Review
Rare lung disease and orphan drug development Paolo Spagnolo, Roland M du Bois, Vincent Cottin
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.
Lancet Respir Med 2013; 1: 479–87
Introduction
See Articles page 445
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.
Rare diseases 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 www.thelancet.com/respiratory Vol 1 August 2013
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 patient, the annual total cost in the USA amounts to billions of dollars.7 The rarer the disorder, the more tests and health-care visits are usually needed to make the correct diagnosis, which results in greater expense, unnecessary tests, and missed opportunities for early intervention. Additionally, a 2012 report8 from the UK emphasises the existence of excessive variation in care across the National Health Service between patients with rare diseases; this inequity is intolerable for patients, and contributes to their loss of confidence in the healthcare system.
Diagnostic difficulties During their career any specialist or general practitioner will come across a patient with a rare disease. In such circumstances, physicians should consider the possibility that the patient has a rare disease (and refer them to specialised centres where the diagnosis can be confirmed); however, diagnosis can be difficult because symptoms might be masked, misunderstood, or mistaken for other more common diseases that share similar symptoms, especially in the early stages.9 Specific clusters of atypical symptoms, delayed or unexpected responses to therapy, and suggestive family history could precipitate early referral to specialist units.10,11 The need for more global and accessible educational methods for rare diseases is clear.
Published Online June 25, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70085-7 See Editorial page 423 See Comment page 424 See Spotlight page 443
Centre for Rare Lung Diseases, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Modena, Italy (P Spagnolo MD); Imperial College, London, UK (Emeritus Prof R M du Bois MD); and National Reference Centre for Rare Pulmonary Diseases, Department of Respiratory Medicine, Louis Pradel Hospital, Hospices Civils de Lyon, University Claude Bernard Lyon 1, Lyon, France (Prof V Cottin MD) Correspondence to: Dr Paolo Spagnolo, Centre for Rare Lung Diseases, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Modena, Italy [email protected]
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 affect only a few hundred people worldwide (eg, pulmonary alveolar microlithiasis or 479
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idiopathic pulmonary haemosiderosis), or even fewer (eg, hereditary emphysema due to elastin mutations with cutis laxa). Furthermore, few disorders are of Estimated prevalence (per 100 000) α1-antitrypsin deficiency
33
Adult acute respiratory distress syndrome
30
Idiopathic pulmonary fibrosis
26
Systemic sclerosis
21·5
Pulmonary arterial hypertension
19·5
Chronic thromboembolic pulmonary hypertension
17
Dermatomyositis, polymyositis
17
Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease)
16·25
Sarcoidosis
15
Bronchopulmonary dysplasia
13
Cystic fibrosis
12·6
Small-cell lung cancer
11·2
Tuberous sclerosis
8·8
Granulomatosis with polyangiitis (Wegener’s)
6·6
Primary ciliary dyskinesia
5
Congenital lobar emphysema
4·5
Common variable immunodeficiency
4
Acute interstitial pneumonia
3·8
Mixed connective tissue disease
3·8
Mesothelioma
3·1
Graft versus host disease
2·76
Bronchogenic cyst
2
Scimitar syndrome
2
Tracheal agenesis
2*
Lysinuric protein intolerance
1·6
Interstitial pneumonia with antisynthetase antibodies
1·5
Hypereosinophilic syndromes including pulmonary eosinophilia
1·5
Idiopathic and/or familial pulmonary arterial hypertension
1·5
Legionellosis
1·5
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
1
Goodpasture syndrome
0·64
Lymphangioleiomyomatosis
0·56
Birt-Hogg-Dubé syndrome
0·5
X-linked agammaglobulinaemia
0·45
Relapsing polychondritis
0·35
Adult pulmonary Langerhans cell histiocytosis
0·17
Hermansky-Pudlak syndrome
0·15
Dyskeratosis congenita
0·1
Idiopathic (autoimmune) pulmonary alveolar proteinosis
0·1
Infectious diseases are excluded from this list. Only diseases with a prevalence of more than 0·1 per 100 000 are included. Data from Orphanet.6 *At birth.
Table: Estimated prevalence (per 100 000) in Europe of some of the rare diseases that affect the lung
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genetic origin and affect only the lung (eg, lung diseases related to surfactant proteins A, B, and C), whereas others are systemic and the lung is only one of the organs affected (eg, systemic sclerosis, tuberous sclerosis, and neurofibromatosis). Other disorders affect only one sex (eg, sporadic lymphangioleiomyomatosis, which almost exclusively affects women of childbearing age). Diseases caused by one mutated gene (eg, α1-antitrypsin deficiency, surfactant protein disorders, or cystic fibrosis) could potentially lend themselves to family screening. Screening is crucial because diseases diagnosed at an early stage are more likely to be treated and, with the knowledge that a rare disease is present in the family, other members are less likely to be misdiagnosed.16 Interest in rare lung diseases has increased greatly in the past 20 years. The availability of newer instruments that increase diagnostic precision has contributed greatly to the finding that many rare lung diseases are chronic and idiopathic rather than of genetic origin, and affect adults.17 For example, according to evidence-based guidelines,18 the pattern detected by a high-resolution CT scan that is characterised by coarse subpleural, basal-predominant reticular abnormality with honeycombing (so-called usual interstitial pneumonia pattern) is diagnostic of idiopathic pulmonary fibrosis—after careful exclusion of all known causes of lung fibrosis—and obviates the need for further invasive procedures (eg, surgical lung biopsy). Idiopathic pulmonary fibrosis, the most common and lethal of all idiopathic interstitial pneumonias, with a median survival of 3 years from diagnosis, is a disease that is both rare and orphan.19 Until 2000, little effort had been put into the search for novel therapies for idiopathic pulmonary fibrosis, and only about 100 patients had been enrolled in four low-quality clinical trials. However, during the past decade, more than 3000 patients have been enrolled in clinical studies, an impressive achievement for a rare disease.20,21 But, the model for research success in rare lung diseases is pulmonary arterial hypertension, a disease that is characterised by remodelling of the small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and right ventricular failure.22,23 During the past two decades, advances in understanding of the pathobiology of pulmonary arterial hypertension have led to the completion of several successful clinical trials, and the approval of eight drugs that target several mechanistic pathways including the endothelin, nitric oxide, and prostacyclin pathways. Findings from these trials have significantly affected the prognosis and quality of life of patients;24 nonetheless, pulmonary arterial hypertension is still a severe disease with a poor prognosis.25 This approach is being used in research into idiopathic pulmonary fibrosis, and could be useful to design improved treatments for other rare lung diseases. www.thelancet.com/respiratory Vol 1 August 2013
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Diagnostic delay and unnecessary procedures
Nomenclature and coding
For many individuals who develop a rare disease, the period between the emergence of the first symptoms and the correct diagnosis often incurs unacceptable and high-risk delays. For example, many patients have repeat episodes of pneumothorax before being diagnosed with lymphangioleiomyomatosis.26 Misdiagnosis can also lead to unnecessary risks (pregnancy or air travel in the case of lymphangioleiomyomatosis, or unnecessary invasive procedures in patients with Hermansky-Pudlak syndrome who are prone to bleeding).27 Lamas and coworkers28 reported a greater than 2 year delay in access to specialised care for patients with idiopathic pulmonary fibrosis, with a longer delay associated with an increased risk of death, which was independent of disease severity. In a large observational study29 done in France, which used data from multicentre registries, a similar diagnostic delay in access was reported in patients with pulmonary arterial hypertension. This delay is particularly unacceptable given that patients with some disorders can lead a healthy life if diagnosed in a timely fashion and treated appropriately. Additionally, once correctly diagnosed a patient with a rare disease no longer needs irrelevant tests, ineffective (or even harmful) treatments, or superfluous hospital admissions, with substantial savings for the health-care system. Appropriate information and medical skills on rare diseases are insufficient, and access to care is difficult. A 2005 EURORDIS survey30 of 5980 patients with eight different rare diseases showed that 25% of patients had to wait between 5 years and 30 years from first symptoms to a final diagnosis. 