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Active-Control Antiepileptic Drug Trials in the Newly Diagnosed Patient: Are We Getting Closer?
Epilepsy & Behavior 3, 109 –112 (2002) doi:10.1006/ebeh.2002.0340, available online at http://www.idealibrary.com on
EDITORIAL Active-Control Antiepileptic Drug Trials in the Newly Diagnosed Patient: Are We Getting Closer? Jacqueline A. French, M.D. Department of Neurology, Hospital of the University of Pennsylvania, 400 Spruce Street, Philadelphia, Pennsylvania 19104-4283 Received February 12, 2002; accepted for publication February 13, 2002
In this issue, Brodie and colleagues present results of an active control trial comparing a potential new antiepileptic drug, remacemide, with the drug that is considered the “standard of care” for newly diagnosed patients with partial epilepsy, namely, carbamazepine. There are two major reasons why this trial is of particular significance. The first is that a novel methodology called sequential analysis was employed. The second is that this is the first published trial in which a new antiepileptic drug (AED) was demonstrated to be statistically inferior to carbamazepine at a therapeutic dose. This is even more significant because the drug had already been proven effective in an adjunctive trial in refractory patients. These are critical pieces of data in the continuing debate regarding the ideal methodology to demonstrate efficacy of new drugs as monotherapy in the newly diagnosed population. The first question that needs to be addressed is whether it is necessary to perform specific trials in the newly diagnosed population. There are several compelling arguments in favor of performing such trials. Registration trials for determining safety and efficacy of new antiepileptic drugs are almost always done in an adjunctive design (1). In other words, the drug under investigation is added to any AEDs the subject may already be taking to control their seizures. This design allows a placebo control group, which would otherwise be very difficult for such a serious disease. Much has been written about the type of population treated in the typical randomized placebo-controlled phase III adjunctive efficacy trial. Patients tend to have an epilepsy duration of years to decades. Median seizure frequency is 10 seizures/month. Patients have typically failed up to 10 AEDs (2). Recently, results from several studies have implied that there may be fundamental differences between newly diagnosed patients and refractory patients. Early in the course of treatment, patients separate into easily treatable or refractory. In one study, patients had an almost 50% chance of responding to initial therapy. If they failed initial therapy for efficacy reasons, they had only a 10% likelihood of becoming seizure free over the next 5 years despite multiple drug trials (3). Another important discovery is that newly diagnosed patients often respond to relatively lower doses than are needed in refractory patients (4). 1525-5050/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.
109
110
Jacqueline A. French
The stark separation of epilepsy patients into a “treatable group” and a “refractory group” raises the question of whether newly diagnosed epilepsy and refractory epilepsy are fundamentally the same disease, with similar underlying pathophysiology. If not, is it unreasonable to imagine that drugs may be more advantageous in one group than another? This may well be the case for remacemide, which controlled seizures in refractory patients who had failed carbamazepine, but was not as effective as carbamazepine in a trial of initial therapy. Clearly, these results underscore the need for continued controlled trials in the newly diagnosed epilepsy population, even after drugs have been proven effective in refractory patients. Also, adjunctive trials may overrepresent the potential toxicity of new antiepileptic drugs due to pharmacokinetic and pharmacodynamic interactions. For example, in a trial performed in refractory patients in which lamotrigine was added to baseline therapy, 20% of patients reported dizziness (5). However, when the baseline therapy was subsequently removed, the proportion fell to 7%. What made this even more remarkable was that the drugs that were withdrawn were enzyme inducers, and therefore the lamotrigine serum levels doubled once the patients were converted to monotherapy. Similarly, an improved tolerability in monotherapy was seen in a trial of oxcarbazepine (6). The markedly improved tolerability of lamotrigine and oxcarbazepine in monotherapy would be important factors in selecting these drugs for use in newly diagnosed patients. Although the benefit of performing trials in the newly diagnosed population and/or in other monotherapy