Clinical Trials for Antiepileptic Drugs: From Add-On to Monotherapy and Dose-Related Designs
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[>rug lnforniurion Journnl, Vol. 31. pp. 685-695. 1991 Printed in the IJSA. All right5 reserved.
CLINICAL TRIALS FOR ANTIEPILEPTIC DRUGS: FROM ADD-ON TO MONOTHERAPY AND DOSE-RELATED DESIGNS VOLKEKMOCKEL,PHD Clinical Scientist. Parke-Davis GmbH Berlin, International Clinical Kesearch CNS. Freiburg, Germany
“Add-on’’ parullel designs have frequently been used t o demonstrute efficacy for a new aritiepileptic drug in refractory patients. I t might be very difficult to shon effects iti this putient populutiori, which is becornirig more refractoty as more trmtments become ci~wiluble.Therefore, a selectiori f . r rr.spon.sive putients ( “eririchmerit design ”) might be introduced. In contrast, various “rnonotherap~ designs ’’ have beeri developed. Withiri the equivulence approcich, standard treiitmiwt i s used u s the control, avoiding the use of plucebo. Recent modifications ( “therapeutic.equivulence design”) avoid problems ussociated Hith statistical anal) f o r equivalence triuls. Superioritv of the experimental antiepiIcptic drug to plucebo can be demonstrated in presurgical epileptic patients. A further approuch represents the “therupeutic ,failure design. ’* The rise of a low-dose cornparutor avoids placebo. Alternatiivly, designs might be based on the necessity to apply vurious dosing steps of an antiepileptic drug or to define n dose-response relationship. Overull, nith the de~~eloprrierit (fa number of new tmtiepileptic drugs. the cliriiciil evaluation has resulted iri the application of lien innovntive concepts ,fiw cliriical triois.
Key Words: Parallel group design; Add-on design; Monotherapy design; Equivalence design
INTHODUCTION THE DEVELOPMENT OF NEW antiepileptic drugs (AED) has made it necessary to challenge the established designs for clinical trials and to look for new concepts to denionstrate efficacy. The choice of the appropriate concept depends on various factors. First. the therapeutic approach of whether to treat epileptic patients by single or multi-
Keprint address: Dr. Volker Mikkel, P a r k e - t h i s GmbH Berlin. International Clinical Kesearch CNS. Mooswaldallee 1-9, D-79090 Freiburg, Germany.
ple AEDs influences trial design. A large portion of the patient population to be included in a monotherapy study will have had a recent diagnosis of epilepsy. In these patients the chances of predicting the response to a new drug in monotherapy are better than for patients with incomplete seizure control by previous mono- or poly-therapy (1). Nevertheless. the latter population may respond to a single new AED. Indirect evidence is given by presurgical evaluation of seizure frequency. After withdrawal of AEDs in the period before surgery the number of seizures is not necessarily increased. Although there
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Volker Miickel
686
seems to be a general trend toward monotherapy, thus far no study has been carried out showing that a single AED is superior to a combination of two drugs representing the classical add-on ap
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