Clinical trials of investigational antiepileptic drugs: monotherapy designs

• Published in: Epilepsia (Copenhagen) Vol. 32; no. 5; p. 716
• Main Authors: Pledger, G W, Kramer, L D
• Format: Journal Article
• Language: English
• Published: United States 01.09.1991
• Subjects: Anticonvulsants - therapeutic use; Clinical Protocols - standards; Double-Blind Method; Drugs, Investigational - therapeutic use; Electroencephalography; Epilepsy - drug therapy; Ethics, Medical; Hospitalization; Humans; Placebos; Randomized Controlled Trials as Topic - methods; Randomized Controlled Trials as Topic - standards; Research Design - standards
• ISSN: 0013-9580
• DOI: 10.1111/j.1528-1157.1991.tb04715.x

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.