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Öksüz İlaçlar ve Öksüz İlaçların Yeni İlaç Geliştirilmesindeki YeriOrphan Drugs and The Role of Orphan Drugs In Novel Drug Development
Abstract
Son yıllarda yeni ilaç geliştirme çalışmaları kapsamında yapılan araştırmalarda, öksüz ilaçların çok önemli bir yerinin olduğu görülmektedir. Öksüz ilaçların geliştirilmesiyle, nadir hastalıkların tedavisinde kullanılacak yararlı yeni ilaçların elde edilmesi mümkün olabileceği gibi, etkinliği kanıtlanmış bu ilaçların, henüz tedavisi mümkün olmayan pek çok hastalığın tedavisi için de öncü olması beklenmektedir. Bu çalışmada, öksüz ilaçların, mevcut durumuna ilişkin araştırma ve değerlendirme yapılması amaçlanmıştır. Çalışma kapsamında yapılan literatür taramaları sonucunda, öksüz ilaçlar hakkında yaşanan son gelişmeler ve bu ilaçlarla ilgili araştırma-geliştirme çalışmalarının artmasını sağlayan yasa ve programlar detaylı olarak sunulmuştur. Öksüz ilaçlarla ilgili sunulan sayısal veriler, bu ilaçların yeni ilaç geliştirilmesindeki yerinin önemini göstermektedir.
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Background
Orphan drug designations are a useful proxy to investigate trends in rare disease drug development. Drug developers must receive a designation before they are eligible for the economic incentives of the Orphan Drug Act in the United States. We created a database of all orphan drugs designated between 1983 and 2019 that included numerous drug characteristics, including therapeutic area. In addition, we constructed a “broad disease” categorization of designations as an alternative to therapeutic area, based on disease etiology and age of onset rather than organ system. By looking at the pattern of orphan drug designations over the past four decades, this analysis studied the impact of the evolving rare disease drug development landscape and considers the future of rare disease therapies over the coming decades.
Results
Between 1983 and 2019, a total of 5099 drugs and biologics received orphan drug designation. Designations more than doubled between the 1980s and 1990s, almost doubled between the 1990s and 2000s, and almost tripled in number between the 2000s and 2010s. The top three therapeutic areas represented in the orphan drug designations were: oncology (1910, 37%), neurology (674, 13%), and infectious diseases (436, 9%). The broad disease categorization found that the proportion of designations for pediatric-onset diseases has increased in the most recent decade to 27%.
Conclusions
Analysis of the last four decades of orphan drug designation indicates seismic shifts have occurred in the rare disease drug development space. The number of designations granted more than quadrupled between the 1990s and 2010s. While these substantial increases led to growth in the absolute number of designations within all therapeutic areas (bar one) and broad disease categories, the relative proportions have seen considerable change over time. In the most recent decade, there have been notable increases in the proportion of drugs in oncology, pediatric-onset diseases, and neurologic disorders. The dramatic rise in overall orphan designations over the past four decades suggests we may continue to see an upward trajectory in designations leading to an increased number of approvals for drugs and biologics designed specifically for diagnosing, preventing, and treating rare diseases in the coming decades.
Background
In the European Union (EU) and United States (US), specific regulations have been released to provide incentives to develop and sell orphan medicinal products.
We analysed the status of orphan drugs designated that not yet received a marketing authorisation or already marketed for patients affected by rare diseases in the EU and US up to December 2015. For each drug, the following data were extracted: designation date, active substance(s), orphan condition and indication, trade name, approved therapeutic indication, approved ages, genetic nature of disease and if affects children.
Results
In the EU, 1264 Orphan Drug Designations have been granted and 133 medicinal products were approved covering a total of 179 indications and 122 rare conditions. Among these, 79 were approved under Regulation (EC)141/2000 (65 still listed in the Orphan Medicinal Products Register and 14 lost the orphan designation but still authorised) and 23 were approved centrally by the European Agency before the Orphan Regulation entered into force. On the other hand, in the US 3082 designations and 415 orphan products, covering a total of 521 indications and 300 rare conditions, were granted. As a result, the mean of designations per year is 79 in the EU and 93.4 in the US, while the mean of approved indications per year is 8.5 in the EU and 15.8 in the US.
No orphan product is marketed in the EU for bone and connective tissue, ophthalmic, poisoning/overdose, renal, urinary and reproductive rare diseases. Among the marketed medicinal products, only 46.6% in the EU and 35.2% in the US are approved for children.
