Epilepsy&

Epilepsy & Behavior 4 (2003) 457–463

Behavior

www.elsevier.com/locate/yebeh

Controversies in Epilepsy and Behavior

Translating monotherapy trials into clinical practice:a look into the abyss

Santiago Arroyoa,* and Emilio Peruccab

a Department of Neurology, Medical College of Wisconsin, Froedtert Hospital, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USAb Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy

Received 2 July 2003; accepted 14 July 2003

Abstract

To be approved for monotherapy by regulatory authorities, new antiepileptic drugs (AEDs) must first be tested in well-controlled

studies in refractory patients (conversion to monotherapy trials) or in patients with newly diagnosed epilepsy. However, the ap-

plicability of the information obtained in these trials to day-to-day clinical practice is limited. Clinical trials in newly diagnosed

patients, particularly those allowing dose flexibility, offer more useful information, but a close scrutiny of methodological details is

required to avoid misinterpretation of the findings. In many instances, the neurologist has a drug with a label, but lacks critical

information on optimal titration rates, optimal target and maintenance dosages, response rates in populations with different epilepsy

syndromes, different age ranges and comorbidities, and long-term safety data. Such information becomes available only through

general clinical experience, well-designed phase IV studies, and postmarketing surveillance.

� 2003 Elsevier Inc. All rights reserved.

Keywords: Monotherapy; Antiepileptic drugs; Anticonvulsants; Polytherapy; Clinical trials

1. Introduction

The ideal way to manage epilepsy is with a mono-

therapy regimen. In fact, the majority of patients with

new-onset seizure disorders can be treated successfully

with a single antiepileptic drug (AED) [1]. The use of a

single drug has advantages over polytherapy in terms ofbetter tolerability, avoidance of drug interactions, better

compliance, and lower costs [2].

Over the past 15 years a number of second-generation

AEDs (felbamate, gabapentin, lamotrigine, levetirace-

tam, oxcarbazepine, tiagabine, topiramate, vigabatrin,

and zonisamide) have been introduced into the thera-

peutic armamentarium of epilepsy. All of them, except

felbamate and oxcarbazepine, were approved initiallyfor add-on therapy, and only later were some of these

AEDs also granted an indication for monotherapy use

after completion of monotherapy trials [3]. Such trials

* Corresponding author. Fax: 1-414-259-0469.

E-mail address: sarroyo@mcw.edu (S. Arroyo).

1525-5050/$ - see front matter � 2003 Elsevier Inc. All rights reserved.

doi:10.1016/j.yebeh.2003.07.011

are required by law to obtain this indication both in the

United States and in Europe.

Data obtained in regulatory trials are used to deter-

mine the mode of use of an AED in routine clinical

practice. However, the complexity of clinical trials and

the purpose for which these trials are designed make it

difficult for many neurologists to evaluate the practicalimplications of trial-generated data [4]. In this article we

discuss the limitations of data derived from monother-

apy trials with respect to their applicability to clinical

practice.

2. Why are AEDs not approved with a wide indication?

Up to the early 1980s, the Federal Drug Adminis-

tration (FDA) of the United States and other regulatory

agencies granted AEDs a nonrestrictive indication for

the treatment of partial or generalized seizures, without

differentiating whether the drugs were to be used ad-

junctively or as monotherapy. In this way, carbamaze-

pine, phenytoin, phenobarbital, and primidone received

458 Controversies in Epilepsy and Behavior / Epilepsy & Behavior 4 (2003) 457–463

blanket regulatory approvals for their use in epilepsy.However, for the last 20 years, the FDA and other

agencies started to require proof of efficacy and safety

separately for adjunctive use and for monotherapy [5–7].

The reason for this change in policy was based on the

principle that a drug indication should be approved only

for those dosages and those populations for which

evidence of efficacy and safety has been provided in

well-controlled clinical trials.New AEDs are evaluated initially in adjunctive

therapy trials because, given the serious nature of seizure

disorders, it is generally considered unethical to test a

new AED as monotherapy without any evidence that

the same drug is effective when added onto preexisting

medication. Therefore, regulatory agencies consider that

if a drug was found to be efficacious as add-on in pa-

tients refractory to conventional medications, the sci-entific evidence permits only adjunctive therapy use [2].

Although the neurological community has sometimes

criticized this ‘‘regulatory loop,’’ there is in fact evidence

that these requirements are fully justified. For example,

the efficacy of three new AEDs (remacemide, vigabatrin,

and tiagabine) in monotherapy was worse than that of

carbamazepine [8–11]. Adverse effect profiles may also

differ between mono- and polytherapy regimens: inparticular, while side effects are usually more common

during combination therapy, this is not always true. For

example, paresthesias are reported much more fre-

quently when topiramate is used as monotherapy [12].

