Epileptic Disorders

, Volume 14, Issue 2, pp 124–131 | Cite as

What clinical trial designs have been used to test antiepileptic drugs and do we need to change them?

  • Emilio Perucca
Progress in Epileptic Disorders Workshop on AED Trials


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.

Key words

epilepsy antiepileptic drug trial design regulatory guideline randomised controlled trial review 


  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. Brodie MJ, Perucca E, Ryvlin P, et al. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007; 68: 402–408.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. Chadwick D. Monotherapy clinical trials of new antiepileptic drugs: design, indications, and controversies. Epilepsia 1997; 38: S16–S20.PubMedCrossRefGoogle Scholar
  8. Coatsworth JJ. Studies on the Clinical Efficacy of Marketed Antiepileptic Drugs. NINDS Monograph # 12. Washington (DC): US Government Printing Office, 1971.Google Scholar
  9. 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.Google Scholar
  10. 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.Google Scholar
  11. 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.Google Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. Drug Amendments Act of 1962 (Public Law 87-781, 21 USC 355).Google Scholar
  14. Fattore C, Perucca E. Novel medications for epilepsy. Drugs 2011; 71: 2151–2178.PubMedCrossRefGoogle Scholar
  15. Faught E, Holmes GL, Rosenfeld WE, et al. Randomized, controlled, dose-ranging trial of carisbamate for partial-onset seizures. Neurology 2008; 71: 1586–1593.PubMedCrossRefGoogle Scholar
  16. French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia 2010aa; 51: 1936–1943.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. Goa KL, Ross SR, Chrisp P. Lamotrigine. A review of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1993; 46: 152–176.PubMedCrossRefGoogle Scholar
  20. Gram L, Bentsen KD, Parnas J, Flachs H. Controlled trials in epilepsy: a review. Epilepsia 1982; 23: 491–519.PubMedCrossRefGoogle Scholar
  21. Gram L, Klosterskov P, Dam M. Gamma-Vinyl GABA: a double-blind placebo-controlled trial in partial epilepsy. Ann Neurol 1985; 17: 262–266.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. Gruber CM Jr, Mosier JM, Grant P. Objective comparison of primidone and phenobarbital in epileptics. J Pharmacol Exp Ther 1957; 120: 184–187.PubMedGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. Hauptmann A. Luminal bei Epilepsie. Münch med Wochenschr 1912; 59: 1907–1909.Google Scholar
  26. Hauptmann A. Erfahrungen aus der Behandlung der Epilepsie mit Luminal. Münch med Wochenschr 1919; 46: 1319–1321.Google Scholar
  27. Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol 1979; 8: 7–20.PubMedCrossRefGoogle Scholar
  28. Himwich HE. Report of committee on research 111: anticonvulsant and convulsant agents. Epilepsia (3rd series) 1952; 1: 145–152.Google Scholar
  29. Karlawish JH, French J. The ethical and scientific shortcomings of current monotherapy epilepsy trials in newly diagnosed patients. Epilepsy Behav 2001; 2: 193–200.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. Marson AG, Williamson PR. Interpreting regulatory trials in epilepsy. Curr Opin Neurol 2009; 22: 167–173.PubMedCrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. Merritt HH, Putnam TJ. Sodium diphenyl hydantoinate in the treatment of convulsive disorders. J Am Med Soc 1938; 111: 1068–1073.Google Scholar
  35. Perucca E. Designing clinical trials to assess antiepileptic drugs as monotherapy: difficulties and solutions. CNS Drugs 2008; 22: 917–938.PubMedCrossRefGoogle Scholar
  36. Perucca E. When clinical trials make history: demonstrating efficacy of new antiepileptic drugs as monotherapy. Epilepsia 2010; 51: 1933–1935.PubMedCrossRefGoogle Scholar
  37. Perucca E, Tomson T. Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res 1999; 33: 247–262.PubMedCrossRefGoogle Scholar
  38. Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol 2011; 10: 446–456.PubMedCrossRefGoogle Scholar
  39. Perucca E, French J, Bialer M. Development ofnewantiepileptic drugs: challenges, incentives, and recent advances. Lancet Neurol 2007; 6: 793–804.PubMedCrossRefGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. Rimmer EM, Richens A. Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy. Lancet 1984; 1: 189–190.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. Sachdeo R. Monotherapy clinical trial design. Neurology 2007; 69: S23–S27.PubMedCrossRefGoogle Scholar
  44. Shorvon SD. Drug treatment of epilepsy in the century of the ILAE: the first 50 years, 1909–1958. Epilepsia 2009; 50: 69–92.PubMedCrossRefGoogle Scholar
  45. Spangler R. The crotalin treatment of epilepsy. Epilepsia 1913; 3: 307–318.CrossRefGoogle Scholar
  46. White PT, Plott D, Norton J. Relative anticonvulsant potency of primidone; a double-blind comparison. Arch Neurol 1966; 14: 31–35.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar

Copyright information

© John Libbey Eurotext and Springer-Verlag France 2012

Authors and Affiliations

  1. 1.Clinical Pharmacology Unit, Department of Internal Medicine and TherapeuticsUniversity of Pavia and National Neurological Institute IRCCS C Mondino FoundationPaviaItaly
  2. 2.Clinical Pharmacology UnitUniversity of PaviaPaviaItaly

Personalised recommendations