settings is difficult to dispute, the methodology of doing so is very much under debate. In Europe, the common practice is to perform active-control trials, in which the new antiepileptic drug is directly compared with a standard such as carbamazepine (7–9). The outcome of these trials is often demonstration of similar efficacy in both study arms, but better tolerability and fewer dropouts due to side effects in those patients randomized to the new drug. This is not surprising, given the high responder rate in this population. Lack of demonstration of an efficacy difference in these trials is unsatisfying for two reasons. The first is that these studies often are not powered to show true equivalence, making the results less interpretable. More importantly, there has been a great deal of debate as to whether an active control trial in the newly diagnosed population has assay sensitivity. Assay sensitivity is defined as the ability of a given trial design to demonstrate a difference between treatment arms, if one truly exists. There are many examples of disease states and trial designs that have failed to show assay sensitivity. The most notorious are trials of antidepressants in patients with depression. Although there is no doubt that antidepressants are pharmacologically active, many trials have been performed in which they failed to separate from placebo (10). The fear that active control trials will not display assay sensitivity has prevented the FDA from accepting these trials as proof of efficacy in monotherapy. The corollary of this is that only one drug, oxcarbazepine, has approval by the FDA for use as initial monotherapy. Three active-control trials were performed comparing oxcarbazepine with phenytoin, carbamazepine, and valproic acid. Each trial showed no efficacy difference between oxcarbazepine and the comparator (11–13). These trials were not sufficient to obtain a monotherapy approval. Approval was gained only after a trial was performed in newly diagnosed epilepsy patients that demonstrated superiority of oxcarbazepine to placebo (14). Although this was definitive proof of efficacy, ethical issues have been raised with respect to randomizing patients with diagnosed epilepsy to placebo (15–17). In addition, the clinical validity of such trials has been questioned (18). The true importance of the trial of remacemide, 2002 Elsevier Science (USA) All rights reserved.
©
111
Editorial
using sequential analysis, is that it demonstrates assay sensitivity, in that remacemide was found to be statistically inferior to carbamazepine. This result reignites the hope that active-control trials will be acceptable proof of monotherapy effectiveness in the future. The sequential analysis design used in the Brodie study was a relatively efficient means of performing an active-control trial in the newly diagnosed population. The statistical aim of the trial was to demonstrate inferiority of either carbamazepine or remacemide, or to demonstrate no difference. The advantage of sequential analysis is that if there is a significant difference between treatment arms, as there was in this case, the design allows for early termination, thereby preventing additional patients from being exposed to an inferior treatment. If, however, there is little or no difference between treatments, more patients are enrolled until there is sufficient statistical power to prove no difference between treatments. Proof of no difference would require a large number of enrolled patients; potentially the remacemide trial could have required anywhere between 700 and 1200 patients to prove no difference (19). Since, as noted above, prior trials have as often as not demonstrated no difference, pharmaceutical companies would need to be prepared for the expense of a large sample size, if sequential analysis is undertaken. Sequential analysis is ideal when there is an efficacy difference between two treatments, as was the case in this study. But what of the more common scenario, when two treatments are the same? Sequential analysis may be more powerful in truly demonstrating no difference, albeit at the expense of enrolling a large patient cohort. Even so, this hard-won result will not lead to FDA approval of new drugs for use in monotherapy in the newly diagnosed population. Before this can happen, assay sensitivity of this methodology will need to be demonstrated in more than one trial. This can only occur if several drugs are found inferior to carbamazepine using this methodology, an outcome that is not entirely desirable, nor is it highly likely. Until or unless this occurs, the controversy and the debate will continue as to the most appropriate methodology of monotherapy trials in the newly diagnosed population.
REFERENCES 1. 2.
3. 4. 5. 6. 7.
8.
9.