If all the existing market approvals were merged, 362 additional therapeutic indications in the EU and 72 in the US would be covered.
Conclusions
Our data show that notwithstanding the incentives issued, the number of medicines for rare diseases is still limited, and this is more evident in certain therapeutic areas. However, by merging all the existing approvals, patients would benefit of substantial advantages in both geographic areas. Efforts and cooperation between EU and US seem the only way to speed up the development and marketing of drugs for rare diseases.
Australia, Canada, and Japan have evaluated how their governments can facilitate the development of medical products to treat rare disorders. Each has established programs and/or policies to support the development of products to address unmet medical needs in small populations and to ensure their citizens access to such essential medicines.Japan implemented an Orphan Product Program in 1993. Australia's program, initiated in 1998, was developed in collaboration with the United States Food and Drug Administration to facilitate the exchange and review of data on orphan drugs. Canada's assessment, published in 1996, determined that a standalone orphan drug program was not currently warranted, as existing legislation and regulatory policies allow early access to essential medicinal products.In reviewing these programs/policies along with those in the United States and Europe, it is interesting that only Japan designates medical devices as orphan products. Government grants for development are available in the United States, Canada, and Japan. Defined periods of market exclusivity apply in the United States and Europe. Market exclusivity is based on normal patent protection in Australia, Canada, and Japan; however, in Japan the time until generic competition is allowed is primarily defined by the reexamination period, which is extended for orphan products. All the policies allow regulatory fees to be waived or reduced, and a priority or accelerated review of the marketing application can usually be expected.
Background
Families of children living with a rare disease report significant health and social burden, however, few studies have systematically examined family needs by using validated tools to assess the scope and extent of this burden. Our aim was to develop a comprehensive survey to assess health, psychosocial and financial impacts on Australian families caring for a child with a rare disease.
Methods
We developed a self-administered survey for parents/carers incorporating pre-validated tools. The survey included questions about experiences of diagnosis, health services use and needs, needs for peer and financial supports. Forty-seven families attending the state-wide Genetic Metabolic Disorders Service at the Children’s Hospital at Westmead, Sydney were invited to participate.
Results
Of 46 families who received the survey, 30 (65%) completed it. Most (93%) found the survey acceptable and relevant (91%). Patients were 1–17 years old, 14 (47%) male, and 12 (40%) non-Caucasian. Eighteen (60%) had a lysosomal storage disease and 12(40%) had a mitochondrial disorder. Eleven (38%) saw 3–5 doctors and four (14%) saw 6–10 doctors before receiving the correct diagnosis; 43% felt diagnosis was delayed. Four (13%) were dissatisfied with the way diagnosis was given, due to insensitive style of communication, inadequate information and psychological support. Psychosocial impact was moderate to high for 90% of families and the level of impact was not dependent on the level of health functioning of the child. Twenty-six (87%) wanted, but only 13(43%) received, information about peer-support groups. The 30 children accounted for 168 visits to general practitioners and 260 visits to specialist doctors; 21 (70%) children had at least one admission to hospital, including one who had 16 admissions in the previous 12 months. Most families (77%) received financial assistance but 52% believed this was insufficient. Families benefited from a specialised multi-disciplinary clinic but called for patient-held electronic medical records.
Conclusions
Australian families caring for children with genetic metabolic disorders are adversely impacted by delays in diagnosis, lack of easy access to peer support groups and lack of psychological support. Further research is needed to estimate economic impact and to analyse health service delivery models for children with rare diseases in Australia.
In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.
According to the Regulation (EC) N. 141/2000 of the European Parliament and of the Council, rare diseases are life-threatening or chronically debilitating conditions, affecting no more than 5 in 10 000 persons in the European Community. It is estimated that between 6000 to 8000 distinct rare diseases affect up to 6% of the total EU population. Therefore, these conditions can be considered rare if taken individually but they affect a significant proportion of the European population when considered as a single group. Several initiatives have been undertaken at international, European and national level to tackle public health as well as research issues related to the prevention, diagnosis, treatment and surveillance of these diseases. The development of innovative and effective medical products for their diagnosis and treatment is frequently hampered by several factors, including the limited knowledge of their natural history, the difficulties in setting up clinical studies due to the limited numbers of patients affected by a specific disease, the weak interest of sponsors due to the restricted market opportunities. Therefore, incentives and other facilitations have been adopted in many parts of the world, including in the EU, in order to facilitate the development and commercialization of diagnostic tools and treatments devoted to rare diseases. This paper illustrates mainly the European initiatives and will discuss the problematic and controversial aspects surrounding orphan drugs. Finally, activities and measures adopted in Italy are presented.
This paper reports a study to assess stress, well-being and supportive resources experienced by mothers and fathers of children with rare disabilities, and how these variables were affected by an intensive family competence intervention.
Despite diagnosis-specific studies, little overall knowledge exists about life-consequences for families of children with rare disorders.
We used a prospective design with baseline data and two follow-ups (at 6 and 12 months) after an intervention. The intervention aimed at empowering parents in managing their child's disability. Parents from all parts of Sweden visiting a national centre for families of children with rare disabilities were consecutively selected (n = 136 mothers, 108 fathers). Instruments of parental stress, social support, self-rated health, optimism and life satisfaction and perceived physical or psychological strain were used. Stratified analyses were carried out for mothers and fathers, and related to parental demands: single mothers, full-time employment, participation in a parent association, child's age and type of disability.
We found high parental stress, physical and emotional strain among mothers, especially among single mothers. Fathers showed high stress related to incompetence, which decreased after the intervention. Decreased strain was found among full-time working mothers and fathers after the intervention. Parents' perceived knowledge and active coping and mothers' perceived social support were increased at follow-up. Factors related to parents' overall life satisfaction (57-70% explained variance) changed after the intervention, from being more related to internal demands (perceived strain, incompetence and social isolation) to other conditions, such as problems related to spouse, paid work and social network.
Parents, especially fathers and full-time working parents, may benefit from an intensive family competence programme.
Historically, patients with rare diseases have been underserved by commercial drug development. In several jurisdictions, specific legislation has been enacted to encourage the development of drugs for rare diseases (orphan drugs), which would otherwise not be commercially viable. However, because of the small market, these drugs are often very expensive. Under the standard methods of health technology assessment (HTA) incorporating economic evaluation, orphan drugs do not usually prove to be cost-effective and this, coupled with their high cost, means that funding and patient access may be limited. However, these restrictions may not be in line with societal preferences. Therefore, this study discusses whether the standard methods of HTA are adequate for assisting decisions on patient access to and funding of orphan drugs and outlines a research agenda to help understand the societal value of orphan drugs and issues surrounding their development, funding, and use.
Compared with other common diseases in the general population, a rare disease is a health condition that affects a small number of people. The progressive, life-threatening and multi-dimensional nature of these diseases requires the development of an effective health policy. The aim of this study is to examine health policy for rare diseases from a historical point of view in Turkey. Public Health Law No. 1593 provides the basis for policies developed in the field of rare diseases. In the early 2000s, genetic screening programs have been launched (neonatal metabolic and endocrine disease, inherited blood diseases, biotinidase deficiency, phenylketonuria, congenital hypothyroidism, adrenal hyperplasia, cystic fibrosis, etc.). Since 2007, Turkey has been a member of Orphanet. The Draft Guide to Orphan Drugs was published by the Ministry of Health in 2009. Since 2014, the public authorities, universities, and NGOs have been particularly interested in rare diseases. The civil society initiative 'Rare Diseases Network' was established in 2018 under the leadership of patients and their families. Some reports on rare diseases were published by TÜHKE and the TAÇESE in 2019. The Parliamentary Investigation Commission has been set up to determine the situation of some rare diseases. The Rare Diseases Department was established within the Ministry of Health in 2020. It is recommended that the National Action Plan on Rare Diseases and Orphan Drugs should be implemented to develop policies, in particular access to healthcare services, and provide economic and psychosocial support.
Orphan drugs are designated drug substances that are intended to treat rare or ‘orphan’ diseases. More than 7000 rare diseases are known that collectively affect some 6-7% of the developed world’s population; however, individually, any single, rare disease may only affect a handful of people making them commercially unattractive for the biopharmaceutical industry to target.
Ground breaking legislation, starting with the Orphan Drug Act that was passed in the US in 1983 to provide financial incentives for companies to develop orphan drugs, has sparked ever increasing interest from biopharmaceutical companies to tackle rare diseases. These developments have made rare diseases, and the orphan drugs that treat them, sufficiently attractive to pharmaceutical development and many pharmaceutical companies now have research units dedicated to this area of research. It is therefore timely to review the area of orphan drugs and some of the basic science, drug discovery and regulatory factors that underpin this important, and growing, area of biomedical research.
Written by a combination of academic and industry experts working in the field, this text brings together expert authors in the regulatory, drug development, genetics, biochemistry, patient advocacy group, medicinal chemistry and commercial domains to create a unique and timely reference for all biomedical researchers interested in finding out more about orphan drugs and the rare diseases they treat.
