Obtained effect size as a function of sample size in approved antidepressants

Abstract

The high failure rate of antidepressant trials has spurred exploration of the factors that affect trial sensitivity. In the current analysis, Food and Drug Administration antidepressant drug registration trial data compiled by Turner et al. is extended to include the most recently approved antidepressants. The expanded dataset is examined to further establish the likely population effect size (ES) for monoaminergic antidepressants and to demonstrate the relationship between observed ES and sample size in trials on compounds with proven efficacy. Results indicate that the overall underlying ES for antidepressants is approximately 0.30, and that the variability in observed ES across trials is related to the sample size of the trial. The current data provide a unique real-world illustration of an often underappreciated statistical truism: that small N trials are more likely to mislead than to inform, and that by aligning sample size to the population ES, risks of both erroneously high and low effects are minimized. The results in the current study make this abstract concept concrete and will help drug developers arrive at informed gate decisions with greater confidence and fewer risks, improving the odds of success for future antidepressant trials.

Antidepressants versus placebo in major depression: an overview

“…In summary, given the constraints enforced by the regulators and the inability to control for multiple factors that may influence antidepressant clinical trial outcomes, it is more realistic to set up low expectations. In this context, a recent report by Gibertini et al provides a useful model. These investigators analyzed the data from 81 monoaminergic antidepressant trials conducted in the past three decades, submitted to the FDA for the approval of fifteen antidepressants.…”

Flibanserin for Premenopausal Hypoactive Sexual Desire Disorder: Pooled Analysis of Clinical Trials

“…[14][15][16] In comparison, the weighted average effect size of 15 antidepressant medications in an analysis of 81 placebo-controlled studies was *0.30. 17 The central nervous system (CNS) effects of flibanserin may not underlie only the efficacy of the drug, but also its safety and tolerability profile. The AE profile of flibanserin reported in this pooled analysis is similar to those of other CNS-acting products [18][19][20][21] and consistent with previous reports for flibanserin.…”

The Impact of Underpowered Studies on Clinical Trial Results

“…It is perhaps an underappreciated truism that statistically underpowered studies with small sample sizes (often earlyphase studies) are highly likely to both under-and overestimate treatment effect sizes (2,3). By considering large effects from small studies to be true effects rather than overestimation errors, some researchers have concluded that smaller trials are more advantageous.…”