A New Population-Enrichment Strategy to Improve Efficiency of Placebo-Controlled Clinical Trials of Antidepressant Drugs

• Published in: Clinical pharmacology and therapeutics 2010-11, Vol.88 (5), p.634-642
• Main Authors: Merlo‐Pich, E, Alexander, R C, Fava, M, Gomeni, R
• Format: Article
• Language: English
• Subjects: Antidepressive Agents - therapeutic use; Biological and medical sciences; Computer Simulation; Data Interpretation, Statistical; Databases as Topic; Depressive Disorder, Major - drug therapy; Humans; Medical sciences; Multicenter Studies as Topic - methods; Multicenter Studies as Topic - statistics & numerical data; Patient Selection; Pharmacology. Drug treatments; Placebo Effect; Randomized Controlled Trials as Topic - methods; Randomized Controlled Trials as Topic - statistics & numerical data; Reproducibility of Results; Sample Size; Treatment Outcome
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/clpt.2010.159

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%. Clinical Pharmacology & Therapeutics (2010) 88 5, 634–642. doi: 10.1038/clpt.2010.159