Orphan Drug Development Research Articles

Letter from the Editors

Last year we successfully introduced a new journal: The Journal of Rare Diseases and Orphan Drugs (JRDOD) is a peer-reviewed open-access medical journal that publishes original research, reviews, case reports, and letters covering a broad field of its specialty. We intend to publish articles stimulating to read, educate, and inform readers with the most up-to-date research in genetics, rare diseases, and new orphan drug development in different stages of clinical trials. Journal topics are centered on patients living with undiagnosed rare diseases, the importance of a diagnosis, individual approaches to treatments. We hope that this journal will increase awareness of many difficult to diagnosed and treat medical conditions.

Development and Use of Gene Therapy Orphan Drugs-Ethical Needs for a Broader Cooperation Between the Pharmaceutical Industry and Society.

Gene therapy orphan medicinal products constitute a unique group of new drugs which in case of hereditary diseases are usually administered only once at an early age, in the hope to provide sufficient gene product to last for the entire life of the patients. The combination of an exceptionally large single payment and the life-long clinical follow-up needed for understanding the long-term benefits and safety of gene therapy, represent new types of scientific, financial, social and ethical challenges for the pharmaceutical industry, regulators and society. With special consideration of the uniqueness and importance of gene therapy, the authors propose a three points plan for a close cooperation between the pharmaceutical industry and society to develop orphan gene therapy. (1) In fully transparent health technology negotiations a close and long-lasting, contractually fixed cooperation should be established between the manufacturers and local health-care stakeholders for sharing the medical and scientific benefits, the financial risks as well as the burdens of the post-authorization clinical and regulatory development. (2) The parties should agree on a fair, locally affordable drug price without the usually very high premium price calculated to compensate for the low number of patients. In case of high manufacturing costs, the companies should offer prolonged, 15–20 years long payment by installment with risk-sharing, especially considering that the late outcome of the treatment is unknown. Society should assist scientifically and financially organizing a specific patient registry, treatment in specialized hospitals and adequate long-term follow-up of patients, the coordinated management of financial transactions related to the risk sharing program. (3) The post-authorization treatment and prolonged observation of additional new cases coordinated by society should provide real world data needed for the modern complex regulatory evaluation of gene therapy products by the competent authorities. We assume that fair sharing of the benefits and risks as well as a well-organized cooperation of society with the industry in collecting real world evidence might result in better drug evaluation and improved accessibility due to lower prices. The outlined concept might support gene therapy more efficiently than the presently requested outstandingly high prices.

Letter of Editor

We are pleased to announce a new addition to SciencePower Publishing House, LLC journal collection: Journal of Rare Diseases and Orphan Drugs (JRDOD), a peer-reviewed open-access medical journal that publishes original research, reviews, case reports, and letters covering a broad field of its specialty.
 Why do we need a new journal? Because the science moves fast all around the Planet and new technology opened new horizons for the prevention and treatment of rare and genetically based disorders.
 Rare disease and disorders often need a multidisciplinary care team, deep knowledge of healthcare providers, and extensive patients’ and patient families’ support. It may take years until a disease is recognized and/or diagnosed. Spreading knowledge about rare disease conditions among biomedical scientists and physicians from the different subspecialty fields including genetics, pediatrics, cardiology, pulmonary, gastroenterology, rheumatology, neurology, dietary science, and other related disciplines is one of the goals of this journal, which we will be widely advertised within the medical community.
 Patients with special conditions could be “Rare, but Not Alone” and we want to add our voice to those patient advocacies.
 We also want to spread knowledge about orphan drugs. Well known fact that an orphan drug is a medication (pharmaceutical) that remains underdeveloped due to the lack of a company to find the drug profitable because the numbers of patients, who will benefit from the treatment, are small and so the potential market for new drugs to treat these rare diseases is also small. This situation fortunately somewhat changed in 1983, when the U.S. Congress passed the Orphan Drug Act. It facilitated and charged the orphan drugs' developmental landscape. Nowadays the FDA established the Office of Orphan Product Development (OOPD) to help with the development of orphan drugs (and other medical products for rare disorders), including FDA support for research grants.
 The international medical community has recognized the need to increase research and development of orphan drugs. We hope that our journal will be a small contribution to the promotion of wellbeing of people with rare disease conditions.
 Our publisher motto is "Superbi progressu aspiramus ad maximum" (the proud aspire to great promise).
 Please, consider submitting your next manuscript to the Journal of Rare Diseases and Orphan Drugs.

