of the healthcare system. The strategy for collaboration includes six programs: i) to establish a mechanism for collaboration, ii) to implement standards of care, iii) to enhance quality control, iv) to ensure the supply of drugs, v) to set up a registry, and vi) to enhance clinical research. These programs will play a pivotal role in combating rare diseases in the future and eventually achieving the goal of creating a proper and consistent mechanism to treat and manage rare diseases.

Rare disease prevention and treatment: the need for a level playing field.

Pharmacogenetic tests are being used increasingly to prevent rare and potentially life-threatening adverse drug reactions. For many tests, however, cost-effectiveness is hard to demonstrate, and with the exception of a few cases, widespread implementation remains a distant prospect. Many orphan drugs for rare diseases are also not cost effective but are nonetheless normally reimbursed. In this article, we argue that the health technology assessment of pharmacogenetic tests aimed to prevent rare but severe adverse drug reactions should be on a level playing field with orphan drugs. This is supported by a number of arguments, concerning the severity, rarity and iatrogenic nature of adverse drug reactions, the distribution of benefits and costs and societal preference towards prevention over treatment.

Societal Preferences For Funding Orphan Drugs In The UK: A Person Trade Off Study

Orphan drugs for rare diseases tend to be high cost treatments. Current practice by UK health technology assessment organisations suggests that rarity in itself may be justification for exceeding standard thresholds of cost effectiveness. This study aims to examine whether or not there is support among the UK general public for prioritising treatments of patients with rare diseases. Using PTO design, the preferences of 1000 people for allocating fixed funds between a drug treatment for patients with rare versus common diseases were determined. Further samples (n=500 each) were asked to allocate funding between a drug treatment for rare disease and i) increase waiting list or ii) reduced NHS staffing. Costs and treatment benefits were varied in each scenario. The general population generally preferred to distribute funds equally between patients with a common disease and those with a rare disease. Distribution of preferences for treating patients with: (i) rare, (ii) common disease, or (iii) equal allocation of funds, were: 32%, 14%, 54%. When cost of rare disease treatment increased, we observed less support for treating rare disease patients (19%, 54%, 27%). However, this was reversed if the drug also offered greater treatment benefits (71%, 50%, 44%). When asked to trade off between the alternative framing scenarios, respondents preferred to not increase waiting lists (45%, 9%, 46%, equal cost scenario) to fund treatments for rare diseases. However, respondents preferred replacing vacant NHS staff posts when treatment cost increased (31.2%, 34.4%, 34.4%). There is little support among the UK general public for prioritising treatments on the basis of disease rarity alone; although there was a preference observed when treatment benefit was greater, despite the increase in cost. This suggests that there may be a preference for funding high cost treatments for rare disease patients but only if treatment benefit was high.

The (Ir)relevance of Group Size in Health Care Priority Setting: A Reply to Juth

How to handle orphan drugs for rare diseases is a pressing problem in current health-care. Due to the group size of patients affecting the cost of treatment, they risk being disadvantaged in relation to existing cost-effectiveness thresholds. In an article by Niklas Juth it has been argued that it is irrelevant to take indirectly operative factors like group size into account since such a compensation would risk discounting the use of cost, a relevant factor, altogether. In this article we analyze Juth’s argument and observe that we already do compensate for indirectly operative factors, both outside and within cost-effectiveness evaluations, for formal equality reasons. Based on this we argue that we have reason to set cost-effectiveness thresholds to integrate equity concerns also including formal equality considerations. We find no reason not to compensate for group size to the extent we already compensate for other factors. Moreover, groups size implying a systematic disadvantage also on a global scale, i.e. taking different aspects of the health condition of patients suffering from rare diseases into account, will provide strong reason for why group size is indeed relevant to compensate for (if anything).

The availability and affordability of orphan drugs for rare diseases in China.

