Table 2.

Historical Factors Complicating Randomized Controlled Trials in COPD

1. Definition of the disease and its severity has been primarily focused on a single parameter (spirometry)

2. The paucity of regulatory accepted “qualified” intermediate efficacy endpoints and validated biomarkers

3. The nonnormal distribution of important trial outcomes

4. Differing patterns of disease progression

5. Slow FEV1 decline, which is further compounded by dropout or death among the sickest

6. Disease heterogeneity: described as different phenotypes and endotypes (e.g., emphysema, airways disease, lung microbiome, neutrophilic vs. eosinophilic inflammation, aberrant tissue repair)

7. Variability of endpoints and their confounders (e.g., washout of background medications, diurnal variation, seasonal effect)

Definition of abbreviation: COPD = chronic obstructive pulmonary disease.