Review
Rare lung disease and orphan drug development

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Summary

Rare diseases are a major health-care burden worldwide. Very little is known about the cause, behaviour, and treatment of these disorders, and thus non-specialist health-care providers and patients are left without sufficient knowledge to manage these diseases. Up to 3 million Europeans are estimated to have a rare lung disease. Several organisations—many of which are patient led—attempt to raise the profile of rare lung diseases to improve understanding and management of these disorders. Incentives have now been introduced in the USA and Europe that encourage the pharmaceutical industry to invest in targets that might otherwise not appeal because of small target populations. Despite many intrinsic challenges and obstacles, considerable progress is constantly being made in the research and development of drugs for rare disorders.

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

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

References (74)

  • S Aymé et al.

    Empowerment of patients: lessons from the rare diseases community

    Lancet

    (2008)
  • CG Glasgow et al.

    Lymphangioleiomyomatosis (LAM): molecular insights lead to targeted therapies

    Respir Med

    (2010)
  • RC Griggs et al.

    Clinical research for rare disease: opportunities, challenges, and solutions

    Mol Genet Metab

    (2009)
  • O Wellman-Labadie et al.

    The US Orphan Drug Act: rare disease research stimulator or commercial opportunity?

    Health Policy

    (2010)
  • 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

  • M Weston et al.

    Forgotten conditions: misdiagnosed and unsupported, how patients are being let down

  • AW Knight et al.

    The common problem of rare disease in general practice

    Med J Aust

    (2006)
  • AW Knight et al.

    International conferences on rare diseases: initiatives in commitment, patient care and connections

    Med J Aust

    (2007)
  • ME Haffner et al.

    Two decades of orphan product development

    Nat Rev Drug Discov

    (2002)
  • J-F Cordier

    Introduction

    Eur Respir Mon

    (2011)
  • M Wästfelt et al.

    A journey of hope: lessons learned from studies on rare diseases and orphan drugs

    J Intern Med

    (2006)
  • KW Southern et al.

    Newborn screening for cystic fibrosis

    Cochrane Database Syst Rev

    (2009)
  • S Harari et al.

    Global effort against rare and orphan diseases

    Eur Respir Rev

    (2012)
  • G Raghu et al.

    Idiopathic pulmonary fibrosis: evidence based guidelines for diagnosis and management

    Am J Respir Crit Care Med

    (2011)
  • V Cottin

    Changing the idiopathic pulmonary fibrosis treatment approach and improving patient outcomes

    Eur Respir Rev

    (2012)
  • P Spagnolo et al.

    Non-steroid agents for idiopathic pulmonary fibrosis

    Cochrane Database Syst Rev

    (2010)
  • M Humbert et al.

    Treatment of pulmonary arterial hypertension

    N Engl J Med

    (2004)
  • DS O'Callaghan et al.

    Treatment of pulmonary arterial hypertension with targeted therapies

    Nat Rev Cardiol

    (2011)
  • DS O'Callaghan et al.

    A critical analysis of survival in pulmonary arterial hypertension

    Eur Respir Rev

    (2012)
  • SR Johnson et al.

    European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis

    Eur Respir J

    (2010)
  • WA Gahl et al.

    Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome)

    N Engl J Med

    (1998)
  • DJ Lamas et al.

    Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study

    Am J Respir Crit Care Med

    (2011)
  • M Humbert et al.

    Pulmonary arterial hypertension in France: results from a national registry

    Am J Respir Crit Care Med

    (2006)
  • F Faurisson

    Survey of the delay in diagnosis for 8 rare diseases in Europe: EurordisCare2

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