Abstract
Designs used to evaluate the efficacy and safety of antiepileptic drugs (AEDs) have evolved considerably over the years. A major impulse to develop methodologically sound randomised controlled trials dates back to the Kefauver-Harris Drug Amendment of 1962, through which the US congress introduced the requirement of substantial evidence for proof of efficacy in a new drug application. The mainstay for the initial approval of most new AEDs has been, and still is, the placebo-controlled adjunctive therapy trial, which evolved over the years from the cross-over to the parallel-group design. In the early days, when few AEDs were available, enrolment of patients into these trials was relatively easy and prolonged placebo exposure could be justified by lack of alternative treatment options. With more than 20 drugs now available to treat epilepsy, however, exposing patients to placebo or to a potentially ineffective investigational agent faces practical and ethical concerns. Recruitment difficulties have led sponsors to markedly increase the number of trial sites, but there is evidence that this may adversely affect the ability to differentiate between effective and ineffective treatments. Methodological and practical difficulties are also encountered with monotherapy trials. Because regulatory guidelines for monotherapy approval differ between Europe and the US, sponsors need to pursue separate and costly development programs on the two sides of the Atlantic. Moreover, the scientific validity of the monotherapy trial paradigms currently used in Europe (the non-inferiority design) and in the US (the conversion to monotherapy design with historical controls) has been questioned. This article will review these issues in some detail and discuss how trial designs and regulatory approval processes may evolve in the future to address these concerns.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Arroyo S, Dodson WE, Privitera MD, et al. Randomized dose-controlled study of topiramate as first-line therapy in epilepsy. Acta Neurol Scand 2005; 112: 214–222.
Arzimanoglou A, Ben-Menachem E, Cramer J, Glauser T, Seeruthun R, Harrison M. The evolution of antiepileptic drug development and regulation. Epileptic Disord 2010; 12: 3–15.
Baulac M, Leon T, O’Brien TJ, Whalen E, Barrett J. A comparison of pregabalin, lamotrigine, and placebo as adjunctive therapy in patients with refractory partial-onset seizures. Epilepsy Res 2010; 91: 10–19.
Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: a summary of the Tenth Eilat Conference (EILAT X). Epilepsy Res 2010; 92: 89–124.
Brodie MJ, Perucca E, Ryvlin P, et al. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007; 68: 402–408.
Brodie MJ, Lerche H, Gil-Nagel A, et al. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology 2010; 75: 1817–1824.
Chadwick D. Monotherapy clinical trials of new antiepileptic drugs: design, indications, and controversies. Epilepsia 1997; 38: S16–S20.
Coatsworth JJ. Studies on the Clinical Efficacy of Marketed Antiepileptic Drugs. NINDS Monograph # 12. Washington (DC): US Government Printing Office, 1971.
Coatsworth JJ, Penry JK. General principles. Clinical efficacy and use. In: Woodbury DM, Penry JK, Schmidt RP. Antiepileptic Drugs. New York: Raven Press, 1972: 87.
Committee for Proprietary Medicinal Products (CPMP). Note for guidance on clinical investigation of medicinal products in the treatment of epileptic disorders. (CPMP/EWP/566/98 rev 1). London: CPMP, 16 November 2000.
Committee for Medicinal Products for Human Use. Guidance on clinical investigation of medicinal products in the treatment of epileptic disorders. (CPMP/EWP/566/98 rev 2). London: Committee for Medicinal Products for Human Use, 22 July 2010.
Dam M, Ekberg R, Løyning Y, Waltimo O, Jakobsen K. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989; 3: 70–76.
Drug Amendments Act of 1962 (Public Law 87-781, 21 USC 355).
Fattore C, Perucca E. Novel medications for epilepsy. Drugs 2011; 71: 2151–2178.
Faught E, Holmes GL, Rosenfeld WE, et al. Randomized, controlled, dose-ranging trial of carisbamate for partial-onset seizures. Neurology 2008; 71: 1586–1593.
French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia 2010aa; 51: 1936–1943.
French JA, Costantini C, Brodsky A, von Rosenstiel P; N01193 Study Group. Adjunctive brivaracetam for refractory partialonset seizures: a randomized, controlled trial. Neurology 2010b; 75: 519–525.
Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; 47: 1094–1120.
Goa KL, Ross SR, Chrisp P. Lamotrigine. A review of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1993; 46: 152–176.
Gram L, Bentsen KD, Parnas J, Flachs H. Controlled trials in epilepsy: a review. Epilepsia 1982; 23: 491–519.
Gram L, Klosterskov P, Dam M. Gamma-Vinyl GABA: a double-blind placebo-controlled trial in partial epilepsy. Ann Neurol 1985; 17: 262–266.
