We searched PubMed, Medline, and Embase for articles published from January, 1990, to December, 2012. We used the terms “rare disease”, “rare lung disease”, “orphan lung disease”, and “treatment”, and selected the citations for this focused Review on the basis of their specific applicability to areas pertinent to rare diseases and the lung. We largely focused on publications in the past 10 years that have provided pivotal insights into the subject matter of this Review. We also searched
ReviewRare lung disease and orphan drug development
Introduction
Rare diseases are a group of disorders linked by the qualities of being infrequent and unusual. Often, rare diseases are also known as orphan diseases, referring to the fact that affected patients feel that nobody cares about their disorder and that little, if any, research is done to improve diagnosis and management. In Europe, a disease is referred to as rare if it affects fewer than one in 2000 individuals, whereas in the USA, according to the definition of the US National Institutes of Health Office of Rare Diseases, rare is a disease or disorder that affects fewer than 200 000 people, or affects more than 200 000 but for which there is no reasonable expectation that the cost of drug development and availability for such a disease will be recovered from sales.1, 2 Far more uncommon are the so-called ultra-rare disorders with a suggested prevalence of a thousandth that for rare disorders—one in 2 000 000 or less—although there is no internationally accepted definition.3
Rare diseases range from those with a low incidence and poor survival (eg, pulmonary arterial hypertension, idiopathic pulmonary fibrosis, and severe-combined immunodeficiency syndrome), to those with a low incidence and fairly long survival (eg, cystic fibrosis, connective tissue diseases), to those with a higher incidence but short survival (eg, acute respiratory distress syndrome). Between 6000 and 8000 rare diseases exist, many of which have a genetic basis, affect children at a very early age, and are life threatening or chronically debilitating.4, 5
In this Review, we focus on the challenges in the diagnosis, research, and treatment of, and in the communication with patients and health-care providers about rare diseases, with particular attention to diseases that affect the lung.
Section snippets
Economic consequences
Although difficult to estimate, the burden of rare diseases in terms of suffering and loss of human life is enormous. A regularly updated survey undertaken by Orphanet6 based on data published in peer-reviewed journals provides an estimate of the prevalence of several rare diseases. The economic burden of rare diseases seems massive. According to the US National Institutes of Health Office of Rare Diseases, with a conservative approximation of average yearly health-care costs of US$5000 per
Rare lung diseases
At least 1·2–2·5 million American patients and 1·5–3 million European patients are affected by rare lung diseases,12, 13 although cases have not been precisely indexed.14 Furthermore, and similar to most rare diseases, few of these disorders have been studied carefully and only a very small proportion are considered treatable by biomedical standards.15 Some disorders are fairly common and affect as many as tens of thousands of patients (eg, sarcoidosis or cystic fibrosis; table), whereas others
Clinical trials of orphan drugs
Clinical trials of orphan drugs have many obstacles; one of the most challenging is the recruitment of an adequate number of patients to obtain sufficient evidence of efficacy and safety. Patients are often diagnosed late in their disease course, and thus are excluded from clinical research studies because novel therapy is unlikely to be efficacious in the context of extensive irreversible organ damage. In this situation, randomised, double-blind, placebo-controlled trials, which provide the
Issues for drug developers and funders
Historically, the pharmaceutical industry has been reluctant to invest in research and development of drugs for rare diseases because of the low probability that the investment would be recovered by the expected sales of the product under normal market conditions. This situation radically changed in the early 1980s thanks to a US-based patient organisation, the Organization for Rare Disorders, and the Orphan Drug Act,2 which acknowledged the medical needs of patients with rare diseases, and
The future of rare lung diseases
The past decade has seen both a growing interest from the medical community and major advances in the specialty of rare diseases. Substantial progress for some diseases, including idiopathic pulmonary fibrosis, lymphangioleiomyomatosis (panel 4, figure 1), and pulmonary arterial hypertension, has been made possible by the tremendous concerted effort of dedicated academic researchers and clinicians, patient organisations, health authorities, and pharmaceutical companies.13, 74 These examples
Search strategy and selection criteria
References (74)
Care for patients with ultra-rare disorders
Eur J Med Genet
(2011)- et al.
Why rare diseases are an important medical and social issue
Lancet
(2008) - et al.