Opportunities and barriers for innovation and entrepreneurship in orphan drug development

Orphan diseases pose both a challenge to the global medical community and an opportunity for it to focus on global peace engineering and innovation. Where, any single orphan disease is rare, when taken as a whole they affect more than 250 million people throughout the world. This number by comparison is larger than the global number of cancer and AIDS patients. We add to the literature by mapping the available knowledge in the orphan drug development field and exploring the tensions at play for innovation and entrepreneurship in this field. We further add to the literature by providing a framework to review this field based on social systems theory. Our review highlights the gaps in research and proposes a path forward in understanding of and learning from the orphan drug development field.

Quantitative retrospective natural history modeling for orphan drug development.

The natural history of most rare diseases is incompletely understood and usually relies on studies with low level of evidence. Consistent with the goals for future research of rare disease research set by the International Rare Diseases Research Consortium in 2017, the purpose of this paper is to review the recently developed method of quantitative retrospective natural history modeling (QUARNAM) and to illustrate its usefulness through didactically selected analyses examples in an overall population of 849 patients worldwide with seven (ultra-) rare neurogenetic disorders. A quantitative understanding of the natural history of the disease is fundamental for the development of specific interventions and counseling afflicted families. QUARNAM has a similar relationship to a published case study as a meta-analysis has to an individual published study. QUARNAM relies on sophisticated statistical analyses of published case reports focusing on four research questions: How long does it take to make the diagnosis? How long do patients live? Which factors predict disease severity (eg, genotypes, signs/symptoms, biomarkers)? Where can patients be recruited for studies? Useful statistical techniques include Kaplan-Meier estimates, cluster analysis, regression techniques, binary decisions trees, word clouds, and geographic mapping. In comparison to other natural history study methods (prospective studies or retrospective studies such as chart reviews), QUARNAM can provide fast information on hard clinical endpoints (ie, survival, diagnostic delay) with a lower effort. The choice of method for a particular drug development program may be driven by the research question and may encompass combinatory approaches.

Orphan Drug Development in Cardiovascular Medicine.

Orphan Drug Development in Cardiovascular Medicine.

Determining the Topic Evolution and Sentiment Polarity for Albinism in a Chinese Online Health Community: Machine Learning and Social Network Analysis.

BackgroundThere are more than 6000 rare diseases in existence today, with the number of patients with these conditions rapidly increasing. Most research to date has focused on the diagnosis, treatment, and development of orphan drugs, while few studies have examined the topics and emotions expressed by patients living with rare diseases on social media platforms, especially in online health communities (OHCs).ObjectiveThis study aimed to determine the topic categorizations and sentiment polarity for albinism in a Chinese OHC, Baidu Tieba, using multiple methods. The OHC was deeply mined using topic mining, social network analysis, and sentiment polarity analysis. Through these methods, we determined the current situation of community construction, identifying the ongoing needs and problems experienced by people with albinism in their daily lives.MethodsWe used the albinism community on the Baidu Tieba platform as the data source in this study. Term frequency–inverse document frequency, latent dirichlet allocation models, and naive Bayes were employed to mine the various topic categories. Social network analysis, which was completed using the Gephi tool, was employed to analyze the evolution of the albinism community. Sentiment polarity analysis was performed using a long short-term memory algorithm.ResultsWe identified 8 main topics discussed in the community: daily sharing, family, interpersonal communication, social life and security, medical care, occupation and education, beauty, and self-care. Among these topics, daily sharing represented the largest proportion of the discussions. From 2012 to 2019, the average degree and clustering coefficient of the albinism community continued to decline, while the network center transferred from core communities to core users. A total of 68.43% of the corpus was emotional, with 35.88% being positive and 32.55% negative. There were statistically significant differences in the distribution of sentiment polarity between topics (P<.001). Negative emotions were twice as high as positive emotions in the social life and security topic.ConclusionsThe study reveals insights into the emotions expressed by people with albinism in the Chinese OHC, Baidu Tieba, providing health care practitioners with greater appreciation of the current emotional support needed by patients and the patient experience. Current OHCs do not exert enough influence due to limited effective organization and development. Health care sectors should take greater advantage of OHCs to support vulnerable patients with rare diseases to meet their evidence-based needs.

Access and Unmet Needs of Orphan Drugs in 194 Countries and 6 Areas: A Global Policy Review With Content Analysis.

