Abstract
Variability in placebo response greatly complicates the design, conduct, and interpretation of clinical trials of antidepressant medications. To identify factors that impact detection of antidepressant–placebo differences, we conducted a meta-analysis of all relevant phase II–IV clinical trials for major depressive disorder conducted by the manufacturer of venlafaxine and desvenlafaxine completed by March 2011. We examined 15 factors potentially relevant to trial outcomes, using the standardized mean difference on the Hamilton Rating Scale for Depression (HAM-D17) score as the primary outcome. Thirty trials comprising 8933 patients were included. In univariate analyses, antidepressant efficacy (ie, drug vs placebo difference) was predicted most strongly (β=3.74, p=0.0002) by the proportion of patients in the trial enrolled from academic sites. Other factors predicting larger drug–placebo differences included lower participant completion rate, fewer post-baseline study visits, earlier year of study, and study drug (venlafaxine>desvenlafaxine). In multivariate meta-regression modeling, only the proportion of patients from academic sites maintained statistical significance as a predictor of drug–placebo separation for both HAM-D17 continuous score change (β=2.24, p=0.034) and response rate (β=2.26, p=0.035). Including a higher proportion of academic sites may increase the ability to detect differences between active drug and placebo in clinical trials of major depressive disorder.
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Acknowledgements
This analysis was sponsored by Wyeth Research, which was acquired by Pfizer in October 2009. Dr Dunlop is supported by NIH grant K23MH086690. The corresponding author had full access to all the data in the study, and had final responsibility for the decision to submit for publication. Pfizer provided no compensation to Drs Dunlop or Thase for conducting this analysis. Medical writing support was provided by Peter Mathisen, PhD and Dennis Stancavish, MA of Embryon LLC, A Division of Advanced Health Media, and Diane Sloan, PharmD and Lorraine Sweeney, BA of Peloton Advantage, LLC and was funded by Pfizer.
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Drs Dunlop and Thase were responsible for the design of the analysis. Mr Musgnung, Dr Guico-Pabia, and Dr Ninan reviewed the Pfizer database for the relevant studies and data extraction. Drs Wun and Fayyad jointly conducted the statistical analyses and wrote the statistical analysis section of the Patients and Methods. The remainder of the manuscript was written by Drs Dunlop and Thase. All authors reviewed and approved the final version of the manuscript.
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In the past 3 years, Dr Dunlop has received honoraria for consulting work done for Bristol- Myers Squibb, MedAvante, Inc., and Pfizer. He has also received research support from AstraZeneca, Bristol-Myers Squibb, Evotec, Forest, GlaxoSmithKline, Novartis, Ono Pharmaceuticals, Pfizer, Takeda, and Transcept. Dr Wun was a paid contractor to Pfizer in the development of this manuscript and was responsible for the statistical analysis. Dr Thase has been a consultant/advisor to the following organizations: Alkermes, AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Mylan Laboratories (DeyPharma), Forest Laboratories (PGx), Gerson Lehman Group, Guidepoint Global, H. Lundbeck A/S, MedAvante, Inc., Merck and Co. Inc. (formerly Schering Plough), Neuronetics, Inc., Otsuka, Ortho-McNeil Pharmaceuticals (Johnson & Johnson), Pamlab, L.L.C., Pfizer, PharmaNeuroboost, Shire US Inc., Supernus Pharmaceuticals, Takeda, and Transcept Pharmaceuticals. Dr Thase has also received grant support from the Agency for Healthcare Research and Quality, Eli Lilly &Co., Forest Pharmaceuticals, GlaxoSmithKline (ended July 2010), National Institute of Mental Health, Otsuka Pharmaceuticals, PharmNeuroboost, and Roche. Prior to 30 June 2010, he participated in Speaker Bureaus for the following organizations: AstraZeneca, Bristol-Myers Squibb, Dey Pharmaceutical, Eli Lilly & Co., Merck and Co. Inc., and Pfizer. He has equity holdings in MedAvante, Inc. Dr Thase receives royalties from the American Psychiatric Foundation, Guilford Publications, Herald House and W.W. Norton & Company. His spouse was currently employed with Peloton Advantage, LLC, a company that does business with Pfizer. Drs Guico-Pabia, Fayyad, and Mr Musgnung have been employees of Pfizer for the past 3 years. Dr Ninan was employed by Pfizer during the time this manuscript was developed.
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Dunlop, B., Thase, M., Wun, CC. et al. A Meta-analysis of Factors Impacting Detection of Antidepressant Efficacy in Clinical Trials: The Importance of Academic Sites. Neuropsychopharmacol 37, 2830–2836 (2012). https://doi.org/10.1038/npp.2012.153
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DOI: https://doi.org/10.1038/npp.2012.153
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