Providing an up-to-date monograph, this book covers the basic science, drug discovery and regulatory elements behind orphan drugs and will appeal to medicinal and pharmaceutical chemists, biochemists and anyone working within the fields of rare disease research and drug development or pharmaceuticals in industry or academia.
Orphan drugs are designated drug substances that are intended to treat rare or ‘orphan’ diseases. More than 7000 rare diseases are known that collectively affect some 6-7% of the developed world’s population; however, individually, any single, rare disease may only affect a handful of people making them commercially unattractive for the biopharmaceutical industry to target.
Ground breaking legislation, starting with the Orphan Drug Act that was passed in the US in 1983 to provide financial incentives for companies to develop orphan drugs, has sparked ever increasing interest from biopharmaceutical companies to tackle rare diseases. These developments have made rare diseases, and the orphan drugs that treat them, sufficiently attractive to pharmaceutical development and many pharmaceutical companies now have research units dedicated to this area of research. It is therefore timely to review the area of orphan drugs and some of the basic science, drug discovery and regulatory factors that underpin this important, and growing, area of biomedical research.
Written by a combination of academic and industry experts working in the field, this text brings together expert authors in the regulatory, drug development, genetics, biochemistry, patient advocacy group, medicinal chemistry and commercial domains to create a unique and timely reference for all biomedical researchers interested in finding out more about orphan drugs and the rare diseases they treat.
Providing an up-to-date monograph, this book covers the basic science, drug discovery and regulatory elements behind orphan drugs and will appeal to medicinal and pharmaceutical chemists, biochemists and anyone working within the fields of rare disease research and drug development or pharmaceuticals in industry or academia.
High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.
Patients with rare diseases deserve the same quality, safety and efficacy in medicines as other patients with more common conditions. However, for rare diseases, the cost of developing and bringing a drug to market would not normally be recovered by expected sales. In order to encourage development and research, a supportive legislative and regulatory framework known as orphan drug designation has been adopted for medicines for rare diseases in a number of countries and regions. Although similarities exist, the criteria and processes for designation are not internationally harmonised and this editorial summarises orphan drug designation in Europe, the USA and Japan.
Purpose:
To assess the methodological quality of Orphan Medicinal Product (OMP) dossiers and discuss possible reasons for the small number of products licensed.
Methods:
Information about orphan drug designation, approval, refusal or withdrawal was obtained from the website of the European Medicines Agency and from the European Public Assessment Reports.
Results:
From 2000 up to 2010, 80.9 % of the 845 candidate orphan drug designations received a positive opinion from the European Medicines Agency (EMA)'s Committee on Orphan Medicinal Products. Of the 108 OMP marketing authorizations applied for, 63 were granted. Randomised clinical trials were done for 38 OMPs and placebo was used as comparator for nearly half the licensed drugs. One third of the OMPs were tested in trials involving fewer than 100 patients and more than half in trials with 100-200 cases. The clinical trials lasted less than one year for 42.9 % of the approved OMPs.
Conclusion:
Although there may have been some small improvements over time in the methods for developing OMPs, in our opinion, the number of patients studied, the use of placebo as control, the type of outcome measure and the follow-up have often been inadequate. The present system should be changed to find better ways of fostering the development of effective and sustainable treatments for patients with orphan diseases. Public funds supporting independent clinical research on OMPs could bridge the gap between designation and approval. More stringent criteria to assess OMPs' efficacy and cost/effectiveness would improve the clinical value and the affordability of products allowed onto the market.
The definition of a rare disease is not universal and depends on the legislation and policies adopted by each region or country. The main objective of this article is to describe and discuss the legal framework and the regulatory environment of orphan drugs worldwide. Some reflections and discussions on the need for specific orphan drug legislation or policies are described at length. Furthermore, some aspects of the history of each region in respect of the orphan drug legislation evolution are outlined. This article describes and compares the orphan drug legislation or policies of the following countries or regions: United Sates of America (US), European Union (EU), Japan, Australia, Singapore, Taiwan and Canada. The incentives described in the orphan drug legislations or policies, the criteria for designation of orphan status and the authorisation process of an orphan drug are also described and compared. The legislations and policies are to some extent similar but not the same. It is important to understand the main differences among all available legislative systems to improve the international collaboration in the field of orphan drugs and rare diseases.