40% of respondents reported an initial wrong diagnosis, which led to unnecessary interventions including inappropriate surgery (16%) and inappropriate medical therapy (33%). 10% were believed to have a psychosomatic disorder. A quarter of patients had to travel to another region for diagnosis and 2% travelled abroad. Once a diagnosis was reached, 35% felt that it was announced in “poor or unacceptable conditions”. Furthermore, and perhaps most importantly, 18% of respondents felt that they were “rejected” by a health-care professional because of disease complexity or associated symptoms. Some progress has been made in countries that have identified and designated expert centres or so-called reference centres in the specialty of rare diseases. The aims of expert centres are to increase the knowledge of the epidemiology of rare diseases; to develop information for patients, health professionals, and the general public; to organise access to diagnosis and treatment; to ensure the quality of health care; to develop support for patients’ associations; and to undertake National and European research. European Reference networks are being established by the European Commission.31 Additionally, the US National Institutes of Health has introduced a programme for undiagnosed diseases with insights into rare diseases.32
The frequency of uncommon diseases is difficult to measure precisely. A further challenge is the confusion with disease definition and coding. For example, hepatopulmonary syndrome is a rare disorder (which arises in the setting of commonly-occurring liver diseases) and is defined by liver disease, intrapulmonary vascular dilatation, and abnormal gas exchange.33 However, because the definition of abnormal gas exchange varies widely, diverse diagnostic thresholds complicate patient identification and recruitment.11 Similarly, most physicians are unfamiliar with the complex diagnostic criteria required for proper coding of rare diseases. The US National Center for Health Statistics reported an almost ten-fold increase in idiopathic pulmonary arterial hypertension mortality in individuals older than 65 years between 1979 and 2002,34 whereas 2010 survival analyses35–37 from large registries reported better survival estimates. The sudden change in mortality is a result of both misclassification of patients with suspected idiopathic pulmonary arterial hypertension in databases predating the early 2000s and changes in the International Classification of Diseases (ICD) nomenclature.38 The ICD coding system distinguishes only “primary or idiopathic” (ICD code 416·0) or “secondary” (416·8) pulmonary hypertension, and many of the disorders listed by Orphanet (with Orpha codes) do not have an ICD code, emphasising the inadequacy of the present system of disease classification. Clearly, the revision of the 10th version of the ICD is urgently needed. Furthermore, expert consensus statements and guidelines—not available for most rare diseases—would undoubtedly help with consistent disease definitions and harmonisation of diagnosis and management across nations.
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Clinical research in rare diseases 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 best evidence on which to assess the efficacy of a novel medical treatment,39 are often impossible to do (or are severely underpowered). Therefore, many orphan medicines are prohibited from receiving marketing authorisation. Alternative study designs and methods such as single patient, crossover, sequential, and adaptive study approaches have been used, although none is universally applicable.40 A clinical trial41 of itraconazole in patients with chronic granulomatous disease—a rare disorder in which the 481
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failure of phagocytes to produce hydrogen peroxide causes recurrent life-threatening infections and excessive granuloma formation that can affect the lung—has shown some of the difficulties (and options) in the investigation of new therapies for rare diseases. In this study, which took 10 years to enrol only 39 patients, the investigators used an alternating design; patients were randomly assigned to receive either itraconazole or placebo for 1 year and then switched to the other therapy every year. Thus, all participants Panel 1: Some organisations for patients with rare lung disease • • • • • • • • • • • • • • • • •
Pulmonary Fibrosis Trust: http://www.pulmonaryfibrosistrust.org Pulmonary Fibrosis UK group: http://www.pulmonaryfibrosis.org.uk Pulmonary Fibrosis Foundation: http://www.pulmonaryfibrosis.org The Coalition for Pulmonary Fibrosis: http://www.coalitionforpf.org Irish Lung Fibrosis Foundation: http://www.ilfa.ie WASOG (World Association of Sarcoidosis and Other Granulomatous Disorders)— includes several national sites: http://www.wasog.org/patient_societies.htm Sarcoidosis Association: http://www.sa-uk.org Sarcoidosis and Interstitial Lung Association: http://www.sila.org.uk Sarcoidosis National Resource Center: http://www.nsrc-global.net Raynaud’s and Scleroderma Association: http://www.raynauds.org.uk Scleroderma Society: http://www.sclerodermasociety.co.uk Scleroderma Foundation: http://www.scleroderma.org Hermansky-Pudlak Syndrome Network: http://www.hermansky-pudlak.org The Lymphangioleiomyomatosis (LAM) Foundation: http://www.thelamfoundation.org LAM Health Project: http://www.lamhealthproject.org Tuberous Sclerosis Alliance: http://www.tsalliance.org Pulmonary Hypertension Association: http://www.phassociation.org, http://www.phaeurope.org, http://www.phacanada.ca/en, http://www.phassociation.uk.com
Panel 2: Useful websites for rare diseases • Orphanet: http://www.orpha.net • Information for patients • Information for doctors • Networking research • Nomenclature of disease • Method for aiding the diagnosis of rare (especially genetic) disorders • Directory of medical laboratories providing diagnostic tests • Directory of expert centres • Inventory of orphan drugs • The European Lung Foundation: http://www.european-lung-foundation.org • The European Organisation for Rare Diseases: http://www.eurordis.org • The European Union Committee of Experts on Rare Diseases: http://www.eucerd.eu • British Paediatric Orphan Lung Disease: http://www.bpold.co.uk • National Organization for Rare Disorders (NORD): http://www.rarediseases.org • Office of Rare Disease Research, US National Institutes of Health: http://www.rarediseases.info.nih.gov • Rare Diseases Clinical Research Network, US National Institutes of Health: http://rarediseasesnetwork.epi.usf.edu • International Rare Disease Research Consortium: http://www.irdirc.org
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received both the new treatment and the placebo. This trial, which showed that itraconazole effectively reduced the frequency of fungal infections in patients with chronic granulomatous disease, shows how resource optimisation and use of non-traditional study designs could affect clinical practice on the basis of information that is less definitive than is usually needed.42 A suboptimum study design has also proved successful in patients with hereditary haemorrhagic telangiectasia—a rare inherited vascular disorder characterised by recurrent epistaxis, cutaneous telangiectasia, and visceral, including lung, arteriovenous malformations.43 In an open-label noncomparative trial44 of 25 patients, bevacizumab, a vascular endothelial growth factor inhibitor, effectively decreased both cardiac output and the number and duration of episodes of epistaxis in patients with hereditary haemorrhagic telangiectasia and severe liver involvement, although the short duration of treatment (2·5 months) and follow-up (6 months) does not allow results to be drawn on the long-term efficacy and safety of bevacizumab. Another key issue for clinical trials of orphan drugs is the choice of clinically meaningful endpoints. In disorders with a poor prognosis, survival is the most logical outcome to measure the efficacy of a given drug. However, such trial design is feasible only in diseases that are fairly common and have a short survival (eg, inoperable pancreatic carcinoma or melanoma). When a mortality study is impracticable, an alternative approach is the use of predictors of survival. For example, in idiopathic pulmonary fibrosis, forced vital capacity— an accepted measure of lung function and disease change, and the best clinically meaningful endpoint in clinical trials of this disease—is also helpful in outcome prediction. A categorical decline in forced vital capacity of 5–10% during a 6-month period is associated with an increased risk of death in the next year.45–47 Another challenge to clinical trials of rare disease is that the number of patients included is usually too small to identify uncommon side-effects; thus, a complete knowledge of the safety profile of an orphan drug can be obtained only after widespread clinical use and by means of post-marketing surveillance programmes.