Translation of rare disease research into orphan drug development: disease matters
Drug Discov Today
(2009) - et al.
Rare lung disease research: strategies for improving identification and recruitment of research participants
Chest
(2011) - et al.
Perspectives for improving the evaluation and access of therapies for rare lung diseases in Europe
Respir Med
(2012) - et al.
Idiopathic pulmonary fibrosis
Lancet
(2011) - et al.
Pulmonary arterial hypertension
J Am Coll Cardiol
(2008) - et al.
The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases
Genet Med
(2012) - et al.
International Classification of Diseases coding changes lead to profound declines in reported idiopathic pulmonary arterial hypertension mortality and hospitalizations: implications for database studies
Chest
(2011) Clinical trials of orphan medicines
Lancet
(2008)
Empowerment of patients: lessons from the rare diseases community
Lancet
Lymphangioleiomyomatosis (LAM): molecular insights lead to targeted therapies
Respir Med
Clinical research for rare disease: opportunities, challenges, and solutions
Mol Genet Metab
The US Orphan Drug Act: rare disease research stimulator or commercial opportunity?
Health Policy
Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products
Congressional findings for the orphan drug act
Orphanet report series – prevalence of rare diseases: bibliographic data
Breathing in America: Diseases, progress, and hope. Chapter 18 – Rare lung diseases
Forgotten conditions: misdiagnosed and unsupported, how patients are being let down
The common problem of rare disease in general practice
Med J Aust
International conferences on rare diseases: initiatives in commitment, patient care and connections
Med J Aust
Two decades of orphan product development
Nat Rev Drug Discov
Introduction
Eur Respir Mon
A journey of hope: lessons learned from studies on rare diseases and orphan drugs
J Intern Med
Newborn screening for cystic fibrosis
Cochrane Database Syst Rev
Global effort against rare and orphan diseases
Eur Respir Rev
Idiopathic pulmonary fibrosis: evidence based guidelines for diagnosis and management
Am J Respir Crit Care Med
Changing the idiopathic pulmonary fibrosis treatment approach and improving patient outcomes
Eur Respir Rev
Non-steroid agents for idiopathic pulmonary fibrosis
Cochrane Database Syst Rev
Treatment of pulmonary arterial hypertension
N Engl J Med
Treatment of pulmonary arterial hypertension with targeted therapies
Nat Rev Cardiol
A critical analysis of survival in pulmonary arterial hypertension
Eur Respir Rev
European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis
Eur Respir J
Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome)
N Engl J Med
Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study
Am J Respir Crit Care Med
Pulmonary arterial hypertension in France: results from a national registry
Am J Respir Crit Care Med
Survey of the delay in diagnosis for 8 rare diseases in Europe: EurordisCare2
Cited by (44)
Traits, trends and hits of orphan drug designations in cystic fibrosis
2023, Journal of Cystic FibrosisCarbohydrate-based drugs launched during 2000−2021
2022, Acta Pharmaceutica Sinica BCitation Excerpt :Though the exact mechanism of action was not clear, MgIG (46) was approved for anti-inflammatory and hepatoprotective treatment by NMPA in 2005. Orphan diseases, also known as rare diseases, are a group of disorders associated with the infrequent and unusual qualities, and 80 percent of the reported cases have a genetic basis474,475. Although hard to estimate, the burden of orphan diseases is tremendous, both in terms of loss of human life and economic burden474.
Stem cell-based Lung-on-Chips: The best of both worlds?
2019, Advanced Drug Delivery ReviewsCitation Excerpt :However, by integrating multiple cell types, immune cells, and a dynamic mechanochemical environment, Organs-on-Chip technology provides the ability to also study non-cell-autonomous diseases such as asthma, in which environmental agents in concert with airway and immune cells generate a diversity of phenotypes. Lastly, Lung-on-Chip systems combined with iPSCs could facilitate research in rare pulmonary diseases for which there are no preclinical disease models [169]. In the following, we will discuss diseases that might benefit from stem cell-based Lung-on-Chip system.
Management of Idiopathic Pulmonary Fibrosis
2018, Interstitial Lung DiseasePulmonary lymphangioleiomyomatosis: From pathogenesis to management
2016, Revue des Maladies RespiratoiresPaediatric orphan lung diseases in Asia
2016, The Lancet Respiratory Medicine