Clinical trials of investigational antiepileptic drugs: monotherapy designs.
The standard designs for safety and efficacy trials of investigational antiepileptic drugs are placebo-controlled, add-on trials and active control equivalence studies. These designs, motivated by medical ethics, have serious evidential limitations. Add-on trials are frequently criticized as insensitive and difficult to interpret in the presence of drug interactions; active control equivalence studies are not probative of test drug activity. As an alternative, we describe two trial designs: a placebo-control design with inpatients who in undergoing a presurgery seizure evaluation have had all antiepileptic drugs discontinued; and an active-control design aimed at showing the test drug superior to the control treatment, thus avoiding the interpretational difficulties of no-difference outcomes. A critical feature of these new designs is the limitation of subject exposure to unacceptable treatments. This is accomplished through protocol criteria--corresponding to therapeutic failure--which both terminate a subject's trial participation and form the basis of efficacy comparisons.
Epilepsy Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892.
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GW
Pledger
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LD
Kramer
D000927:Anticonvulsants / Q000627:therapeutic use*; D002985:Clinical Protocols / Q000592:standards; D004311:Double-Blind Method; D015507:Drugs, Investigational / Q000627:therapeutic use*; D004569:Electroencephalography; D004827:Epilepsy / Q000188:drug therapy*; D004992:Ethics, Medical; D006760:Hospitalization; D006801:Humans; D010919:Placebos; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000592:standards; D012107:Research Design / Q000592:standards
D000927:Anticonvulsants; D015507:Drugs, Investigational; D010919:Placebos