Patient organisations Several well established patient organisations exist both nationally and internationally, with a focus on either a specific rare disease or rare diseases in general. These organisations are crucial in the education and support of patients and their families, in fundraising for basic and clinical research, and in encouragement of participation in clinical trials, the results of which may lead to more focused research.48,49 The LAM Foundation is a clear example of how advances can be made when patients and researchers work together towards a common goal.50 Founded in 1995 and driven by the www.thelancet.com/respiratory Vol 1 August 2013
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tremendous motivation of a mother of a young patient with lymphangioleiomyomatosis and the networking power of the internet, the LAM Foundation has funded several studies that have substantially improved our knowledge of the disease pathobiology; we now know that the disease results from the aberrant proliferation of smooth muscle-like cells (so-called lymphangioleiomyomatosis cells) that infiltrate the lungs (among other organs) and cause progressive loss of lung function and respiratory failure.51–53 Other organisations that combine education, support, and research include the Raynaud’s and Scleroderma Association in the UK, HTAP (an association of patients with pulmonary arterial hypertension) in France, and the Pulmonary Fibrosis Foundation in the USA (panel 1).
Policy initiatives Maximisation of resources and coordination of research efforts are key for success in the specialty of rare diseases. The National Organization for Rare Diseases (panel 2) is a US-based non-profit network of patient organisations, health-care providers, and individuals, which provides links to national and international rare disease groups. Similar information and support is offered in Europe by the European Organisation for Rare Disorders (panel 2), a non-governmental patientdriven coalition of patient organisations. In 2009, the European Commission established the European Union Committee of Experts on Rare Diseases (panel 2), an expert task force fostering cooperative actions across Europe in the specialty of rare diseases. Furthermore, the European Union has recommended that member countries establish and implement plans to combat rare diseases by the end of 2013.31 Since then, the European Commission and the US National Institutes for Health Research have launched the International Rare Diseases Research Consortium, which aims to promote international collaboration in the specialty of rare diseases.
Panel 4: A rare lung disease success story; from science to therapy, stimulated by a patient organisation Lymphangioleiomyomatosis is a slowly progressive lung disease, which affects women of childbearing age almost exclusively, with an estimated prevalence of 3·4–7·8 per million adult women, and a median age at diagnosis of 35 years. It is present in 30–40% of women with tuberous sclerosis complex (due to inherited mutations of the TSC1 and TSC2 genes) and occurs sporadically due to acquired somatic mutations of TSC2 in affected lymphangioleiomyomatosis cells. The disease is characterised pathologically by lung infiltration by so-called lymphangioleiomyomatosis cells (smooth muscle-like cells) that stain positive with antibodies against the pre-melanocyte protein HMB-45. The disease manifests with recurrent pneumothorax, chylous pleural effusion, gradual dyspnoea, frequent renal angiomyolipoma (benign tumours with a risk of severe bleeding), and abdominal or thoracic lymphangiomyomas. Pulmonary lymphangioleiomyomatosis causes cystic lung disease progressing to airflow obstruction and chronic respiratory failure. About half the patients have dyspnoea that restricts daily activities within 10 years from the diagnosis. The median survival free of lung transplantation is about 20–30 years. Because of its progressive, relentless course in young women, the disease has particularly pronounced effects on the patient’s life and the doctor–patient relationship.13 Although many features of lymphangioleiomyomatosis are enigmatic, remarkable progress has been made in the past decade in the understanding of disease pathophysiology and translation of basic research into the clinic with a diagnostic biomarker and effective therapy, with tremendous contribution from patients’ associations. Figure 1 shows some of the milestones of the pace of research in lymphangioleiomyomatosis.
Clinical
US Food and Drug Administration: August, 2000, to May, 2013: • Total orphan drug designations: 1789 • Total respiratory orphan drug designations: 153 • Total marketing authorisations: 166 • Total respiratory marketing authorisations: 12 European Medicines Agency: August, 2000, to May, 2013: • Total orphan drug designations: 925 • Total respiratory orphan drug designations: 93 • Total marketing authorisations: 93 • Total respiratory marketing authorisations: 11 *We searched the US Food and Drug Administration Orphan Drug Product designation database and the European Medicines Agency database.
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Time
Panel 3: Orphan drug product designations*
Genetics
Organisations
Science
Therapy
1918: First case of LAM in TSC 1937: First case of non-TSC LAM 1966–1975: Comprehensive description of LAM characteristics 1993: Discovery of TSC2 gene 1995: LAM foundation founded 1996: First LAM foundation research grant awarded 1997: Discovery of TSC1 gene 1998: TSC gene involvement in LAM identified 2000: Identification of TSC2 mutations in renal and pulmonary LAM cells 2001: TSC proteins linked to cell-signalling growth pathway 2002: Sirolimus shrinks kidney tumours in TSC mice 2002: Activation of mTOR pathway downstream of TSC in LAM 2006: Trial of efficacy of sirolimus in LAM begins 2008: Diagnostic use of VEGF-D as a biomarker 2008: Efficacy of sirolimus in angiolipomas 2009: ERS international guidelines for diagnosis and management of LAM 2011: Efficacy of sirolimus in pulmonary LAM 2012: LAM considered a low-grade metastasising neoplasm
Figure 1: Milestones in LAM clinical research and development LAM=lymphangioleiomyomatosis. TSC=tuberous sclerosis. mTOR=mammalian target of rapamycin. VEGF-D=vascular endothelial growth factor D. ERS=European Respiratory Society.