French JA. The art of antiepileptic trial design. Adv Neurol 1998;76:113–23. French J, Dichter M. New antiepileptic drug development: Medical perspective. In: Levy R, Mattson R, Meldrum B, Perucca E, editors. Antiepileptic drugs, 5th ed. New York: Lippincott, Williams & Wilkins, 2002: in press. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314 –9. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001;42:1255– 60. Gilliam F, Vazquez B, Sackellares JC, et al. An active-control trial of lamotrigine monotherapy for partial seizures. Neurology 1998;51:1018 –25. Beydoun A, Sachdeo RC, Rosenfeld WE, et al. Oxcarbazepine monotherapy for partial-onset seizures: a multicenter, double-blind, clinical trial. Neurology 2000;54:2245–51. Chadwick DW, Anhut H, Greiner MJ, et al. A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. International Gabapentin Monotherapy Study Group 945-77. Neurology 1998;51:1282– 8. Chadwick D. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Vigabatrin European Monotherapy Study Group. Lancet 1999;354:13–9. Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet 1995;345:476 –9.
©
2002 Elsevier Science (USA) All rights reserved.
112
Jacqueline A. French 10. 11. 12.
13.
14. 15. 16. 17. 18. 19.
2002 Elsevier Science (USA) All rights reserved.
©
Leber PD. Hazards of inference: the active control investigation. Epilepsia 1989;30(Suppl. 1):S57– 63; discussion S64 – 8. Christe W, Kramer G, Vigonius U, et al. A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res 1997;26:451– 60. Dam M, Ekberg R, Loyning 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 – 6. Guerreiro MM, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res 1997; 27:205–13. Beydoun A, Kutluay E. Oxcarbazepine. Expert Opin Pharmacother 2002;3:59 –71. Chadwick D. Monotherapy clinical trials of new antiepileptic drugs: design, indications, and controversies. Epilepsia 1997;38(Suppl. 9):S16 –20. Chadwick D, Privitera M. Placebo-controlled studies in neurology: where do they stop? Neurology 1999;52:682–5. Karlawish J, French J. The ethical and scientific shortcomings of current monotherapy epilepsy trials in newly diagnosed patients. Epilepsy Behav 2001;2:193–200. French J. Active-control comparative equivalency monotherapy trials in epilepsy (letter to the editor). Epilepsy Behav 2001;2:613– 4. Whitehead J. Monotherapy trials: sequential design. Epilepsy Res 2001;45:81–7.
EDITORIAL Active-Control Antiepileptic Drug Trials in the Newly Diagnosed Patient: Are We Getting Closer? Jacqueline A. French, M.D. Department of Neurology, Hospital of the University of Pennsylvania, 400 Spruce Street, Philadelphia, Pennsylvania 19104-4283 Received February 12, 2002; accepted for publication February 13, 2002
In this issue, Brodie and colleagues present results of an active control trial comparing a potential new antiepileptic drug, remacemide, with the drug that is considered the “standard of care” for newly diagnosed patients with partial epilepsy, namely, carbamazepine. There are two major reasons why this trial is of particular significance. The first is that a novel methodology called sequential analysis was employed. The second is that this is the first published trial in which a new antiepileptic drug (AED) was demonstrated to be statistically inferior to carbamazepine at a therapeutic dose. This is even more significant because the drug had already been proven effective in an adjunctive trial in refractory patients. These are critical pieces of data in the continuing debate regarding the ideal methodology to demonstrate efficacy of new drugs as monotherapy in the newly diagnosed population. The first question that needs to be addressed is whether it is necessary to perform specific trials in the newly diagnosed population. There are several compelling arguments in favor of performing such trials. Registration trials for determining safety and efficacy of new antiepileptic drugs are almost always done in an adjunctive design (1). In other words, the drug under investigation is added to any AEDs the subject may already be taking to control their seizures. This design allows a placebo control group, which would otherwise be very difficult for such a serious disease. Much has been written about the type of population treated in the typical randomized placebo-controlled phase III adjunctive efficacy trial. Patients tend to have an epilepsy duration of years to decades. Median seizure frequency is 10 seizures/month. Patients have typically failed up to 10 AEDs (2). Recently, results from several studies have implied that there may be fundamental differences between newly diagnosed patients and refractory patients. Early in the course of treatment, patients separate into easily treatable or refractory. In one study, patients had an almost 50% chance of responding to initial therapy. If they failed initial therapy for efficacy reasons, they had only a 10% likelihood of becoming seizure free over the next 5 years despite multiple drug trials (3). Another important discovery is that newly diagnosed patients often respond to relatively lower doses than are needed in refractory patients (4). 1525-5050/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.