Three hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs. Pharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis. One hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita= $10 875 vs $3950, P < .001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient= 0.57, P < .001). Globally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs.

ND1 ACCESS AND UNMET NEEDS OF ORPHAN DRUGS IN 194 COUNTRIES AND SIX AREAS: A GLOBAL POLICY REVIEW WITH CONTENT ANALYSIS

300 million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment when compared to other patients. Policies that optimise development, licensing, pricing, and reimbursement of orphan drugs are instrumental in addressing this neglected but significant burden. An overview of global orphan drug policies is proposed to inform policy development.

Orphan drug development and epilepsy with Ana Mingorance

Learn more from Ana Mingorance of the Loulou Foundation about the current status of drug development in epilepsy. In this Expert Perspective, Ana describes how the landscape of this field has changed, with new developments in technology as well as challenges associated with the regulatory approval of new drugs leading to a shift in focus to developing novel drugs to treat orphan epilepsy indications.

Regulatory Strategies for Orphan Drug Development in Canada – Australia

Canada, Australia have evaluated how their governments can facilitate the improvement of scientific merchandise to deal with uncommon issues. Each has hooked up programs and/or policies to help the improvement of merchandise to deal with unmet clinical wishes in small populations and to ensure their citizens get right of entry to such important medicines. Australia’s software, initiated in 1998, changed into evolved in collaboration with the United States Food and Drug Administration to facilitate the alternate and evaluation of facts on orphan tablets. Canada’s evaluation, posted in 1996, determined that a standalone orphan drug software became now not presently warranted, as present regulation and regulatory policies permit early get right of entry to critical medicinal merchandise. The incidences of such diseases were increasing at an extra pace than the speed with which drugs are researched and developed to treat such diseases. One of the fundamental motives is that the pharmaceutical enterprise is not very keen to research the improvement of orphan capsules as those capsules do no longer capture a larger market. This is the modern situation in-spite of the various incentives furnished in the orphan drug act. However, in this article, we’ve tried to focus on present regulatory framework, Current principles of rare sickness, Regulatory Challenges for Rare Disease Drug Development, Regulatory Integrated approach for the improvement and approval of orphan drugs in Canada &amp; Australia.

Pediatric Orphan Drug Indications: 2010-2018.

Orphan drug development is crucial for children, who are disproportionately affected by rare diseases. Data are lacking on the number, nature, and benefit of recently approved pediatric orphan indications. We classified the 402 orphan indications the US Food and Drug Administration approved between 2010 and 2018 as "pediatric" if they were approved for children only or targeted pediatric diseases. We determined the number of unique diseases targeted by pediatric orphan indications and calculated the proportion that were for (1) novel drugs, (2) non-novel drugs approved to treat ≥1 common disease, and (3) non-novel drugs approved only to treat rare diseases. Among pediatric orphan indications eligible for US Food and Drug Administration breakthrough designation (granted to drugs potentially representing major therapeutic advances), we calculated the proportion receiving this designation. Of the 402 orphan indications, 136 (33.8%) were pediatric. These 136 indications targeted 87 unique diseases; 21 diseases were targeted by ≥1 indication. Of the 136 pediatric orphan indications, 60 (44.1%) were for novel drugs, 45 (33.1%) were for non-novel drugs approved to treat ≥1 common disease, and 31 (22.8%) were for non-novel drugs approved only to treat rare diseases. Among 97 indications eligible for breakthrough designation, 20 (20.6%) received this designation. Recent orphan drug development has increased the availability of treatments for pediatric rare diseases. Most pediatric orphan indications expanded use of existing drugs, and many targeted the same disease. Some indications may represent breakthroughs, but substantial unmet need for treatments remains for most pediatric rare diseases.

Orphan drug designation in Europe: A booster for the research and development of drugs in rare diseases