One reason behind the differences in efficacy and toler-

ability between monotherapy and polytherapy trials lies

in the pharmacodynamic interactions during adjunctive

use [13]. Furthermore, it may be argued that the AEDdosage assessed in the severely refractory population in

add-on trials may not be applicable to newly diagnosed

epilepsy patients whose seizures often respond to lower

doses of medication.

3. How does a monotherapy indication influence the way

an AED is prescribed?

In the United States, the FDA does not regulate the

physician�s use of medications. Thus, off-label use is

neither unethical nor illegal, though physicians should

be able to justify their therapeutic choice to an informed

patient. Yet, some practitioners consider off-label use a

legal liability. In a recent survey conducted by the

Practice Committee of the American Epilepsy Society,534 neurologists were asked to provide information on

their prescribing habits: although 92% would prescribe

off-label at some point, 62% of the neurologists and 46%

of the epileptologists felt that the FDA labeling does

influence their practice patterns [7]. Furthermore, the

absence of a monotherapy indication prevents the

pharmaceutical industry from promoting their products

for that indication, which, in turn, is likely to have amajor impact on the way an AED is prescribed. The

situation in Europe is similar, though in some countries

physicians are further discouraged from prescribing

drugs off-label as this precludes reimbursement of the

drug�s cost by national insurance programs.

4. How do we prove that monotherapy works?

The latest Declaration of Helsinki (2000) states that

‘‘the benefits, risks, burdens and effectiveness of a new

method should be tested against those of the best cur-

rent prophylactic, diagnostic and therapeutic methods.

This does not exclude the use of placebo, or no treat-

ment, in studies where no proven prophylactic, diag-

nostic and therapeutic method exists’’ [14]. Thefollowing statement represents the latest version of the

Declaration of Helsinki following the world Medical

General Assembly (2002) that is relevant to clinical trials

in epilepsy:

The WMA hereby reaffirms its position that extreme care must

be taken in making use of a placebo-controlled trial and that in

general this methodology should only be used in the absence of

existing proven therapy. However, a placebo-controlled trial

may be ethically acceptable, even if proven therapy is available,

under the following circumstances:

— Where for compelling and scientifically sound methodologi-

cal reasons its use is necessary to determine the efficacy or safety

of a prophylactic, diagnostic or therapeutic method; or

— Where a prophylactic, diagnostic or therapeutic method is

being investigated for a minor condition and the patients who

receive placebo will not be subject to any additional risk of se-

rious or irreversible harm.

Thus, the use of placebo as the sole therapy is gen-

erally considered ethically unacceptable in epilepsy, and,

consequently, controlled studies need to include an ac-tive treatment arm as comparator. This, however, may

complicate the interpretation of the trial results. For

example, when an investigational AED is compared

with an established AED and both show similar out-

comes in terms of efficacy endpoints, the study may be

regarded by regulatory authorities as lacking assay

sensitivity (i.e., it can be argued that the two treatments

might have been equally ineffective in the specific patientpopulation recruited for the study) [15]. This argument

has been often criticized, as many practitioners feel that

if a new AED appears to be no different from a gold

standard such as carbamazepine, there would be no

doubt of its efficacy. However, this assumption may not

always be true. For example, a review of clinical trials

comparing carbamazepine with new AEDs shows a

seizure-free rate with carbamazepine ranging from 20 to42% [16]. A more disturbing fact can be appreciated in

intent-to-treat analyses of carbamazepine trials in newly

diagnosed epilepsy in which 95% confidence intervals for

Controversies in Epilepsy and Behavior / Epilepsy & Behavior 4 (2003) 457–463 459

efficacy outcomes overlap with confidence limits for theplacebo (or pseudo-placebo) arm in other trials [4,7].

Thus, a trial showing no difference between two treat-

ments cannot be regarded as providing unequivocal

evidence of efficacy, and a design allowing demonstra-

tion of superiority over an appropriate control would

have clear advantages in this context.

A number of such designs have been developed in

recent years [4,17–19]. Invariably, these involve ran-domization of patients to a high dosage of the investi-

gational agent and to a suboptimal dosage of either the

same agent or an established AED. The use of a sub-

optimal dose (sometimes referred to as pseudo-placebo),

however, is controversial as it conflicts with the principle

of equipoise, which, according to the Declaration of

Helsinki, should govern all clinical trials.

The requirements to obtain a monotherapy indica-tion differ somewhat in Europe and in the United States.

The European Agency (EMEA) considers noninferiority

monotherapy trials using an established comparator at

optimized dosages as the best study design, although to

overcome assay sensitivity concerns supportive evidence

from some kind of superiority trial (conversion to

monotherapy or low-dose vs high-dose active control) is

also recommended [6]. The FDA, on the other hand,does not accept noninferiority trials and requires clear

demonstration of superiority versus a comparator, ei-

ther in refractory patients (conversion to monotherapy

design) or in newly diagnosed patients [5].

