title: Modelling placebo response in depression trials using a longitudinal model with informative dropout.
abstract: Dropouts are common events in longitudinal studies in depression. Ignoring missing information may lead to biased and inconsistent assessment of study results. A non-linear model was recently developed to describe the time-course of HAMD-17 clinical score in the placebo arms of antidepressant clinical trials. In this paper we complemented this model by introducing an informative dropout component to jointly estimate HAMD-17 time-course and dropout mechanism. The aims of this work were to: (a) characterise typical placebo response in depression trials in presence of dropouts, (b) explore which dropout mechanism better describe the time-varying probability of a subject to dropout from the trial, and (c) define a framework for the development of clinical trial simulation in depression. A meta-analytic approach was used on placebo data collected in 6 clinical trials including 695 subjects suffering from Major Depressive Disorders. Alternative hypotheses for "missingness" were evaluated using different hazard models. The "Missing Not At Random" performed statistically (p<0.01) better than "Missing At Random", that in turn performed better (p<0.01) than "Missing Completely At Random" model. This finding provided new insights on the validity of the analyses currently used in many longitudinal clinical trials to support the registration of a new medicinal product.
authors.affiliation: Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Verona, Italy. roberto.a.gomeni@gsk.com
authors.forename: Roberto
authors.initials: R
authors.lastname: Gomeni
authors.forename: Agnes
authors.initials: A
authors.lastname: Lavergne
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo-Pich
mesh_terms: D002986:Clinical Trials as Topic; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D016208:Databases, Factual; D003866:Depressive Disorder / Q000188:drug therapy* / Q000523:psychology*; D006801:Humans; D008137:Longitudinal Studies; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D010352:Patient Dropouts / Q000523:psychology* / Q000706:statistics & numerical data*; D015990:Placebo Effect; D011569:Psychiatric Status Rating Scales; D015203:Reproducibility of Results; D012107:Research Design