For the US Food and Drug Administration Orphan Drug Product designation database see http://www.ema.europa.eu/ ema/index.jsp?curl=pages/ medicines/landing/orphan_ search.jsp&mid= WC0b01ac058001d12b For the European Medicines Agency database see http:// www.accessdata.fda.gov/scripts/ opdlisting/oopd/
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Rare lung disease registries and clinical networks Effective progress in rare diseases requires cooperation, particularly to limit overlaps in competitive research efforts that are counterproductive when human and financial resources are scarce. In March, 1996, WHO recommended and promoted international collaborative research in α1-antitrypsin deficiency, a genetic disorder that predisposes to liver disease and early-onset emphysema.54 As a result, the Alpha One International Registry, which includes more than 4000 patients, has not only enabled epidemiological studies to be done, but has also been a valuable source for patient recruitment in clinical trials.55 A further example of a successful multidisease registry is the French Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires, which includes more than 200 physicians and has led to several important publications of rare lung disease.56–59
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 introduced economic incentives intended to stimulate research and development of orphan drugs. These economic incentives included: 7 years of market exclusivity enforced by the US Food and Drug Administration (no similar competitive products can enter the market unless superiority is shown), protocol assistance, fee reduction, regulatory advice, and tax credits. Similar legislation has been introduced in Japan (1993), Australia (1998), and the European Union (2000).60 As a result, the number of orphan drugs that have received marketing authorisation has increased considerably.61–63
Patients and medical community • Create awareness for patient needs and rights • Provide and request information • Promote research • Establish networks and communities
Industry • Research and development for new, safe, and effective drugs • Create competitive environment • Compassionate use programmes • Share knowledge
Figure 2: Multidisciplinary priorities for rare diseases
484
Authorities and regulators • Provide incentives • Foster innovation • Create framework for research and development • Grant timely and equal access to treatment • Adapt regulations to differing needs • Ensure sustainable health-care system
Drug development is a long, arduous, and expensive process that requires close interaction between academia and industry. The first step consists of basic research focusing on the cause of disease, diagnosis, and genetics, and is often undertaken at academic institutions.64 Once a promising compound has been identified, the next stage is to test its safety and efficacy in animal studies. However, the scarcity of knowledge about the pathogenesis of most rare diseases (and absence of pharmaceutical targets), and the paucity of animal models, which at best only partly represent the disease in man, are huge obstacles to preclinical studies. Despite these hurdles, clinical trials are almost exclusively pursued by industry, because this step needs large financial investment (the organisation of a clinical trial in a rare disease has major logistic difficulties as many geographically distinct sites are generally needed to recruit a sufficient number of patients) and highly trained personnel.65 At any stage of the typical 10–12 year development period for a drug, a sponsor can apply for orphan designation (panel 3). The manufacture and marketing of a drug is a long and complex process, as is the creation and maintenance of patient registries that aim to collect information about the value of a drug once it is on the market. These factors, combined with the intrinsic small market, account for the limited interest by most potential sponsors, despite the incentives provided by orphan drug legislation.66 Nonetheless, the research and development encouraged by the Orphan Drug Act has enabled patients with rare diseases to receive treatments that would otherwise never have been approved. However, for health authorities, the expanding list of products granted marketing authorisation has created budgetary dilemmas. One criticism concerns their high cost and public funding; some individuals67 have argued that—particularly in times of economic constraints— spending on rare diseases (which affect only a few patients) does not bring the greatest benefit to the greatest number of people. This criticism has been especially made about drugs previously developed for other indications but which benefit from the orphan drug legislation. However, only a few rare diseases have an available treatment, and the average number of orphan drugs approved every year remains low in the European Union and the USA.67–70 Similarly, it has been argued that orphan drug regulators have provided too many incentives, which allow companies to create a lucrative monopoly through the combination of market exclusivity and high prices. Furthermore, a critical review71 of the quality of dossiers for orphan drugs granted market authorisation identified that common weaknesses included small numbers of patients in clinical trials, short duration of studies in relation to the natural history of the disease, use of surrogate endpoints that have not been adequately validated, and the absence of an active comparator (most studies were www.thelancet.com/respiratory Vol 1 August 2013
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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 websites for information about rare disease organisations, and used information included on their websites and registration information about orphan drugs. Articles published only in English were used.
placebo controlled). However, the success of a development programme is not guaranteed, and the value of orphan drug incentives depends entirely on whether the drug is approved and whether reimbursement is granted.64 Additionally, without incentives, companies will not make the risky investments needed to develop an orphan drug (particularly for very rare diseases).72 Certainly, the chronic disability and reduced quality of life caused by most rare diseases are strong arguments in support of public funding.73
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 show that although a disorder is rare it need not remain orphan without hope of progress in treatment and management. However, this progress needs a multidisciplinary approach and equipoise in collaboration that transcends individual interests to result in a successful outcome (figure 2); thus much work needs to be done. The small number of affected patients and the scarcity of relevant knowledge and skills are major practical limitations. Maximisation of scarce resources, coordination of research efforts, and worldwide sharing of information, data, and samples are key for success in the rare diseases specialty. Specifically, the development of central databases, registries, and multinational research networks is crucial for the design and performance of much-needed robust clinical studies to be undertaken. Similarly, knowledge needs to continue to be exchanged and disseminated between experts in clinical and basic research to provide insights into science and clinical www.thelancet.com/respiratory Vol 1 August 2013
care, thus helping patients and supporting doctors. However, the most important aim is to achieve a short time to diagnosis of rare diseases; without timely diagnosis, no care plan or treatment can be effectively put in place. This aim can only be achieved with the creation of diagnostic and treatment centre networks and with the education of physicians in the diagnostic and management skills required to care for patients with rare diseases. Harmonisation of such training across national boundaries should enhance the opportunities for future national and international collaborations. Contributors PS, RMdB, and VC contributed equally to the conception, development, writing, editing, and final preparation of this Review. Conflicts of interest PS and VC declare that they have no conflicts of interest. In the past 3 years, RMdB has served on scientific advisory boards for InterMune, Actelion, and Boehringer Ingelheim; has been a consultant to Bayer, Novartis, and Merck; and has been a lecturer at symposia organised by InterMune, Boehringer Ingelheim, and GlaxoSmithKline. References 1 The European Parliament and the Council of the European Union. Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products. December, 1999. http://ec.europa.eu/health/files/eudralex/vol-1/ reg_2000_141/reg_2000_141_en.pdf (accessed June 8, 2013). 2 US Food and Drug Administration. Congressional findings for the orphan drug act. January, 1983. http://www.fda.gov/Regulatory Information/Legislation/FederalFoodDrugandCosmeticAct FDCAct/SignificantAmendmentstotheFDCAct/OrphanDrugAct/ default.htm (accessed June 8, 2013). 3 Hennekam RC. Care for patients with ultra-rare disorders. Eur J Med Genet 2011; 54: 220–24. 4 Schieppati A, Henter JI, Daina E, Aperia A. Why rare diseases are an important medical and social issue. Lancet 2008; 371: 2039–41. 5 Heemstra HE, van Weely S, Büller HA, Leufkens HG, de Vrueh RL. Translation of rare disease research into orphan drug development: disease matters. Drug Discov Today 2009; 14: 1166–73. 6 Orphanet. Orphanet report series – prevalence of rare diseases: bibliographic data. November, 2012. http://www.orpha.net/ orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_ decreasing_prevalence_or_cases.pdf (accessed June 8, 2013). 7 American Thoracic Society. Breathing in America: Diseases, progress, and hope. Chapter 18 – Rare lung diseases, 2010. http:// www.thoracic.org/education/breathing-in-america/resources/ chapter-18-rare-lung-diseases.pdf (accessed June 11, 2013). 8 Weston M, Manning J. Forgotten conditions: misdiagnosed and unsupported, how patients are being let down. September, 2012. http://www.2020health.org/dms/2020health/downloads/ reports/2020ForgCond_20-09-12b-1.pdf (accessed June 8, 2013). 9 Knight AW, Senior TP. The common problem of rare disease in general practice. Med J Aust 2006; 185: 82–83. 10 Knight AW, Taruscio D. International conferences on rare diseases: initiatives in commitment, patient care and connections. Med J Aust 2007; 187: 74–77. 11 Gupta S, Bayoumi AM, Faughnan ME. Rare lung disease research: strategies for improving identification and recruitment of research participants. Chest 2011; 140: 1123–29. 12 Haffner ME, Whitley J, Moses M. Two decades of orphan product development. Nat Rev Drug Discov 2002; 1: 821–25. 13 Luisetti M, Balfour-Lynn IM, Johnson SR, et al. Perspectives for improving the evaluation and access of therapies for rare lung diseases in Europe. Respir Med 2012; 106: 759–68. 14 Cordier J-F. Introduction. Eur Respir Mon 2011; 54: vii–viii. http://erm.ersjournals.com/content/ermold/1/SEC3.body.pdf+html (accessed June 8, 2013).