The research and drug development process in rare diseases is challenging in addition to those for common diseases. To stimulate its development, the orphan drug designation (ODD) was introduced in in European Union in 2000. In the present paper, we describe the main characteristics of ODD in European Union in particular the requested criteria for ODD, the overview of the general procedure and the main incentives for Sponsors and finally the predicted factors related to successful development and marketing approval of orphan drugs after designation. In accordance with regulation, an application for ODD must be submitted to European Agency including a scientific part based on relevant scientific literature related to the condition and results on experimental studies with the specific product (and clinical studies if available). Three following criteria are a central position in this application: medical plausibility, rarity and medical significant benefit. The Committee for Orphan Medicinal Products (COMP) is the European Medicines Agency's (EMA) committee responsible for recommending orphan designation of medicines for rare diseases. Even if pre-submission meetings are not mandatory, EMA strongly encourages sponsors to request a pre-submission meeting with the Agency prior to filing an application. Experience has shown that they have a positive impact on the success rate of the applications. The full application should be submitted in English via secure online portal. ODD makes the sponsor eligible for a number of orphan incentives including the 10-year market exclusivity and the protocol assistance by COMP. Based on literature and on the experience accumulated by our team ORPHANDEV F-CRIN-labelled platform the successful translation of rare disease research into orphan drug discovery is dependent of a clearly justified medical significant benefit, the disease class, its prevalence and the disease-specific scientific output, previous experience of the sponsor with a previous successful orphan drug to the market increased.

Orphan Drugs of Personalized Medicine in Bulgaria and Their Cost-Effectiveness

The orphan drugs development is related to the progress of personalized medicine. The relationship between them is based on a treatment tailored to personalized patient needs. Personalized medicine is defined as “providing the right patient with the right drug, at the right dose and at the right time”, while the orphan drug is defined as “intended for the treatment, prevention or diagnosis of a rare disease or condition, which is one that affects less than 200,000 persons in the United States” and no more than 10,000 people for the European Union. The main goal of the article is to study the approved orphan drugs in Bulgaria, determining how many of them are reimbursed by the NHIF and are cost-effective

Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions.

Rare diseases provide a challenge in the evaluation of new therapies. However, orphan drug development is of increasing interest because of the legislation enabling facilitated support by regulatory agencies through scientific advice, and the protection of the molecules with orphan designation. In the landscape of the rare epilepsies, very few syndromes, namely Dravet syndrome, Lennox-Gastaut syndrome and West syndrome, have been subject to orphan drug development. Despite orphan designations for rare epilepsies having dramatically increased in the past 10years, the number of approved drugs remains limited and restricted to a handful of epilepsy syndromes. In this paper, we describe the current state of orphan drug development for rare epilepsies. We identified a large number of compounds currently under investigation, but mostly in the same rare epilepsy syndromes as in the past. A rationale for further development in rare epilepsies could be based on the match between the drug mechanisms of action and the knowledge of the causative gene mutation or by evidence from animal models. In case of the absence of strong pathophysiological hypotheses, exploratory/basket clinical studies could be helpful to identify a subpopulation that may benefit from the new drug. We provide some suggestions for future improvements in orphan drug development such as promoting paediatric drug investigations, better evaluation of the incidence and the prevalence, together with the natural history data, and the development of new primary outcomes.

A Phase II Trial of Topical Sodium Nitrite in Patients with Sickle Cell Disease and Leg Ulcers