The enormous progress in the development of drugs for rare diseases may be attributed to advances in genomic technology, molecular profiling, improved target and biomarker selection, an improved understanding of the natural history and pathophysiology of several orphan diseases, use of integrated quantitative analysis techniques in drug development, and a favorable regulatory climate, but major challenges still remain. Most rare diseases manifest during childhood; about 30% of affected children die before their fifth birthday, and the health and economic burden on survivors can be tremendous.
Orphan drugs are indicated for the treatment of rare diseases which, in the EU, are defined as those with a prevalence of <5 per 10000 inhabitants. Characteristically, these diseases negatively affect health-related quality of life and may be life threatening. The EU has passed legislation to encourage pharmaceutical companies to invest in research programmes into rare diseases, with the aim of developing new, safe and effective orphan drugs.
To describe the status of orphan drugs in five countries in the EU (France, Germany, the UK, Italy and Spain), estimate the mean annual cost per patient and indication of these orphan drugs, and determine the associated cost of these drugs in comparison with overall spending on drugs in each country (year 2007 values).
The analysis was limited solely to costs of orphan drugs with sales data available for 2007. The mean annual cost per patient was estimated using recommended regimens for maintenance dose and duration from the summary of product characteristics. Likewise, the ratio between annual costs per patient for treatment of each disease and its prevalence was calculated. Sales data were available for at least one of the countries studied for 38 of the 44 orphan drugs authorized by the European Medicines Agency. Only 21 products had data available for all five countries studied.
Germany was the country with access to the largest number of orphan drugs (36), followed by the UK (34), Spain (28), France (27) and Italy (25). The mean annual cost per patient and indication of the 38 orphan drugs on the market ranged widely from €331 to €337,501. It appears that orphan drugs indicated to treat diseases with a prevalence of <2 per 10000 inhabitants have higher annual per-patient costs than those indicated to treat diseases with a higher prevalence. The percentage of total drug spending accounted for by orphan drugs in 2007 was 1.7% in France, 2.1% in Germany, 1.0% in the UK, 1.5% in Italy and 2.0% in Spain, with an average overall percentage of 1.7% for these five countries.
In 2007, spending on orphan drugs in five European countries was acceptable in terms of the percentage of these countries' overall drug expenditure. Mean annual costs per patient of orphan drugs varied widely, with costs being related to the prevalence of the disease for which the product is indicated.
This study investigates issues associated with the United States Orphan Drug Act.
A comprehensive orphan drug database was compiled from FDA data and corporate annual reports of major pharmaceutical companies. Analysis allowed the generation of a descriptive orphan drug portrait as well as documentation of orphan drugs along their lifecycle.
Currently, 2002 products have obtained orphan drug designation with 352 drugs obtaining FDA approval. Approximately 33% of orphan drugs are oncology products. On average, products obtain 1.7 orphan designations with approximately 70% obtaining a single designation. At least 9% of orphan drugs have reached blockbuster status with two-thirds having two or more designations. An additional 25 orphan drugs had sales exceeding US$ 100 million in 2008 alone. Since 1983, at least 14 previously discontinued products have been recycled as orphan drugs.
The United States Orphan Drug Act has created issues which, in some cases, have led to commercial and ethical abuses. Orphan Drug Act reform is necessary but current incentives, including 7 year market exclusivity, should be maintained in order to favour patients as well as economic prosperity. Suggested reforms include price regulation, subsidy paybacks for profitable drugs and the establishment of an International Orphan Drug Office.
Over the past 20 years, incentives of the Orphan Drug Act (ODA), the largest single source of extramural clinical grants at the US Food and Drug Administration, have had a substantial impact on public health. ODA incentives have contributed to the development of many innovative biotechnology products, and as our understanding of the human genome evolves, it is anticipated that pharmacogenomics will result in the identification of more 'orphan diseases'.
The word orphan comes from the Greek word orphanos, a child who has lost one parent or both, or an adult who has lost a child. It goes back to the putative Indo-European root ORBH, bereft, as in the Latin word orbus. The obsolete English words orbation and orbity meant orphanhood or childlessness. One who is bereft of freedom is a slave, made to work hard – consider the words for work in some modern European languages, such as the German Arbeit and the Czech robota. In his 1920 play R.U.R. (Rossum's Universal Robots) Karel Capek introduced the word robot (female robotka) for an imagined race of mechanical men and women. And the etymology reminds us of the link between orphans and the workhouse.
In modern English the word orphan is most commonly used in its original Greek sense, but metaphorical meanings have also emerged. An orphan vehicle, for example, is a discontinued model, and an orphan is a line of type that begins a new paragraph at the bottom of a column or page.
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