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Rare lung disease and orphan drug development Paolo Spagnolo, Roland M du Bois, Vincent Cottin
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.
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Introduction
See Articles page 445
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.
Rare diseases 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 www.thelancet.com/respiratory Vol 1 August 2013
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 patient, the annual total cost in the USA amounts to billions of dollars.7 The rarer the disorder, the more tests and health-care visits are usually needed to make the correct diagnosis, which results in greater expense, unnecessary tests, and missed opportunities for early intervention. Additionally, a 2012 report8 from the UK emphasises the existence of excessive variation in care across the National Health Service between patients with rare diseases; this inequity is intolerable for patients, and contributes to their loss of confidence in the healthcare system.
Diagnostic difficulties During their career any specialist or general practitioner will come across a patient with a rare disease. In such circumstances, physicians should consider the possibility that the patient has a rare disease (and refer them to specialised centres where the diagnosis can be confirmed); however, diagnosis can be difficult because symptoms might be masked, misunderstood, or mistaken for other more common diseases that share similar symptoms, especially in the early stages.9 Specific clusters of atypical symptoms, delayed or unexpected responses to therapy, and suggestive family history could precipitate early referral to specialist units.10,11 The need for more global and accessible educational methods for rare diseases is clear.
Published Online June 25, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70085-7 See Editorial page 423 See Comment page 424 See Spotlight page 443
Centre for Rare Lung Diseases, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Modena, Italy (P Spagnolo MD); Imperial College, London, UK (Emeritus Prof R M du Bois MD); and National Reference Centre for Rare Pulmonary Diseases, Department of Respiratory Medicine, Louis Pradel Hospital, Hospices Civils de Lyon, University Claude Bernard Lyon 1, Lyon, France (Prof V Cottin MD) Correspondence to: Dr Paolo Spagnolo, Centre for Rare Lung Diseases, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Modena, Italy [email protected]
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 affect only a few hundred people worldwide (eg, pulmonary alveolar microlithiasis or 479
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idiopathic pulmonary haemosiderosis), or even fewer (eg, hereditary emphysema due to elastin mutations with cutis laxa). Furthermore, few disorders are of Estimated prevalence (per 100 000) α1-antitrypsin deficiency
33
Adult acute respiratory distress syndrome
30
Idiopathic pulmonary fibrosis
26
Systemic sclerosis
21·5
Pulmonary arterial hypertension
19·5
Chronic thromboembolic pulmonary hypertension
17
Dermatomyositis, polymyositis
17
Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease)
16·25
Sarcoidosis
15
Bronchopulmonary dysplasia
13
Cystic fibrosis
12·6
Small-cell lung cancer
11·2
Tuberous sclerosis
8·8
Granulomatosis with polyangiitis (Wegener’s)
6·6
Primary ciliary dyskinesia
5
Congenital lobar emphysema
4·5
Common variable immunodeficiency
4
Acute interstitial pneumonia
3·8
Mixed connective tissue disease
3·8
Mesothelioma
3·1
Graft versus host disease
2·76
Bronchogenic cyst
2
Scimitar syndrome
2
Tracheal agenesis
2*
Lysinuric protein intolerance
1·6
Interstitial pneumonia with antisynthetase antibodies
1·5
Hypereosinophilic syndromes including pulmonary eosinophilia
1·5
Idiopathic and/or familial pulmonary arterial hypertension
1·5
Legionellosis
1·5
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
1
Goodpasture syndrome
0·64
Lymphangioleiomyomatosis
0·56
Birt-Hogg-Dubé syndrome
0·5
X-linked agammaglobulinaemia
0·45
Relapsing polychondritis
0·35
Adult pulmonary Langerhans cell histiocytosis
0·17
Hermansky-Pudlak syndrome
0·15
Dyskeratosis congenita
0·1
Idiopathic (autoimmune) pulmonary alveolar proteinosis
0·1
Infectious diseases are excluded from this list. Only diseases with a prevalence of more than 0·1 per 100 000 are included. Data from Orphanet.6 *At birth.
Table: Estimated prevalence (per 100 000) in Europe of some of the rare diseases that affect the lung
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genetic origin and affect only the lung (eg, lung diseases related to surfactant proteins A, B, and C), whereas others are systemic and the lung is only one of the organs affected (eg, systemic sclerosis, tuberous sclerosis, and neurofibromatosis). Other disorders affect only one sex (eg, sporadic lymphangioleiomyomatosis, which almost exclusively affects women of childbearing age). Diseases caused by one mutated gene (eg, α1-antitrypsin deficiency, surfactant protein disorders, or cystic fibrosis) could potentially lend themselves to family screening. Screening is crucial because diseases diagnosed at an early stage are more likely to be treated and, with the knowledge that a rare disease is present in the family, other members are less likely to be misdiagnosed.16 Interest in rare lung diseases has increased greatly in the past 20 years. The availability of newer instruments that increase diagnostic precision has contributed greatly to the finding that many rare lung diseases are chronic and idiopathic rather than of genetic origin, and affect adults.17 For example, according to evidence-based guidelines,18 the pattern detected by a high-resolution CT scan that is characterised by coarse subpleural, basal-predominant reticular abnormality with honeycombing (so-called usual interstitial pneumonia pattern) is diagnostic of idiopathic pulmonary fibrosis—after careful exclusion of all known causes of lung fibrosis—and obviates the need for further invasive procedures (eg, surgical lung biopsy). Idiopathic pulmonary fibrosis, the most common and lethal of all idiopathic interstitial pneumonias, with a median survival of 3 years from diagnosis, is a disease that is both rare and orphan.19 Until 2000, little effort had been put into the search for novel therapies for idiopathic pulmonary fibrosis, and only about 100 patients had been enrolled in four low-quality clinical trials. However, during the past decade, more than 3000 patients have been enrolled in clinical studies, an impressive achievement for a rare disease.20,21 But, the model for research success in rare lung diseases is pulmonary arterial hypertension, a disease that is characterised by remodelling of the small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and right ventricular failure.22,23 During the past two decades, advances in understanding of the pathobiology of pulmonary arterial hypertension have led to the completion of several successful clinical trials, and the approval of eight drugs that target several mechanistic pathways including the endothelin, nitric oxide, and prostacyclin pathways. Findings from these trials have significantly affected the prognosis and quality of life of patients;24 nonetheless, pulmonary arterial hypertension is still a severe disease with a poor prognosis.25 This approach is being used in research into idiopathic pulmonary fibrosis, and could be useful to design improved treatments for other rare lung diseases. www.thelancet.com/respiratory Vol 1 August 2013
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Diagnostic delay and unnecessary procedures
Nomenclature and coding
For many individuals who develop a rare disease, the period between the emergence of the first symptoms and the correct diagnosis often incurs unacceptable and high-risk delays. For example, many patients have repeat episodes of pneumothorax before being diagnosed with lymphangioleiomyomatosis.26 Misdiagnosis can also lead to unnecessary risks (pregnancy or air travel in the case of lymphangioleiomyomatosis, or unnecessary invasive procedures in patients with Hermansky-Pudlak syndrome who are prone to bleeding).27 Lamas and coworkers28 reported a greater than 2 year delay in access to specialised care for patients with idiopathic pulmonary fibrosis, with a longer delay associated with an increased risk of death, which was independent of disease severity. In a large observational study29 done in France, which used data from multicentre registries, a similar diagnostic delay in access was reported in patients with pulmonary arterial hypertension. This delay is particularly unacceptable given that patients with some disorders can lead a healthy life if diagnosed in a timely fashion and treated appropriately. Additionally, once correctly diagnosed a patient with a rare disease no longer needs irrelevant tests, ineffective (or even harmful) treatments, or superfluous hospital admissions, with substantial savings for the health-care system. Appropriate information and medical skills on rare diseases are insufficient, and access to care is difficult. A 2005 EURORDIS survey30 of 5980 patients with eight different rare diseases showed that 25% of patients had to wait between 5 years and 30 years from first symptoms to a final diagnosis. 