Background Leg ulcerations are a serious and debilitating complication of sickle cell disease (SCD). Patients with SCD and leg ulcers have biomarkers of severe hemolytic anemia, a state associated with low bioavailability of nitric oxide (NO). Therapies directed at restoring NO bioavailability might prove beneficial. We selected topical sodium nitrite for clinical development due to its safety profile and vascular, anti-microbial, antiplatelet, and pro-keratinocyte functions. The nitrite anion is a vasodilator in vivo by generating NO in tissues with low oxygen tension and pH, conditions that are likely present in chronic wounds. Data from our successful phase 1 study showed improved regional blood flow, decreased ulcer pain, and appeared to improve ulcer healing. The dosing data informed the concentration of active ingredient to be used and suggested sodium nitrite efficacy in SCD patients with leg ulcers (Minniti, CP et al, Lancet Haematol 1, e95-e103). Study Design and Methods This is a multicenter, phase 2, prospective, randomized, placebo-controlled study of topical sodium nitrite in patients with SCD and leg ulcers. Primary aim is to determine the safety, tolerability, and effectiveness of twice a week topical application of study ointment for 10 weeks. We hypothesize that sodium nitrite will 1) accelerate wound healing (&gt;25% improvement over placebo arm); and/or 2) decrease pain at the wound site (&gt;20% over placebo). Ulcers measured by ImageJ planimetry software to increase accuracy. The secondary aims are to: a) evaluate the effect of hydroxyurea (HU) on leg ulcer healing in combination with topical sodium nitrite or placebo; b) assess changes in ulcer microbiome after application of sodium nitrite or placebo and how these changes may relate to healing; c) evaluate the dermal composition and microvascular structure in the ulcer beds. We plan to enroll 50 adults with all SCD genotypes and leg ulcers not individually &gt;100 cm2, such that, after an expected 20% dropout, 40 subjects will complete &gt; 8 weeks of treatment. Exclusion criteria: use of PDE5 inhibitors, NO, L-arginine, nitroprusside, nitroglycerine; acute bacterial infection; pre-existing methemoglobinemia (&gt;3.5% on two different occasions); G6PD deficiency. Randomization is stratified by HU use to minimize potential confounding effects on study outcomes. Funded by the Food and Drug Administration (FDA) Division of Orphan Drug Development (# FD-R-0005729); active at two sites (ClinicalTrials.gov NCT02863068). Results We have screened 68 subjects with known history of leg ulcer: 46% were not eligible as the ulcer was closed at the time of screening. Of the 30 eligible, 13 subjects enrolled (12 at Montefiore Medical Center, 1 at the University of Pittsburgh), with 9 subjects randomized. Reasons for screen failure, other than ulcer closed, are depicted in fig 1. Three subjects experienced ulcer decrease &gt;25% in the run-in period and did not have ointment application as per protocol. One subject withdrew due to lack of adherence. Therefore the overall dropout rate at this time is 33%, higher than the 20% anticipated. No study ointment SAEs have been noted, AEs have been minor and non-ointment related. Most SAEs have been VOCs, expected in this patient population and wound infections. Discussion As expected, enrollment of subjects with a rare complication of a rare disease is challenging. The recurrent pattern of ulcers in SCD was the reason why the majority of patients were not able to enroll, as the ulcer was closed at the time of screening. We monitor them closely for possible re-opening. Simplification of protocol-related procedures, such as decrease in number of required visits from twice to once a week by packaging dose-specific blister packs that the patient takes home for self-administration of ointment, has facilitated enrollment. Travel to the center is being addressed. A close relationship between the subjects and study team is essential. Co-location of the wound specialist in the sickle cell clinic and training the research nurse for wound care has helped with recruitment. Disclosures Ogu: Vertex Pharmaceuticals: Consultancy. Kato:Novartis, Global Blood Therapeutics: Consultancy, Research Funding; Bayer: Research Funding. Minniti:Doris Duke Foundation: Research Funding.

Policies and actions to tackle rare diseases at European level.

Rare diseases (RDs) are defined by the European Union as life-threatening or chronically debilitating conditions, with a prevalence lower than 5 per 10 000 inhabitants. Around 6000 diseases are described, affecting between 6% and 8% of the European population. Due to their severity, diffusion and multi-faceted aspects, RD are an area where collaboration in public health, health care and research provides a major integrated added value. Main areas for policy actions include: the development and implementation of European Reference Networks, as a main strategy for sharing of knowledge, clinical expertise and foster research; integration of high-quality patient registries, biobanks, and bioinformatics support, as key infrastructure tools addressing research and healthcare needs; the implementation of National Plans on RD in EU Member States by sharing experiences, capacity building and linking national efforts through a common strategy at a European level; actions driven by the recommendations for primary prevention of congenital anomalies (the main RD group with multifactorial aetiology); policy provisions to foster research and development of orphan drugs.

Orphan drug development in China: progress and challenges

Orphan drug development in China: progress and challenges

How to Advance Research, Education, and Training in the Study of Rare Diseases

How to Advance Research, Education, and Training in the Study of Rare Diseases

Survey of Japanese Orphan Drug Program: Factors Related to Successful Marketing Approval.

The basic components of regulatory and supporting policies for orphan drug development appear similar between the United States and Japan, but drugs designated as orphan drugs have been different between the 2 countries. The probabilities of development success (ie, marketing approval) in designated orphan drugs have also been significantly different. In this study, we analyzed recent outcomes of development for orphan drugs designated from 1993 to 2017 in Japan, considering their development and approval status in the United States. Our analysis showed that success for orphan drug development in Japan was apparently associated with prior approval status in the United States. Company size, orphan development experience, and patient enrichment were also positively associated with successful marketing approval. Although similar designations and priority review systems for orphan drugs have been enacted, economic incentives and regulatory conditions provided by the systems seem to be different between the 2 countries, which may lead to varied performance in orphan designation and approval. We need to pay close attention to the impact of industrial global development strategies when comparing the outcomes and performance of different orphan drug promotion systems.