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Therapeutics

Clinical Development in Rare Diseases: Idiopathic Pulmonary Fibrosis The medical term ‘rare disease’ has some variability in it as the definition of rarity is not standardised internationally. But in general, frequency is defined by the number of affected individuals in the population. Some of these illnesses are extremely rare, so known to be affected by only a few or a few dozens of people in the world, while others occur in hundreds, thousands, or more people. The ‘cut-off point’ of rarity is defined variously in different regions of the world. It is set as 1:1600 in the US1, 1:2000 in the European Union2 and 1:2500 in Japan3. Furthermore, regulation in the EU defines drugs for rare disease as drugs that cure life-threatening or chronically debilitating condition with less than 50 per 100,000 prevalence4. Despite relatively sparse manifestation, the cumulative prevalence of rare disease in the global population is estimated at 6–8 per cent5. For example, one in 17 European citizens suffer from a rare disease (around 30 million people)6. Rare diseases might occur in any part of the body and they often affect several organs, causing life-threatening or chronic debilitating conditions with high complexity. Most of the patients concerned have some disability and their quality of life is impaired by the loss of their autonomy and/or the accompanying severe pain. To date, approximately 7000 rare diseases have been described7. Considering the financial burden and specific therapeutic challenges that rare disease can bring upon modern healthcare systems, their significance is increasingly recognised. Drugs to treat rare medical conditions are called ‘orphan drugs’. From a drug development perspective, orphan drugs present high investment risks compared to widely marketable products due to the relatively small patient population. To encourage drug development for rare diseases, the ‘orphan status’ of a disease/drug is increasingly getting support in competent authorities in various countries. For example, in the US and EU, an orphan designation programme was launched to encourage companies to invest in research and development of new treatments for rare diseases8. Without these incentives it would have been unlikely that the marketing of the product would generate sufficient return to justify the necessary investment. Idiopathic pulmonary fibrosis (IPF) is a rare disease, which affects approximately 15 in each 100,000 people in the EU (which is equivalent to an average of 76,000 inhabitants9); with a prevalence of 38.82 per 100,000 people in the UK (2012)10 and 42.7 per 100,000 in the US (2006)11, both per the broader epidemiologic definition. Notably, its incidence has significantly increased in the third millenium in UK12,13. IPF patients are most often affected from middle age, with a mean age of 66 years at the time of diagnosis14. Manifestation of IPF is limited to the lungs, and characterised by severe, irreversible interstitial fibrosis. The prognosis of IPF is 28 Journal for Clinical Studies

poor with a mean survival of two to three years from the initial diagnosis15. Current Clinical Management The pathogenesis and the aetiology of IPF is presumably multifactorial but clearly not known in depth; however, genetic predisposition and age-related cell deterioration are assumed16. Whereas the ‘honeycombing’ picture is observed in the disease as macroscopic manifestation of the epithelial damage itself, the fibrosis is sustained by the aberrant epithelial repair at the site of the injury17. The progenitor lung epithelial cells which normally replenish the type 2 alveolar epithel cells fail to carry out their function properly: their activation is prolonged with constant release of profibrotic mediators and growth factors, which are referred to as senescence-associated secretory phenotype (SASP) factors18. The adjacent mesenchymal cells and myofibroblasts are the final effectors of scar formation and fibrous transformation of the pulmonary tissue. Senescence and consequent resistance to cell apoptosis also affect the fibroblasts and contribute to their aberrant function as well. By the time the IFP diagnosis is established, the pulmonary tissue is markedly damaged19. Effort dyspnoea is the leading symptom of the disease at the time of the diagnosis and during progression it turns into dyspnoea at rest20. Dry cough is also characteristic throughout the course of IPF. Physical examination may additionally reveal bibasilar inspiratory crackles and finger clubbing on hands. Diagnosis of IPF is based on exclusion of known etiology factors (occupational and environmental factors, e.g. dust; iatrogenic, e.g. radiation treatment and certain medications, e.g. methotrexate), verification of reduced pulmonary function [vital capacity (VC) for lung, increased forced expiratory volume (FEV)1/forced vital capacity (FVC) ratio), and damaged oxygen/carbon dioxide exchange], verification of tissue abnormalities in the lungs by highresolution computer tomography scans and transbronchial lung biopsy or bronchoalveolar lavage. Monitoring the disease progression by measuring functional parameters of the lung is a standard procedure, both in everyday clinical practice and also for efficacy analysis in clinical studies on novel treatments for IPF. Most importantly, the longitudinal decline in FVC value is predictive for IPF progression and mortality; henceforth this parameter has also become a preferred clinical endpoint in clinical trials21. Current guides suggests that a decline of ≥10% from baseline pulmonary function values should be considered as progression (in the absence of an alternative explanation, such as pulmonary infection)22. Beside these the six-metre walk test (6MWT) is another functional indicator of the disease progression, which is often set to monitor the secondary endpoints in IPF treatment studies21. IPF patients face severe complications. An acute exacerbation is a sudden acceleration of the disease that leads to a significant decline in lung function. It has a mortality rate as high Volume 10 Issue 5

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JCS Volume 10 Issue 5  

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JCS Volume 10 Issue 5  

Best Practice Guidelines for the Clinical Research Industry

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