40% of respondents reported an initial wrong diagnosis, which led to unnecessary interventions including inappropriate surgery (16%) and inappropriate medical therapy (33%). 10% were believed to have a psychosomatic disorder. A quarter of patients had to travel to another region for diagnosis and 2% travelled abroad. Once a diagnosis was reached, 35% felt that it was announced in “poor or unacceptable conditions”. Furthermore, and perhaps most importantly, 18% of respondents felt that they were “rejected” by a health-care professional because of disease complexity or associated symptoms. Some progress has been made in countries that have identified and designated expert centres or so-called reference centres in the specialty of rare diseases. The aims of expert centres are to increase the knowledge of the epidemiology of rare diseases; to develop information for patients, health professionals, and the general public; to organise access to diagnosis and treatment; to ensure the quality of health care; to develop support for patients’ associations; and to undertake National and European research. European Reference networks are being established by the European Commission.31 Additionally, the US National Institutes of Health has introduced a programme for undiagnosed diseases with insights into rare diseases.32
The frequency of uncommon diseases is difficult to measure precisely. A further challenge is the confusion with disease definition and coding. For example, hepatopulmonary syndrome is a rare disorder (which arises in the setting of commonly-occurring liver diseases) and is defined by liver disease, intrapulmonary vascular dilatation, and abnormal gas exchange.33 However, because the definition of abnormal gas exchange varies widely, diverse diagnostic thresholds complicate patient identification and recruitment.11 Similarly, most physicians are unfamiliar with the complex diagnostic criteria required for proper coding of rare diseases. The US National Center for Health Statistics reported an almost ten-fold increase in idiopathic pulmonary arterial hypertension mortality in individuals older than 65 years between 1979 and 2002,34 whereas 2010 survival analyses35–37 from large registries reported better survival estimates. The sudden change in mortality is a result of both misclassification of patients with suspected idiopathic pulmonary arterial hypertension in databases predating the early 2000s and changes in the International Classification of Diseases (ICD) nomenclature.38 The ICD coding system distinguishes only “primary or idiopathic” (ICD code 416·0) or “secondary” (416·8) pulmonary hypertension, and many of the disorders listed by Orphanet (with Orpha codes) do not have an ICD code, emphasising the inadequacy of the present system of disease classification. Clearly, the revision of the 10th version of the ICD is urgently needed. Furthermore, expert consensus statements and guidelines—not available for most rare diseases—would undoubtedly help with consistent disease definitions and harmonisation of diagnosis and management across nations.
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Clinical research in rare diseases 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 best evidence on which to assess the efficacy of a novel medical treatment,39 are often impossible to do (or are severely underpowered). Therefore, many orphan medicines are prohibited from receiving marketing authorisation. Alternative study designs and methods such as single patient, crossover, sequential, and adaptive study approaches have been used, although none is universally applicable.40 A clinical trial41 of itraconazole in patients with chronic granulomatous disease—a rare disorder in which the 481
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failure of phagocytes to produce hydrogen peroxide causes recurrent life-threatening infections and excessive granuloma formation that can affect the lung—has shown some of the difficulties (and options) in the investigation of new therapies for rare diseases. In this study, which took 10 years to enrol only 39 patients, the investigators used an alternating design; patients were randomly assigned to receive either itraconazole or placebo for 1 year and then switched to the other therapy every year. Thus, all participants Panel 1: Some organisations for patients with rare lung disease • • • • • • • • • • • • • • • • •
Pulmonary Fibrosis Trust: http://www.pulmonaryfibrosistrust.org Pulmonary Fibrosis UK group: http://www.pulmonaryfibrosis.org.uk Pulmonary Fibrosis Foundation: http://www.pulmonaryfibrosis.org The Coalition for Pulmonary Fibrosis: http://www.coalitionforpf.org Irish Lung Fibrosis Foundation: http://www.ilfa.ie WASOG (World Association of Sarcoidosis and Other Granulomatous Disorders)— includes several national sites: http://www.wasog.org/patient_societies.htm Sarcoidosis Association: http://www.sa-uk.org Sarcoidosis and Interstitial Lung Association: http://www.sila.org.uk Sarcoidosis National Resource Center: http://www.nsrc-global.net Raynaud’s and Scleroderma Association: http://www.raynauds.org.uk Scleroderma Society: http://www.sclerodermasociety.co.uk Scleroderma Foundation: http://www.scleroderma.org Hermansky-Pudlak Syndrome Network: http://www.hermansky-pudlak.org The Lymphangioleiomyomatosis (LAM) Foundation: http://www.thelamfoundation.org LAM Health Project: http://www.lamhealthproject.org Tuberous Sclerosis Alliance: http://www.tsalliance.org Pulmonary Hypertension Association: http://www.phassociation.org, http://www.phaeurope.org, http://www.phacanada.ca/en, http://www.phassociation.uk.com
Panel 2: Useful websites for rare diseases • Orphanet: http://www.orpha.net • Information for patients • Information for doctors • Networking research • Nomenclature of disease • Method for aiding the diagnosis of rare (especially genetic) disorders • Directory of medical laboratories providing diagnostic tests • Directory of expert centres • Inventory of orphan drugs • The European Lung Foundation: http://www.european-lung-foundation.org • The European Organisation for Rare Diseases: http://www.eurordis.org • The European Union Committee of Experts on Rare Diseases: http://www.eucerd.eu • British Paediatric Orphan Lung Disease: http://www.bpold.co.uk • National Organization for Rare Disorders (NORD): http://www.rarediseases.org • Office of Rare Disease Research, US National Institutes of Health: http://www.rarediseases.info.nih.gov • Rare Diseases Clinical Research Network, US National Institutes of Health: http://rarediseasesnetwork.epi.usf.edu • International Rare Disease Research Consortium: http://www.irdirc.org
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received both the new treatment and the placebo. This trial, which showed that itraconazole effectively reduced the frequency of fungal infections in patients with chronic granulomatous disease, shows how resource optimisation and use of non-traditional study designs could affect clinical practice on the basis of information that is less definitive than is usually needed.42 A suboptimum study design has also proved successful in patients with hereditary haemorrhagic telangiectasia—a rare inherited vascular disorder characterised by recurrent epistaxis, cutaneous telangiectasia, and visceral, including lung, arteriovenous malformations.43 In an open-label noncomparative trial44 of 25 patients, bevacizumab, a vascular endothelial growth factor inhibitor, effectively decreased both cardiac output and the number and duration of episodes of epistaxis in patients with hereditary haemorrhagic telangiectasia and severe liver involvement, although the short duration of treatment (2·5 months) and follow-up (6 months) does not allow results to be drawn on the long-term efficacy and safety of bevacizumab. Another key issue for clinical trials of orphan drugs is the choice of clinically meaningful endpoints. In disorders with a poor prognosis, survival is the most logical outcome to measure the efficacy of a given drug. However, such trial design is feasible only in diseases that are fairly common and have a short survival (eg, inoperable pancreatic carcinoma or melanoma). When a mortality study is impracticable, an alternative approach is the use of predictors of survival. For example, in idiopathic pulmonary fibrosis, forced vital capacity— an accepted measure of lung function and disease change, and the best clinically meaningful endpoint in clinical trials of this disease—is also helpful in outcome prediction. A categorical decline in forced vital capacity of 5–10% during a 6-month period is associated with an increased risk of death in the next year.45–47 Another challenge to clinical trials of rare disease is that the number of patients included is usually too small to identify uncommon side-effects; thus, a complete knowledge of the safety profile of an orphan drug can be obtained only after widespread clinical use and by means of post-marketing surveillance programmes.
