Regulatory requirements to demonstrate the efficacy of novel antiepileptic drugs (AEDs) as monotherapy differ between Europe and the United States. European regulators require a comparison with an established, optimally dosed AED, typically using a noninferiority design, whereas the U.S. Food and Drug Administration (FDA) demands demonstration of superiority versus a comparator. Because placebo cannot be used as sole therapy and it is unrealistic to expect that a new AED will be more efficacious than established agents at full dosages, superiority monotherapy trials in epilepsy have traditionally relied on inclusion of controls treated with a suboptimal (low-dose) comparator. In the most common design, refractory patients are randomized to conversion to monotherapy with a full dose of the investigational agent or a low-dose active control, and are required to exit the trial if seizures deteriorate. Efficacy is demonstrated when exit rates are lower in the full-dose group than in controls. Although this design is efficient in demonstrating superiority, the use of suboptimal treatments has been increasingly criticized on ethical grounds. A meta-analysis has now demonstrated that patients randomized to suboptimal treatments in all previous trials had similar outcomes, thereby allowing the build up of a dataset of historical controls against which response to investigational AEDs can be compared in future trials. Use of historical controls has been accepted by the FDA, subject to compliance with rigorous methodologic requirements. Although the avoidance of suboptimal treatments in future trials is a welcome development, the conversion-to-monotherapy design is still far from being fully satisfactory and is not exempt from methodologic concerns.
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