109
110
Jacqueline A. French
The stark separation of epilepsy patients into a “treatable group” and a “refractory group” raises the question of whether newly diagnosed epilepsy and refractory epilepsy are fundamentally the same disease, with similar underlying pathophysiology. If not, is it unreasonable to imagine that drugs may be more advantageous in one group than another? This may well be the case for remacemide, which controlled seizures in refractory patients who had failed carbamazepine, but was not as effective as carbamazepine in a trial of initial therapy. Clearly, these results underscore the need for continued controlled trials in the newly diagnosed epilepsy population, even after drugs have been proven effective in refractory patients. Also, adjunctive trials may overrepresent the potential toxicity of new antiepileptic drugs due to pharmacokinetic and pharmacodynamic interactions. For example, in a trial performed in refractory patients in which lamotrigine was added to baseline therapy, 20% of patients reported dizziness (5). However, when the baseline therapy was subsequently removed, the proportion fell to 7%. What made this even more remarkable was that the drugs that were withdrawn were enzyme inducers, and therefore the lamotrigine serum levels doubled once the patients were converted to monotherapy. Similarly, an improved tolerability in monotherapy was seen in a trial of oxcarbazepine (6). The markedly improved tolerability of lamotrigine and oxcarbazepine in monotherapy would be important factors in selecting these drugs for use in newly diagnosed patients. Although the benefit of performing trials in the newly diagnosed population and/or in other monotherapy settings is difficult to dispute, the methodology of doing so is very much under debate. In Europe, the common practice is to perform active-control trials, in which the new antiepileptic drug is directly compared with a standard such as carbamazepine (7–9). The outcome of these trials is often demonstration of similar efficacy in both study arms, but better tolerability and fewer dropouts due to side effects in those patients randomized to the new drug. This is not surprising, given the high responder rate in this population. Lack of demonstration of an efficacy difference in these trials is unsatisfying for two reasons. The first is that these studies often are not powered to show true equivalence, making the results less interpretable. More importantly, there has been a great deal of debate as to whether an active control trial in the newly diagnosed population has assay sensitivity. Assay sensitivity is defined as the ability of a given trial design to demonstrate a difference between treatment arms, if one truly exists. There are many examples of disease states and trial designs that have failed to show assay sensitivity. The most notorious are trials of antidepressants in patients with depression. Although there is no doubt that antidepressants are pharmacologically active, many trials have been performed in which they failed to separate from placebo (10). The fear that active control trials will not display assay sensitivity has prevented the FDA from accepting these trials as proof of efficacy in monotherapy. The corollary of this is that only one drug, oxcarbazepine, has approval by the FDA for use as initial monotherapy. Three active-control trials were performed comparing oxcarbazepine with phenytoin, carbamazepine, and valproic acid. Each trial showed no efficacy difference between oxcarbazepine and the comparator (11–13). These trials were not sufficient to obtain a monotherapy approval. Approval was gained only after a trial was performed in newly diagnosed epilepsy patients that demonstrated superiority of oxcarbazepine to placebo (14). Although this was definitive proof of efficacy, ethical issues have been raised with respect to randomizing patients with diagnosed epilepsy to placebo (15–17). In addition, the clinical validity of such trials has been questioned (18). The true importance of the trial of remacemide, 2002 Elsevier Science (USA) All rights reserved.