Patient organisations Several well established patient organisations exist both nationally and internationally, with a focus on either a specific rare disease or rare diseases in general. These organisations are crucial in the education and support of patients and their families, in fundraising for basic and clinical research, and in encouragement of participation in clinical trials, the results of which may lead to more focused research.48,49 The LAM Foundation is a clear example of how advances can be made when patients and researchers work together towards a common goal.50 Founded in 1995 and driven by the www.thelancet.com/respiratory Vol 1 August 2013
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tremendous motivation of a mother of a young patient with lymphangioleiomyomatosis and the networking power of the internet, the LAM Foundation has funded several studies that have substantially improved our knowledge of the disease pathobiology; we now know that the disease results from the aberrant proliferation of smooth muscle-like cells (so-called lymphangioleiomyomatosis cells) that infiltrate the lungs (among other organs) and cause progressive loss of lung function and respiratory failure.51–53 Other organisations that combine education, support, and research include the Raynaud’s and Scleroderma Association in the UK, HTAP (an association of patients with pulmonary arterial hypertension) in France, and the Pulmonary Fibrosis Foundation in the USA (panel 1).
Policy initiatives Maximisation of resources and coordination of research efforts are key for success in the specialty of rare diseases. The National Organization for Rare Diseases (panel 2) is a US-based non-profit network of patient organisations, health-care providers, and individuals, which provides links to national and international rare disease groups. Similar information and support is offered in Europe by the European Organisation for Rare Disorders (panel 2), a non-governmental patientdriven coalition of patient organisations. In 2009, the European Commission established the European Union Committee of Experts on Rare Diseases (panel 2), an expert task force fostering cooperative actions across Europe in the specialty of rare diseases. Furthermore, the European Union has recommended that member countries establish and implement plans to combat rare diseases by the end of 2013.31 Since then, the European Commission and the US National Institutes for Health Research have launched the International Rare Diseases Research Consortium, which aims to promote international collaboration in the specialty of rare diseases.
Panel 4: A rare lung disease success story; from science to therapy, stimulated by a patient organisation Lymphangioleiomyomatosis is a slowly progressive lung disease, which affects women of childbearing age almost exclusively, with an estimated prevalence of 3·4–7·8 per million adult women, and a median age at diagnosis of 35 years. It is present in 30–40% of women with tuberous sclerosis complex (due to inherited mutations of the TSC1 and TSC2 genes) and occurs sporadically due to acquired somatic mutations of TSC2 in affected lymphangioleiomyomatosis cells. The disease is characterised pathologically by lung infiltration by so-called lymphangioleiomyomatosis cells (smooth muscle-like cells) that stain positive with antibodies against the pre-melanocyte protein HMB-45. The disease manifests with recurrent pneumothorax, chylous pleural effusion, gradual dyspnoea, frequent renal angiomyolipoma (benign tumours with a risk of severe bleeding), and abdominal or thoracic lymphangiomyomas. Pulmonary lymphangioleiomyomatosis causes cystic lung disease progressing to airflow obstruction and chronic respiratory failure. About half the patients have dyspnoea that restricts daily activities within 10 years from the diagnosis. The median survival free of lung transplantation is about 20–30 years. Because of its progressive, relentless course in young women, the disease has particularly pronounced effects on the patient’s life and the doctor–patient relationship.13 Although many features of lymphangioleiomyomatosis are enigmatic, remarkable progress has been made in the past decade in the understanding of disease pathophysiology and translation of basic research into the clinic with a diagnostic biomarker and effective therapy, with tremendous contribution from patients’ associations. Figure 1 shows some of the milestones of the pace of research in lymphangioleiomyomatosis.
Clinical
US Food and Drug Administration: August, 2000, to May, 2013: • Total orphan drug designations: 1789 • Total respiratory orphan drug designations: 153 • Total marketing authorisations: 166 • Total respiratory marketing authorisations: 12 European Medicines Agency: August, 2000, to May, 2013: • Total orphan drug designations: 925 • Total respiratory orphan drug designations: 93 • Total marketing authorisations: 93 • Total respiratory marketing authorisations: 11 *We searched the US Food and Drug Administration Orphan Drug Product designation database and the European Medicines Agency database.
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Panel 3: Orphan drug product designations*
Genetics
Organisations
Science
Therapy
1918: First case of LAM in TSC 1937: First case of non-TSC LAM 1966–1975: Comprehensive description of LAM characteristics 1993: Discovery of TSC2 gene 1995: LAM foundation founded 1996: First LAM foundation research grant awarded 1997: Discovery of TSC1 gene 1998: TSC gene involvement in LAM identified 2000: Identification of TSC2 mutations in renal and pulmonary LAM cells 2001: TSC proteins linked to cell-signalling growth pathway 2002: Sirolimus shrinks kidney tumours in TSC mice 2002: Activation of mTOR pathway downstream of TSC in LAM 2006: Trial of efficacy of sirolimus in LAM begins 2008: Diagnostic use of VEGF-D as a biomarker 2008: Efficacy of sirolimus in angiolipomas 2009: ERS international guidelines for diagnosis and management of LAM 2011: Efficacy of sirolimus in pulmonary LAM 2012: LAM considered a low-grade metastasising neoplasm
Figure 1: Milestones in LAM clinical research and development LAM=lymphangioleiomyomatosis. TSC=tuberous sclerosis. mTOR=mammalian target of rapamycin. VEGF-D=vascular endothelial growth factor D. ERS=European Respiratory Society.