BackgroundOrphan drugs are intended to treat, prevent or diagnose rare diseases. In recent years, China healthcare policy makers and patients have become increasingly concerned about orphan drug issues. However, very few studies have assessed the availability and affordability of orphan drugs for rare diseases in China. The aim of this study was to provide an overview of the availability and affordability of orphan drugs in China and to make suggestions to improve patient access to orphan drugs.MethodsTwo components of the availability of orphan drugs were examined. Market availability was assessed by the extent to which orphan drugs were marketed in China with a comparison to orphan drugs in international markets, such as the U.S., EU and Japan. We conducted surveys and collected data from 24 tertiary public hospitals in China to measure hospital-level availability of orphan drugs. The affordability of orphan drugs was calculated using hospital dispensary prices and was expressed as days of average daily income required for the cost of a course of treatment. Affordability was also analyzed under the Chinese basic medical insurance system.ResultsOrphan drugs approved in the U.S., EU and Japan had 37.8 %, 24.6 % and 52.4 % market availability in China, respectively. Median availability of 31 orphan drugs surveyed at the 24 tertiary public hospitals was 20.8 % (very low). Within a periodic treatment course, the average treatment cost of 23 orphan drugs is approximately 4, 843. 5 USD, which equates to 505.6 days of per capita net income for an urban resident with a middle income (187.4 days for a high-income urban resident) or 1,582.8 days’s income for a rural resident with a middle income (657.2 days for a high-income rural resident). Except for homoharringtonine, 22 orphan drugs for 14 rare diseases were unaffordable for the most of residents in China. With 5 % out-of-pocket expenses, only three generics could be afforded by middle-income residents, whereas seven drugs for high-income urban residents.ConclusionsThe Chinese government can take more responsibility for improving the availability and affordability of orphan drugs through setting up incentive policies and public platforms for sharing of orphan drug information. Control of the high price of orphan drugs, combined with a joint funding model from both government and private enterprise can efficiently reduce the economic burden of affected patients in China.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0392-4) contains supplementary material, which is available to authorized users.

An Overview of the Orphan Medicines Market in Turkey

BackgroundThe health policies of many countries and regions have already defined orphan drugs for rare diseases. Although there is no official definition of orphan drugs in Turkey, all orphan drugs are covered by reimbursement, regardless of their market authorization status. Thus, a pharmacoeconomic analysis does not have to be presented to the Social Security Institution (Sosyal Güvenlik Kurumu) for reimbursement decisions on orphan drugs. ObjectiveThe aim of this study was to shed light on the use of orphan drugs to aid classifications of rare diseases and assessments of orphan drugs in Turkey. MethodsData for sales of authorized orphan drugs and all other drugs were extracted from the IMS Turkey for 2008, 2009, and 2010. Nonauthorized orphan drug sales data were extracted from records of the Turkish Pharmacists’ Association for the same years. Government prices were obtained from the Sosyal Güvenlik Kurumu. ResultsThe European Medicines Agency has classified more than 60 orphan drugs for rare diseases. Of these, 50 entered the Turkish market in recent years, half of which were authorized. The remaining drugs were imported through the early access procedure. Antineoplastic agents accounted for the largest percentage of orphan drugs, with 58% of the total market share. In 2010, there were 18 such agents in use, at a cost of €120 million. ConclusionsAlthough legislation is not yet in place for orphan drugs in Turkey, recognized pricing and reimbursement policies are in operation. This situation facilitates an analysis of orphan drug prices and reimbursement policies in Turkey.

PSY16 - Payer Management And Pricing Dynamics For Non-Oncology Pharmacy Benefit Orphan Drugs For Rare Diseases In The United States Launched 2004-2014

PSY16 - Payer Management And Pricing Dynamics For Non-Oncology Pharmacy Benefit Orphan Drugs For Rare Diseases In The United States Launched 2004-2014

The Calculation of Molecular Structural Similarity: Principles and Practice

Measures of structural similarity play an important role in chemoinformatics for applications such as similarity searching, database clustering and molecular diversity analysis. A similarity measure comprises three components: a structure representation; a weighting scheme; and a similarity coefficient. The paper introduces these components and describes methods for comparing different measures. The use of similarity measures in chemoinformatics research is illustrated by recent projects in the author's laboratory on: the interactions between a weighting scheme and a similarity coefficient; the design of comparative studies of similarity measures; the use of 2D fingerprints for scaffold-hopping searches; and the registration of orphan drugs for rare diseases.

