title: Limitations of model based dose selection for indacaterol in patients with chronic obstructive pulmonary disease.
abstract: OBJECTIVE
  Indacaterol is a long-acting β-agonist (LABA) approved by FDA in 2011 at a dose of 75 μg once daily for the treatment of chronic obstructive pulmonary disease (COPD). During the review process for indacaterol approval, data were reanalyzed by FDA to evaluate the validity of the model based conclusions regarding dose selection.
  
  
  METHODS
  The same dose response model applied by the sponsor was used to analyze a subset of the original data. Model predictions were compared with observed data to evaluate the model. Subgroups were created to visualize the relationship between key model parameters and covariates. The Emax model structure was evaluated for a meta-analysis.
  
  
  RESULTS
  Patient-level analyses showed that the model based claim of additional benefit of 150 μg over 75 μg for more severe patients is not supported by the data. Mis-specified covariate model structures for key parameters contributed to this inconsistency. The assumed Emax model structure is not supported by the study-level data and the study-level analysis overestimates the incremental difference between two adjacent doses.
  
  
  CONCLUSIONS
  Even though model based drug development is highly desirable, thorough model evaluation and justification is necessary to ensure the validity of related decisions.
authors.affiliation: Office of Clinical Pharmacology, Silver Spring, MD, USA. Yaning.Wang@fda.hhs.gov
authors.forename: Yaning
authors.initials: Y
authors.lastname: Wang
authors.forename: Joo Yeon
authors.initials: JY
authors.lastname: Lee
authors.forename: Theresa
authors.initials: T
authors.lastname: Michele
authors.forename: Badrul A
authors.initials: BA
authors.lastname: Chowdhury
authors.forename: Jogarao V
authors.initials: JV
authors.lastname: Gobburu
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D003661:Decision Support Techniques; D004305:Dose-Response Relationship, Drug; D017277:Drug Approval; D055808:Drug Discovery / Q000379:methods*; D054796:Drug Dosage Calculations; D005541:Forced Expiratory Volume; D006801:Humans; D007189:Indans / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008962:Models, Theoretical; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D015363:Quinolones / Q000008:administration & dosage*; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D013997:Time Factors; D014481:United States
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D007189:Indans; D015363:Quinolones; C510790:indacaterol