Grant SM, Heel RC. Vigabatrin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 1991; 41: 889–926.
Gruber CM Jr, Mosier JM, Grant P. Objective comparison of primidone and phenobarbital in epileptics. J Pharmacol Exp Ther 1957; 120: 184–187.
Halford JJ, Ben-Menachem E, Kwan P, et al. A randomized, double-blind, placebo-controlled study of the efficacy, safety, and tolerability of adjunctive carisbamate treatment in patients with partial-onset seizures. Epilepsia 2011; 52: 816–825.
Hauptmann A. Luminal bei Epilepsie. Münch med Wochenschr 1912; 59: 1907–1909.
Hauptmann A. Erfahrungen aus der Behandlung der Epilepsie mit Luminal. Münch med Wochenschr 1919; 46: 1319–1321.
Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol 1979; 8: 7–20.
Himwich HE. Report of committee on research 111: anticonvulsant and convulsant agents. Epilepsia (3rd series) 1952; 1: 145–152.
Karlawish JH, French J. The ethical and scientific shortcomings of current monotherapy epilepsy trials in newly diagnosed patients. Epilepsy Behav 2001; 2: 193–200.
Kwan P, Brodie MJ, Kalviainen R, Yurkevicz L, Weaver J, Knapp LE. Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial. Lancet Neurol 2011; 10: 881–890.
Marson AG, Williamson PR. Interpreting regulatory trials in epilepsy. Curr Opin Neurol 2009; 22: 167–173.
Matsuo F, Riaz A. Lamotrigine. In: Shorvon S, Perucca E, Engel J Jr. The Treatment of Epilepsy. 3rd edition. Oxford: Blackwell Publishers, 2009: 535–558.
Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985; 313: 145–151.
Merritt HH, Putnam TJ. Sodium diphenyl hydantoinate in the treatment of convulsive disorders. J Am Med Soc 1938; 111: 1068–1073.
Perucca E. Designing clinical trials to assess antiepileptic drugs as monotherapy: difficulties and solutions. CNS Drugs 2008; 22: 917–938.
Perucca E. When clinical trials make history: demonstrating efficacy of new antiepileptic drugs as monotherapy. Epilepsia 2010; 51: 1933–1935.
Perucca E, Tomson T. Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res 1999; 33: 247–262.
Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol 2011; 10: 446–456.
Perucca E, French J, Bialer M. Development ofnewantiepileptic drugs: challenges, incentives, and recent advances. Lancet Neurol 2007; 6: 793–804.
Rheims S, Perucca E, Cucherat M, Ryvlin P. Factors determining response to antiepileptic drugs in randomized controlled trials. A systematic review and meta-analysis. Epilepsia 2011; 52: 219–233.
Rimmer EM, Richens A. Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy. Lancet 1984; 1: 189–190.
Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebocontrolled randomised trials. Lancet Neurol 2011; 10: 961–968.
Sachdeo R. Monotherapy clinical trial design. Neurology 2007; 69: S23–S27.
Shorvon SD. Drug treatment of epilepsy in the century of the ILAE: the first 50 years, 1909–1958. Epilepsia 2009; 50: 69–92.
Spangler R. The crotalin treatment of epilepsy. Epilepsia 1913; 3: 307–318.
White PT, Plott D, Norton J. Relative anticonvulsant potency of primidone; a double-blind comparison. Arch Neurol 1966; 14: 31–35.
Xiao Z, Li JM, Wang XF, et al. Efficacy and safety of levetiracetam (3,000 mg/day) as an adjunctive therapy in Chinese patients with refractory partial seizures. Eur Neurol 2009; 61: 233–239.
Author information
Authors and Affiliations
Corresponding author
Additional information
Updated following presentation and discussion at the 2011 Progress in Epileptic Disorders Workshop on “Antiepileptic Drug Trials: will the future challenge the past” held at the Chaeauform’ La Maison des Contes, Dareizé, 69490, France. The workshop was partly supported by an educational grant from UCB. The program was under the exclusive responsibility of a Scientific Committee composed by Prs. Philippe Ryvlin (France), Emilio Perucca (Italy), Jackie French (USA), Steve White (USA), Graeme Sills (UK) and Alexis Arzimanoglou (France).
About this article
Cite this article
Perucca, E. What clinical trial designs have been used to test antiepileptic drugs and do we need to change them?. Epileptic Disord. 14, 124–131 (2012). https://doi.org/10.1684/epd.2012.0511
Published:
Issue Date:
DOI: https://doi.org/10.1684/epd.2012.0511