title: A new population-enrichment strategy to improve efficiency of placebo-controlled clinical trials of antidepressant drugs.
abstract: The rate-limiting factor in the discovery of novel antidepressants is the inefficient methodology of traditional multicenter randomized clinical trials (RCTs). We applied a model-based approach to a large clinical database (five RCTs in major depressive disorder (MDD), involving 1,837 patients from 124 recruitment centers) with two objectives: (i) to learn about the role of center-specific placebo response in RCT failure and (ii) to apply what is learned to improve the efficiency of RCTs by enhancing the detection of treatment effect (TE). Sensitivity analysis indicated that center-specific placebo response was the most relevant predictor of RCT failure. To reduce the statistical "noise" generated by centers with nonplausible, excessively high/low placebo responses, we developed an enrichment-window strategy. Clinical trial simulation was used to assess the enrichment strategy applied before the standard statistical analysis, resulting in an overall reduction in failure of RCTs from ~50 to ~10%.
authors.affiliation: Neurosciences Center of Excellence for Drug Discovery, GlaxoSmithKline R&D, Verona, Italy. emilio.v.merlo-pich@gsk.com
authors.forename: E
authors.initials: E
authors.lastname: Merlo-Pich
authors.forename: R C
authors.initials: RC
authors.lastname: Alexander
authors.forename: M
authors.initials: M
authors.lastname: Fava
authors.forename: R
authors.initials: R
authors.lastname: Gomeni
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D019992:Databases as Topic; D003865:Major Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D015337:Multicenter Studies as Topic / Q000379:methods* / Q000706:statistics & numerical data; D018579:Patient Selection; D015990:Placebo Effect; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D015203:Reproducibility of Results; D018401:Sample Size; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents