SeriesThe future of chronic obstructive pulmonary disease treatment—difficulties of and barriers to drug development
Introduction
Chronic obstructive pulmonary disease (COPD) is a major global health problem with a rising incidence and morbidity. Prevalence is 9–10% in adults aged older than 40 years.1 Deaths attributable to tobacco are projected to rise from 6·4 million in 2005 to 8·3 million in 2030.2 COPD is expected to account for about 27% of tobacco related deaths and is anticipated to move from the fifth to the fourth leading cause of death worldwide from 2002 to 2030. Over the same period, COPD is expected to move from the eleventh leading cause of global disability-adjusted life-years to the seventh. Nonetheless, few pharmacotherapeutic advances have been made over the past several decades, with most such therapeutic options focusing on inhaled bronchodilators and corticosteroids.
The challenges to drug development in respiratory disorders have been underscored by the high estimated costs associated with drug development.3 The estimated probability of a new drug entering the market for respiratory indications was 16%, the lowest of 11 disorders. The duration of development through phase 3 was longest for respiratory disorders, at a mean of 36 months, and had the greatest overall mean cost of US$1134 million. The challenges of such development are multifactorial and include rudimentary understanding of the biological genesis of human disease, inadequate in-vitro and in-vivo models, unvalidated biomarkers, inefficient physiological and clinical endpoints, and variable regulatory review worldwide.4
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Disease pathogenesis and pathophysiology
COPD has been defined as “a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases”.5 This definition draws attention to the limitations inherent in a clearly defined unifying
Disease heterogeneity and phenotypes
COPD is a complex syndrome.15, 56 Substantial heterogeneity is evident with respect to the clinical presentation of COPD, physiology, imaging, response to therapy, decline in lung function, and survival. The placement of key elements of COPD syndrome into clinically meaningful and useful subgroups or phenotypes will hopefully guide therapy and could be a potential solution to this dilemma. The classical definition of a phenotype corresponds to structural and functional characteristics of an
Endpoints
Many endpoints have been proposed for clinical studies in COPD, ranging from standard and novel physiological tests to patient-reported outcomes and imaging parameters. These have been extensively reviewed previously by an American Thoracic Society and European Respiratory Society task force.96 Our abbreviated discussion draws attention to the existing challenges.
Regulatory challenges
The regulatory process for new pharmacotherapeutic approaches in COPD varies between the USA and the European Union. However, substantial similarities exist in the approaches recommended to drug development (table 1). Some of these differences are exemplified in the development of long term bronchodilators, for which trials are powered on the trough FEV1. Regulatory authorities are also interested in the peak improvement in FEV1 and the relation to the trough FEV1 improvement. In the
Conclusions
COPD is a major global health problem with a rising incidence, morbidity, and financial drain on health-care systems. Pharmacotherapeutic developments for this important disorder have been scarce with most successful efforts focusing on improved bronchodilators and corticosteroids. Major challenges are evident in the development of agents meant to modify disease progression. Importantly, advances in the understanding of the pathogenesis of COPD have identified novel therapeutic targets and more
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