Quantitative Analysis to Guide Orphan Drug Development

The development of orphan drugs for rare diseases has made impressive strides in the past 10 years. There has been a surge in orphan drug designations, but new drug approvals have not kept up. This article presents a three-pronged hierarchical strategy for quantitative analysis of data at the descriptive, mechanistic, and systems levels of the biological system that could represent a standardized and rational approach to orphan drug development. Examples are provided to illustrate the concept.

Orphan Drugs for Rare Diseases: Grounds for Special Status

Abstract Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I‐III Regulatory, Quality, Manufacturing Postmarketing Phase IV In the European Union, rare diseases are defined as life‐threatening or chronically debilitating diseases that occur at such a low prevalence that special initiatives are needed to address them. There is a continuing debate about the special registration, pricing, and reimbursement status that orphan drugs enjoy in many countries. Therefore, the aim of this commentary is to examine the arguments that argue in favor of granting special status to orphan drugs. We conclude that monetary arguments must be carefully balanced with social and ethical motives to avoid unfair treatment of patients with a rare disease. Also, we provide an overview of how the special status of orphan drugs can be put into practice with respect to registration, pricing and reimbursement. Adopting this special status in practice is possible, but not straightforward. Hence we propose a number of policy recommendations, such as risk sharing arrangements, to take account of the special status of orphan drugs.

Orphan Drugs for Rare Diseases

Orphan drugs are intended for diseases with a very low prevalence, and many countries have implemented legislation to support market access of orphan drugs. We argue that it is time to revisit the special market access status of orphan drugs. Indeed, evidence suggests that there is no societal preference for treating rare diseases. Although society appears to assign a greater value to severity of disease, this criterion is equally relevant to many common diseases. Furthermore, the criterion of equity in access to treatment, which underpins orphan drug legislation, puts more value on health improvement in rare diseases than in common diseases and implies that population health is not maximized. Finally, incentives for the development, pricing and reimbursement of orphan drugs have created market failures, including monopolistic prices and the artificial creation of rare diseases. We argue that, instead of awarding special market access status to orphan drugs, there is scope to optimize research and development (R&D) of orphan drugs and to control prices of orphan drugs by means of, for example, patent auctions, advance purchase commitments, pay-as-you-go schemes and dose-modification studies. Governments should consider carefully the right incentive strategy for R&D of orphan drugs in rare diseases.

European solidarity is changing the face of rare diseases

Almost 1 year ago, a BBC fi lm about a teenager called Louisa Ball briefl y captured the imagination of the British public. Called The Real Sleeping Beauty, the fi lm told the story of Louisa and her family as they dealt with the consequences of Louisa’s Kleine-Levin syndrome: a vanishingly rare neurological disorder that causes prolonged episodes of sleep, lasting, in most cases, between 1 and 3 weeks. By focusing on the eff ect that the disorder had on one family, the fi lm makers were able to capture the sense of frustration and isolation caused by a disease about which so little is known that it is impossible to estimate just how rare it is, and, for a short time at least, raise its profi le. But equally, the understandable temptation to focus on the extraordinary stories of individual patients with specifi c rare diseases can obscure a wider truth: that although individuals with any particular rare neurological diseases are—to state the obvious—rare, patients with rare neurological diseases are in fact numerous if they are taken together. And there can be strength in numbers. The European Union defi nes a rare disease as one that aff ects no more than fi ve people in 10 000, although most rare diseases have a prevalence closer to the one in 10 000 mark. However, put all of the estimated 5000–8000 distinct rare diseases together, and between 6% and 8% of the population will experience a rare disease during their lifetime. “If you

PHP7 Orphan Drugs for Rare Diseases in the European Union: Bridging the Gap between Drug Development and Unmet Medical Needs?

PHP7 Orphan Drugs for Rare Diseases in the European Union: Bridging the Gap between Drug Development and Unmet Medical Needs?