Orphan Drug Development Research Articles

Using Artificial Intelligence to Advance the Research and Development of Orphan Drugs

While artificial intelligence has successful and innovative applications in common medicine, could its application facilitate research on rare diseases? This study explores the application of artificial intelligence (AI) in orphan drug research, focusing on how AI can address three major barriers: high financial risk, development complexity, and low trialability. This paper begins with an overview of orphan drug development and AI applications, defining key concepts and providing a background on the regulatory framework of and AI’s role in medical research. Next, it examines how AI can lower financial risks by streamlining drug discovery and development processes, analyzing complex data, and predicting outcomes to improve our understanding of rare diseases. This study then explores how AI can enhance clinical trials through simulations and virtual trials, compensating for the limited patient populations available for rare disease research. Finally, it discusses the broader implications of integrating AI in orphan drug development, emphasizing the potential for AI to accelerate drug discovery and improve treatment success rates, and highlights the need for ongoing innovation and regulatory support to maximize the benefits of AI-driven research in healthcare. Based on those results, we discuss the implications for traditional and AI-powered business in the drug industry.

Drivers of Pharmaceutical Compounding: Regional Experience Analysis Using Irkutsk Pharmacy Organisations as a Case Study

INTRODUCTION. National pharmacy compounding is a priority for providing the population with medicinal products, particularly the medicinal products lacking in the Russian Federation. Investigating opportunities to improve the operation of compounding pharmacies in the Russian Federation remains essential, especially in the context of the developing personalised approach to treatment, growing practice of orphan drug development, and import substitution needs.AIM. This study aimed to identify the factors driving the development of compounding pharmacies under the current conditions.MATERIALS AND METHODS. The study focused on the Russian regulatory framework for pharmacy compounding, as well as the range of dosage forms and administration routes of the medicinal products that had been produced and packaged by the compounding pharmacies in Irkutsk in 2021–2023.RESULTS. This study showed a demand for compounded medicinal products among both healthcare providers and patients. These medicinal products covered a traditional range of compounded medicines, including custom formulae, medicines for paediatrics and geriatrics, stock preparations, and pharmacy-packaged items. In 2021–2023, the mean annual production of Irkutsk pharmacy organisations amounted to ~500,000 units of compounded medicinal products, with a variety of doses and dosage forms. The medicinal products were compounded using ~100 different active substances and over 20 approved medicinal products. This study examined the evolution of Russian pharmacy compounding legislation. The key aspects included the establishment of a pharmaceutical quality system for compounded medicinal products, the extension of shelf life for specific dosage forms, and the authorisation to use medicinal products approved in the Eurasian Economic Union in compounding. The study showed that the main factors driving the operation of compounding pharmacies were the ongoing regulatory framework transformation and the transition from standardised treatment to personalised medicine. The main impediments for compounding pharmacies included the lack of state support, the ban on compounding medicinal products produced by pharmaceutical companies, the shortage of skilled staff, the inadequate supply of equipment (first of all, production machinery), the poor availability of active substances and excipients in small packages, and the challenges associated with regulatory control and oversight over the quality of compounded medicinal products.CONCLUSIONS. Further stimulation of the active development of compounding pharmacies requires further investigation into their operation in other regions, which will help to develop legal arrangements for the federal and regional state support of compounding pharmacies, procure up-to-date materials and equipment, and train the staff for compounding pharmacies.

Targeted Therapies, Novel Antibodies, and Immunotherapies in Advanced Non-Small Cell Lung Cancer: Clinical Evidence and Drug Approval Patterns.

Since 2011, the US FDA has approved 30 new drugs for use in advanced non-small cell lung cancer (NSCLC), mainly comprising tyrosine kinase inhibitors and immune checkpoint inhibitors. NSCLC with oncogene driver alterations is amenable to treatment with targeted drugs, usually small-molecule inhibitors. In these cases, the demonstration of high overall response rates, coupled with a lasting duration of response, has allowed for accelerated approval in the United States, based on single-cohort or multicohort trials. Confirmatory clinical evidence was subsequently provided through postmarketing trials. In NSCLC without such driver alterations, regulatory agencies in both the United States and the European Union set clinical evidence expectations that foster the conduct of studies primarily focused on determining survival or event-free survival, based on randomized controlled trial designs. This review analyzes the approval patterns of novel therapeutics for NSCLC with a focus on small-molecule inhibitors that target driver alterations, as well as biologics. The latter include mAbs inhibiting immune checkpoints like PD-(L)1 or cell surface receptors and antibody-drug conjugates, highly potent biologics linked to a cytotoxic compound. The differentiation of NSCLC into oncogene- and non-oncogene-addicted subtypes determines drug development strategies, the extent of the clinical development program, access to orphan drug development incentives, and regulatory approval strategies.

Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis.

Advancements in the molecular genetics of epidermolysis bullosa (EB) and ichthyosis, two rare inherited skin conditions, have enabled the identification of genetic variants that cause these diseases. Alongside technological advancements in genetic medicine, the identification of variants causal of these rare skin conditions has led to preclinical research and the clinical development of various in vivo and ex vivo gene and cell therapies for their treatment. Gene and cell therapies are considered to be the most advanced forms of personalized medicine, demonstrating safety and efficacy in numerous rare diseases. Although the orphan drug development boom has resulted in regulatory approval of multiple gene and cell therapies for various rare conditions, the application of these modalities to rare inherited skin conditions remains limited. Nonetheless, there are successful examples of both in vivo gene therapy- and ex vivo cell therapy-based approaches developed to treat EB and ichthyosis. This review highlights preclinical research and the clinical development of gene and cell therapies for multiple subtypes of these two devastating congenital skin conditions, including a gene therapy recently approved by the U.S. Food and Drug Administration for the treatment of recessive dystrophic EB.

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.

Navigating Intellectual Property Rights: Patentability and Market Exclusivity for Orphan Drugs in The Evolving Landscape

Intellectual property is an intangible property created with the endeavor of human intellect. This concept is formulated for the recognition and value for the inventions, creation of mind, literary or artistic work, designs, and traditional knowledge can be given recognition by providing Intellectual Property Rights. Intellectual property is necessary for the progress and well-being of the humanity so that new inventions and creations, further innovations are encouraged. Patent gives exclusive rights for product and process whereby without the permission of the patent owner invention cannot be commercialized. Patent Law is developed as per the standards prescribed in the TRIPS agreement globally. Patent rights are also granted for drugs as pharmaceutical research is expensive and unpredictable. Pharmaceutical sector protects their inventions by product or process patent rights. Nowadays rare diseases or orphan’s diseases caused by genetic alterations have become a threat for human life. It has become a necessity to develop new drugs or orphan drugs to treat these rare disorders even though it is fewer in numbers. In US and EU once a drug receives the status of orphan is attained the protection is limited to 10 to 12 years of protection from commercialization. In such scenario the companies who have spent millions for their Research and Development will not be in a situation to take back the investment. High revenue or capital investment is hindering the development of orphan drugs. Orphan drug exclusivity with the patent protection will definitely help in encouraging more inventions for rare diseases thereby generating a world without disease. This paper surmises upon the importance of patent to orphan drugs and exclusivity to the manufactures which can be achieved only by appropriate policy decisions and regulatory framework.

Successes and pitfalls in orphan drug development for sickle cell disease

AbstractSickle cell disease (SCD) is a hereditary red cell disorder with a large disease burden at a global level. In the United States and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the United States and Europe over the last 2 decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 ODs for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021), development of 34 of 57 ODs was completed. Four ODs were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared with products targeting disease consequences. Large companies showed a fourfold higher success rate compared with small-medium enterprises. Failures in clinical development were mainly seen in phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study end point, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical end points.

Evaluation of orphan drug therapies and associated monitoring guidelines

Orphan drugs, designed for the treatment and prevention of rare medical conditions known as orphan diseases, are infrequently accessible due to their high costs and limited research. The prevalence of rare diseases varies across countries based on population demographics. The Food and Drug Administration (FDA) has approved over 770 drugs with 77 designations for orphan status. Some of these drugs, often discovered by the pharmaceutical industry, are both highly valuable and expensive. When using orphan drugs, specific parameters need to be monitored. Therapeutic monitoring should align with the patient's physical condition and the severity of the disease. This article aims to comprehensively examine the development of orphan drugs and their monitoring protocols.