©
111
Editorial
using sequential analysis, is that it demonstrates assay sensitivity, in that remacemide was found to be statistically inferior to carbamazepine. This result reignites the hope that active-control trials will be acceptable proof of monotherapy effectiveness in the future. The sequential analysis design used in the Brodie study was a relatively efficient means of performing an active-control trial in the newly diagnosed population. The statistical aim of the trial was to demonstrate inferiority of either carbamazepine or remacemide, or to demonstrate no difference. The advantage of sequential analysis is that if there is a significant difference between treatment arms, as there was in this case, the design allows for early termination, thereby preventing additional patients from being exposed to an inferior treatment. If, however, there is little or no difference between treatments, more patients are enrolled until there is sufficient statistical power to prove no difference between treatments. Proof of no difference would require a large number of enrolled patients; potentially the remacemide trial could have required anywhere between 700 and 1200 patients to prove no difference (19). Since, as noted above, prior trials have as often as not demonstrated no difference, pharmaceutical companies would need to be prepared for the expense of a large sample size, if sequential analysis is undertaken. Sequential analysis is ideal when there is an efficacy difference between two treatments, as was the case in this study. But what of the more common scenario, when two treatments are the same? Sequential analysis may be more powerful in truly demonstrating no difference, albeit at the expense of enrolling a large patient cohort. Even so, this hard-won result will not lead to FDA approval of new drugs for use in monotherapy in the newly diagnosed population. Before this can happen, assay sensitivity of this methodology will need to be demonstrated in more than one trial. This can only occur if several drugs are found inferior to carbamazepine using this methodology, an outcome that is not entirely desirable, nor is it highly likely. Until or unless this occurs, the controversy and the debate will continue as to the most appropriate methodology of monotherapy trials in the newly diagnosed population.
REFERENCES 1. 2.
3. 4. 5. 6. 7.
8.
9.
French JA. The art of antiepileptic trial design. Adv Neurol 1998;76:113–23. French J, Dichter M. New antiepileptic drug development: Medical perspective. In: Levy R, Mattson R, Meldrum B, Perucca E, editors. Antiepileptic drugs, 5th ed. New York: Lippincott, Williams & Wilkins, 2002: in press. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314 –9. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001;42:1255– 60. Gilliam F, Vazquez B, Sackellares JC, et al. An active-control trial of lamotrigine monotherapy for partial seizures. Neurology 1998;51:1018 –25. Beydoun A, Sachdeo RC, Rosenfeld WE, et al. Oxcarbazepine monotherapy for partial-onset seizures: a multicenter, double-blind, clinical trial. Neurology 2000;54:2245–51. Chadwick DW, Anhut H, Greiner MJ, et al. A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. International Gabapentin Monotherapy Study Group 945-77. Neurology 1998;51:1282– 8. Chadwick D. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Vigabatrin European Monotherapy Study Group. Lancet 1999;354:13–9. Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet 1995;345:476 –9.
©
2002 Elsevier Science (USA) All rights reserved.
112
Jacqueline A. French 10. 11. 12.
13.
14. 15. 16. 17. 18. 19.
2002 Elsevier Science (USA) All rights reserved.
©
Leber PD. Hazards of inference: the active control investigation. Epilepsia 1989;30(Suppl. 1):S57– 63; discussion S64 – 8. Christe W, Kramer G, Vigonius U, et al. A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res 1997;26:451– 60. Dam M, Ekberg R, Loyning 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 – 6. Guerreiro MM, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res 1997; 27:205–13. Beydoun A, Kutluay E. Oxcarbazepine. Expert Opin Pharmacother 2002;3:59 –71. Chadwick D. Monotherapy clinical trials of new antiepileptic drugs: design, indications, and controversies. Epilepsia 1997;38(Suppl. 9):S16 –20. Chadwick D, Privitera M. Placebo-controlled studies in neurology: where do they stop? Neurology 1999;52:682–5. Karlawish J, French J. The ethical and scientific shortcomings of current monotherapy epilepsy trials in newly diagnosed patients. Epilepsy Behav 2001;2:193–200. French J. Active-control comparative equivalency monotherapy trials in epilepsy (letter to the editor). Epilepsy Behav 2001;2:613– 4. Whitehead J. Monotherapy trials: sequential design. Epilepsy Res 2001;45:81–7.