Magnitude and pattern of placebo response in clinical trials of antiepileptic medications: Data from the Food and Drug Administration 1996-2016.

ABSTRACT

This study aimed to replicate and extend the findings of previous investigations looking at treatment responses in antiepileptic clinical trials over time and to examine the effects of subject age and duration of treatment. To address the potential biases of published literature, we examined the reported data from 14 investigational antiepileptic drugs (AEDs) (34 trials, 59 treatment arms, 10,783 patients) reviewed and approved by the US FDA (1996-2016). For each treatment arm, we recorded drug and placebo response (percent reduction in seizure frequency), calculated effect sizes, and examined these measures over time. Regression analysis showed that placebo response has increased significantly over time (R2=0.292, p=0.001) from 5% to 20% reduction in seizure frequency in 20years. Response to drug treatment appears to have increased in parallel but the trend was not statistically significant (p=0.143). Effect sizes have remained stable over time (p=0.084). Treatment duration was not related to treatment response or outcomes. Including younger patients in trials appeared to predict lower drug response (ß=1.44, p=0.012) and effect size (ß=0.014, p=0.047) but not placebo response (p=0.141). These FDA-reviewed and source-verified data support and extend prior findings from published literature that response to placebo treatment is noticeably increasing over time, nearly quadrupling in magnitude, while AED efficacy remains the same due to a parallel increase in drug response. The rise in placebo response appears to be an ongoing phenomenon rather than a mere historical artifact. Future design and interpretation of data from clinical trials of investigational antiepileptic drugs can be informed by these observations.