Orphan drug development: Challenges, regulation, and success stories

Orphan drug development: Challenges, regulation, and success stories

Orphan drugs approved in Canada: health technology assessment, price negotiation, and government formulary listing

ABSTRACT Background The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have incentives to stimulate the development and marketing of orphan drugs. Health Canada has none. Methods We identified 82 FDA and/or EMA-designated orphan drugs approved by one or both agencies between 2015 and 2020 that were also authorized in Canada. We tracked the drugs through health technology assessments (HTAs), price negotiations, and listing in government drug plans to assess the time required for these processes. Results Median times for HTAs and price negotiations suggest a delay of around a year, but the median wait time between marketing authorization and price negotiation completion was over 18 months. Conclusions Listing of orphan drugs in Canadian government drug plans is closely aligned with reimbursement recommendations and outcomes of price negotiations. Medicines with unsuccessful price negotiations are not listed. However, not all drugs with successful negotiations are listed by all provinces and listing does not guarantee patient access. Compared with Americans and some western Europeans, Canadians with rare disorders continue to suffer from a lack of timely and equitable access to innovative treatments. A comprehensive orphan drug policy would improve Canadians’ access to the innovative treatments on the research horizon.

New orphan disease therapies from the proteome of industrial plasma processing waste- a treatment for aceruloplasminemia

Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation.

User Centered Rare Disease Clinical Trial Knowledge Graph (RCTKG).

Drug development in rare diseases is challenging due to the limited availability of subjects with the diseases and recruiting from a small patient population. The high cost and low success rate of clinical trials motivate deliberate analysis of existing clinical trials to understand status of clinical development of orphan drugs and discover new insight for new trial. In this project, we aim to develop a user centered Rare disease based Clinical Trial Knowledge Graph (RCTKG) to integrate publicly available clinical trial data with rare diseases from the Genetic and Rare Disease (GARD) program in a semantic and standardized form for public use. To better serve and represent the interests of rare disease users, user stories were defined for three types of users, patients, healthcare providers and informaticians, to guide the RCTKG design in supporting the GARD program at NCATS/NIH and the broad clinical/research community in rare diseases.

Implementation status of pharmacological studies in the development of orphan drugs

BackgroundThe nonclinical as well as clinical development of orphan drugs is difficult, owing to unknown pathophysiology and the absence of animal models. Both, the U.S. Food and Drug Administration (FDA) Guidance and European Medicines Agency (EMA) Guidelines, for orphan drug development describe non-clinical studies, but lack specific information, such as animal species and study design. Against this background, this study aimed to elucidate efficient methods for evaluating nonclinical efficacy based on a review report of orphan drugs approved in Japan.ResultsA total of 184 orphan drugs, including 84 anticancer and 100 non-anticancer drugs, approved in Japan from January 2010 to December 2019 were investigated. Some anticancer drugs progressed to clinical development without distinct efficacy data in nonclinical studies. Patient-derived cells have been used for some drugs due to a lack of established cell lines. Cells used for non-clinical studies were devised for drugs indicated for cancers resistant to prior therapies, tumours with specific amino acid mutations in the target molecules, and solid tumours with specific biomarkers. For some non-anticancer drugs, similar disease animal models and normal animals were used for evaluation, since animal models did not exist. Biomarkers have been used specifically for evaluation in normal animals and as endpoints in some clinical trials.ConclusionsIt was possible to evaluate drug efficacy by flexibly designing nonclinical studies according to disease characteristics for potentials orphan drugs. These approaches, which are not described in detail in the EMA Guideline or FDA Guidance, may thus lead to approval.

EVENT STUDY ON DRUG APPROVALS - IMPACT OF ORPHAN DRUG APPROVALS ON THE SHAREHOLDER VALUE OF PHARMACEUTICAL COMPANIES

The pharmaceutical industry is controversially discussed. Nevertheless, there is a con-sensus that the need for new medicines is undeniable. In particular, the treatment of rare diseases with orphan drugs is characterized by a high unmet medical need. Regulatory incentive schemes seek to stimulate orphan drug research and development (R&D). This is also reflected in the increasing approvals during the last two decades. Orphan drugs have gained relevance and become a more attractive business for pharmaceutical compa-nies (Blonda et al., 2021, p. 2)

Challenges in development and management of orphan drugs—a case study of Prussian blue insoluble

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.