For the US Food and Drug Administration Orphan Drug Product designation database see http://www.ema.europa.eu/ ema/index.jsp?curl=pages/ medicines/landing/orphan_ search.jsp&mid= WC0b01ac058001d12b For the European Medicines Agency database see http:// www.accessdata.fda.gov/scripts/ opdlisting/oopd/
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Rare lung disease registries and clinical networks Effective progress in rare diseases requires cooperation, particularly to limit overlaps in competitive research efforts that are counterproductive when human and financial resources are scarce. In March, 1996, WHO recommended and promoted international collaborative research in α1-antitrypsin deficiency, a genetic disorder that predisposes to liver disease and early-onset emphysema.54 As a result, the Alpha One International Registry, which includes more than 4000 patients, has not only enabled epidemiological studies to be done, but has also been a valuable source for patient recruitment in clinical trials.55 A further example of a successful multidisease registry is the French Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires, which includes more than 200 physicians and has led to several important publications of rare lung disease.56–59
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 introduced economic incentives intended to stimulate research and development of orphan drugs. These economic incentives included: 7 years of market exclusivity enforced by the US Food and Drug Administration (no similar competitive products can enter the market unless superiority is shown), protocol assistance, fee reduction, regulatory advice, and tax credits. Similar legislation has been introduced in Japan (1993), Australia (1998), and the European Union (2000).60 As a result, the number of orphan drugs that have received marketing authorisation has increased considerably.61–63
Patients and medical community • Create awareness for patient needs and rights • Provide and request information • Promote research • Establish networks and communities
Industry • Research and development for new, safe, and effective drugs • Create competitive environment • Compassionate use programmes • Share knowledge
Figure 2: Multidisciplinary priorities for rare diseases
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Authorities and regulators • Provide incentives • Foster innovation • Create framework for research and development • Grant timely and equal access to treatment • Adapt regulations to differing needs • Ensure sustainable health-care system
Drug development is a long, arduous, and expensive process that requires close interaction between academia and industry. The first step consists of basic research focusing on the cause of disease, diagnosis, and genetics, and is often undertaken at academic institutions.64 Once a promising compound has been identified, the next stage is to test its safety and efficacy in animal studies. However, the scarcity of knowledge about the pathogenesis of most rare diseases (and absence of pharmaceutical targets), and the paucity of animal models, which at best only partly represent the disease in man, are huge obstacles to preclinical studies. Despite these hurdles, clinical trials are almost exclusively pursued by industry, because this step needs large financial investment (the organisation of a clinical trial in a rare disease has major logistic difficulties as many geographically distinct sites are generally needed to recruit a sufficient number of patients) and highly trained personnel.65 At any stage of the typical 10–12 year development period for a drug, a sponsor can apply for orphan designation (panel 3). The manufacture and marketing of a drug is a long and complex process, as is the creation and maintenance of patient registries that aim to collect information about the value of a drug once it is on the market. These factors, combined with the intrinsic small market, account for the limited interest by most potential sponsors, despite the incentives provided by orphan drug legislation.66 Nonetheless, the research and development encouraged by the Orphan Drug Act has enabled patients with rare diseases to receive treatments that would otherwise never have been approved. However, for health authorities, the expanding list of products granted marketing authorisation has created budgetary dilemmas. One criticism concerns their high cost and public funding; some individuals67 have argued that—particularly in times of economic constraints— spending on rare diseases (which affect only a few patients) does not bring the greatest benefit to the greatest number of people. This criticism has been especially made about drugs previously developed for other indications but which benefit from the orphan drug legislation. However, only a few rare diseases have an available treatment, and the average number of orphan drugs approved every year remains low in the European Union and the USA.67–70 Similarly, it has been argued that orphan drug regulators have provided too many incentives, which allow companies to create a lucrative monopoly through the combination of market exclusivity and high prices. Furthermore, a critical review71 of the quality of dossiers for orphan drugs granted market authorisation identified that common weaknesses included small numbers of patients in clinical trials, short duration of studies in relation to the natural history of the disease, use of surrogate endpoints that have not been adequately validated, and the absence of an active comparator (most studies were www.thelancet.com/respiratory Vol 1 August 2013
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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 websites for information about rare disease organisations, and used information included on their websites and registration information about orphan drugs. Articles published only in English were used.
placebo controlled). However, the success of a development programme is not guaranteed, and the value of orphan drug incentives depends entirely on whether the drug is approved and whether reimbursement is granted.64 Additionally, without incentives, companies will not make the risky investments needed to develop an orphan drug (particularly for very rare diseases).72 Certainly, the chronic disability and reduced quality of life caused by most rare diseases are strong arguments in support of public funding.73
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 show that although a disorder is rare it need not remain orphan without hope of progress in treatment and management. However, this progress needs a multidisciplinary approach and equipoise in collaboration that transcends individual interests to result in a successful outcome (figure 2); thus much work needs to be done. The small number of affected patients and the scarcity of relevant knowledge and skills are major practical limitations. Maximisation of scarce resources, coordination of research efforts, and worldwide sharing of information, data, and samples are key for success in the rare diseases specialty. Specifically, the development of central databases, registries, and multinational research networks is crucial for the design and performance of much-needed robust clinical studies to be undertaken. Similarly, knowledge needs to continue to be exchanged and disseminated between experts in clinical and basic research to provide insights into science and clinical www.thelancet.com/respiratory Vol 1 August 2013
care, thus helping patients and supporting doctors. However, the most important aim is to achieve a short time to diagnosis of rare diseases; without timely diagnosis, no care plan or treatment can be effectively put in place. This aim can only be achieved with the creation of diagnostic and treatment centre networks and with the education of physicians in the diagnostic and management skills required to care for patients with rare diseases. Harmonisation of such training across national boundaries should enhance the opportunities for future national and international collaborations. Contributors PS, RMdB, and VC contributed equally to the conception, development, writing, editing, and final preparation of this Review. Conflicts of interest PS and VC declare that they have no conflicts of interest. In the past 3 years, RMdB has served on scientific advisory boards for InterMune, Actelion, and Boehringer Ingelheim; has been a consultant to Bayer, Novartis, and Merck; and has been a lecturer at symposia organised by InterMune, Boehringer Ingelheim, and GlaxoSmithKline. References 1 The European Parliament and the Council of the European Union. Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products. December, 1999. http://ec.europa.eu/health/files/eudralex/vol-1/ reg_2000_141/reg_2000_141_en.pdf (accessed June 8, 2013). 2 US Food and Drug Administration. Congressional findings for the orphan drug act. January, 1983. http://www.fda.gov/Regulatory Information/Legislation/FederalFoodDrugandCosmeticAct FDCAct/SignificantAmendmentstotheFDCAct/OrphanDrugAct/ default.htm (accessed June 8, 2013). 3 Hennekam RC. Care for patients with ultra-rare disorders. Eur J Med Genet 2011; 54: 220–24. 4 Schieppati A, Henter JI, Daina E, Aperia A. Why rare diseases are an important medical and social issue. Lancet 2008; 371: 2039–41. 5 Heemstra HE, van Weely S, Büller HA, Leufkens HG, de Vrueh RL. Translation of rare disease research into orphan drug development: disease matters. Drug Discov Today 2009; 14: 1166–73. 6 Orphanet. Orphanet report series – prevalence of rare diseases: bibliographic data. November, 2012. http://www.orpha.net/ orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_ decreasing_prevalence_or_cases.pdf (accessed June 8, 2013). 7 American Thoracic Society. Breathing in America: Diseases, progress, and hope. Chapter 18 – Rare lung diseases, 2010. http:// www.thoracic.org/education/breathing-in-america/resources/ chapter-18-rare-lung-diseases.pdf (accessed June 11, 2013). 8 Weston M, Manning J. Forgotten conditions: misdiagnosed and unsupported, how patients are being let down. September, 2012. http://www.2020health.org/dms/2020health/downloads/ reports/2020ForgCond_20-09-12b-1.pdf (accessed June 8, 2013). 9 Knight AW, Senior TP. The common problem of rare disease in general practice. Med J Aust 2006; 185: 82–83. 10 Knight AW, Taruscio D. International conferences on rare diseases: initiatives in commitment, patient care and connections. Med J Aust 2007; 187: 74–77. 11 Gupta S, Bayoumi AM, Faughnan ME. Rare lung disease research: strategies for improving identification and recruitment of research participants. Chest 2011; 140: 1123–29. 12 Haffner ME, Whitley J, Moses M. Two decades of orphan product development. Nat Rev Drug Discov 2002; 1: 821–25. 13 Luisetti M, Balfour-Lynn IM, Johnson SR, et al. Perspectives for improving the evaluation and access of therapies for rare lung diseases in Europe. Respir Med 2012; 106: 759–68. 14 Cordier J-F. Introduction. Eur Respir Mon 2011; 54: vii–viii. http://erm.ersjournals.com/content/ermold/1/SEC3.body.pdf+html (accessed June 8, 2013).
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