Innovations in Outcomes and Designs of Clinical Trials for Respiratory Drug Development

Abstract

Clinical trials for the development of respiratory drugs have for years been reliant upon measurements of physiologic tests, combined with the use of questionnaires. New drugs were mostly administered by inhalation and increasingly in fixed combinations. However, these lung function tests have a lack of sensitivity for patient-relevant clinical outcomes. Moreover, new insights in phenotypes and endotypes of these diseases in the basic mechanisms and the discovery of new targets for therapy, have led to the need for a more personalized patient-centered approach and precision medicine.In recent years, a great number of techniques have been proposed but some need further validation. These include fractional exhaled nitric oxide, health-related quality of life and the use of biomarkers like blood and sputum eosinophils and neutrophils, IgE, sIgE, periostin, copeptin and specific cytokines. Additionally, exhaled breath condensate and lung deposition studies by functional residual imaging and by local bronchial pharmacokinetics can be used. In rare diseases like cystic fibrosis, Lung Clearance Index and CT and PET scan fusion images seem to be valuable outcome measurements. Lastly leverage of lung function tests can be done by using body plethysmography, measuring respiratory impedance, variability and the use of modeling and simulation.The need for a patient-centric approach through all stages of clinical development is becoming mandatory. So, an evolution from classical randomized clinical trials (RCTs) to more efficient and patient-relevant designs will be seen more in the future. RCTs will remain necessary for regulatory submission but more efficient and adaptive designs with lower heterogeneity and the use of pragmatic trials are needed. This evolution from undefined targets to a more targeted approach will lead us closer to precision medicine.In this overview, the unmet medical need for better outcomes and study designs in the development of treatments for respiratory diseases, are discussed.