Cross-national comparative study of orphan drug policies in Saudi Arabia, the United States, and the European Union

BackgroundRare 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. ObjectiveThe 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. MethodLists 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. ResultA 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. ConclusionFewer 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.

How to START? Four pillars to optimally begin your orphan drug development

Drug development is a complex, resource intensive and long process in any disease area, and developing medicines to treat rare diseases presents even more challenges due to the small patient populations, often limited disease knowledge, heterogeneous clinical manifestations, and disease progression. However, common to all drug development programs is the need to gather as much information as possible on both the disease and the patients’ needs ahead of the development path definition. Here, we propose a checklist named START, a tool that provides an overview of the key pillars to be considered when starting an orphan drug development: STakeholder mapping, Available information on the disease, Resources, and Target patient value profile. This tool helps to build solid foundations of a successful patient-centered medicines development program and guides different types of developers through a set of questions to ask for guidance through the starting phase of a rare disease therapeutic pathway.

Analysis of Incentive Policies and Initiatives on Orphan Drug Development in China: Challenges, Reforms and Implications

ObjectivesRare 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.MethodsPolicies 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.ResultsA 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.ConclusionsOrphan 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.

Regulation of the Launch of Orphan Drugs on the Market of the Eurasian Economic Union as a Mechanism to Increase the Availability of Treatment for Rare Diseases (Review)

Introduction. Providing high-quality, effective and safe drugs intended for the treatment of rare (orphan) diseases among the population of the Member States of the Union is one of the most significant and promising development vectors for manufacturers-developers. Ensuring the availability of medicines (MP) for patients suffering from rare diseases should be regulated by state incentives for the development and launch of orphan drugs on the market by domestic manufacturers through updating and timely updating of regulatory legal acts in the field of drug registration, as well as providing benefits when initiating the registration process.Text. The article assessed the possibilities and prospects for the introduction of orphan drugs into circulation within the framework of the Eurasian Economic Union for domestic manufacturers.Conclusion. A review of the possibilities and prospects for launching orphan drugs for domestic manufacturers indicates the need to develop regulatory and legal regulation of aspects of pharmaceutical development in order to increase the availability of treatment for patients with rare diseases, both at the level of the Russian Federation and within the legal framework of the Eurasian Economic Space.

A Comprehensive Review on the Prospects and Impediments for the Innovation of Orphan Drug Development in India, Australia and the USA

This article highlights the comprehensive review of the prospects and impediments to the innovation of orphan drug development. Orphan medications are used to treat rare diseases. Orphan medication products have been one of the fastest-increasing sectors of drug research. Orphan diseases represent an issue for the world's health sector and a chance to concentrate on innovation. Many nations around the world continue to struggle with rare diseases. Several parties must come up with fresh and innovative solutions to assist the millions of people worldwide who suffer from uncommon diseases. To strategically develop their treatments, pharmaceutical industries concentrate on rare diseases and hinge on novel alliances. To accelerate the research and approval of new drugs, regulatory agencies like US FDA and TGA have developed a wide variety of strategies like financial aid. The process of developing an orphan medicine is the same as for common diseases but requires substantial resources and infrastructure. Several nations including the USA and Australia have implemented orphan drug legislation, which successfully advocated research and development for the creation of novel medication used in the treatment of rare disorders. The purpose of orphan drug regulations was to encourage research and development by providing incentives for the creation of drugs that have the potential to cure millions of individuals suffering from rare illnesses. Prospects related to innovation of orphan drug developments like fee waivers, reimbursements, tax credits and market exclusivity and the majority of the impediments are related to orphan drug pricing patterns, the lack of treatment and diagnosis for rare diseases, regulatory constraints, and the approval process. The individual patient is the major focus of the orphan medication market. For example, the majority of the impediments are related to orphan drug pricing patterns, the lack of treatment and diagnosis for rare diseases, regulatory constraints, and the approval process.