The trial designs used to address these regulations

differ according to the characteristics of the patient

populations. In refractory patients, two types of designs

are employed: the outpatient conversion to monother-apy and the inpatient presurgical withdrawal to mono-

therapy [19]. Both involve a short-term assessment

aimed at demonstrating superiority over a suboptimal

comparator or placebo. In newly diagnosed epilepsy,

two types of designs have also been applied: the supe-

riority design, which is usually a medium-term com-

parison versus a suboptimal comparator or placebo, and

the noninferiority design, which typically involves alonger-duration assessment [3]. Each of these ap-

proaches is briefly discussed in the sections below.

5. Outpatient conversion to monotherapy trials in patients

with refractory epilepsy

In this design, patients whose seizures are uncon-trolled with preexisting AED treatment are randomized

under double-blind conditions to a high dosage of the

investigational drug or a low dose of either the same

drug or an established AED (low-dose or pseudo-pla-

cebo arm) [19]. Baseline AED medication is then pro-

gressively reduced and eventually discontinued, leading

to a 12- to 16-week monotherapy period; those who are

unable to convert are considered treatment failures(noncompleters) and are included in the time-to-exit

analyses. Basically, the trial measures time to exit due to

fulfillment of one of the exit criteria, the aim being to

demonstrate that exit due to seizure deterioration occurs

more commonly in the low-dose than in the high-dose

group. Typical exit criteria include: a twofold increase in

partial seizure frequency in any 28-day period relative to

baseline; a twofold increase in the highest consecutive 2-day partial seizure frequency relative to baseline; oc-

currence of a single generalized seizure if none occurred

during the 6 months prior to randomization; or pro-

longation or worsening of generalized seizures requiring

intervention.

In trials conducted so far according to this design,

more than 70% of patients met exit criteria in the low-

dose (pseudo-placebo) arm. Patients randomized to ahigh dose of an effective investigational AED continued

in the trial for significantly longer periods; however,

more than 40% of these patients eventually met exit

criteria before completing the monotherapy phase [19].

Exposing patients to suboptimal therapy in these trials

has been criticized on ethical grounds [20]. To overcome

this concern it has been suggested that response to high-

dosage therapy could simply be compared with re-sponses observed in historical controls randomized to

suboptimal treatment in previous trials [4,7,21,22].

5.1. An example

Gilliam et al. [22] reported on a randomized double-

blind trial in which 156 patients on carbamazepine or

phenytoin monotherapy were randomly assigned to re-ceive increasing doses of lamotrigine (target dose, 300–

500mg/day) or a relatively low dose of valproic acid

(target dose, 1000mg/day). During an 8-week transition

period, carbamazepine or phenytoin was withdrawn and

the patients entered a 12-week monotherapy period. The

study drug was discontinued in patients who met pre-

determined escape criteria for seizure worsening. Sig-

nificantly more patients on lamotrigine completed thetrial (56% vs 20%), and the time to meet the escape

criteria was significantly longer in lamotrigine-treated

patients than in the valproic acid-treated patients (168

days vs 57 days).

5.2. What can we learn from this type of trial?

This trial design was driven by purely regulatoryconcerns, and it did not provide information that may

be of much use for routine clinical practice. Basically,

the findings of this study suggest that the investigational

drug, at high dosages, protects against seizure deterio-

ration after discontinuation of baseline AED therapy

[19]. These findings could be of some value when dis-

continuing concomitant medication in a patient who

460 Controversies in Epilepsy and Behavior / Epilepsy & Behavior 4 (2003) 457–463

had responded well to adjunctive therapy. However, thistype of study is fraught with the following limitations:

1. These studies do not necessarily assess the outcome

of conversion to monotherapy in a group of patients

who had responded satisfactorily to an optimized dos-

age of the investigational drug.

2. The dosages of the investigational drug and rates

of downtitration of preexisting medication are unlikely

to provide an estimate of the optimal dosages (and op-timal downtitration rates) to be used in day-to-day

practice.

3. The endpoints for exiting the trial may not neces-

sarily be applicable to decision making outside a trial

protocol.

4. The characteristics of the study population may

differ from those of a typical population in which con-

version to therapy is likely to be attempted in clinicalpractice.

5. The trial provides no information on clinical ben-

efit, because endpoints are based on seizure deteriora-

tion rather than improvement.

6. Most importantly, this type of study does not

provide any information on the efficacy, tolerability,

optimal titration rates, and maintenance dosage re-

quirements in patients with newly diagnosed epilepsywho are started on initial treatment.

6. Inpatient presurgical conversion to monotherapy trials

in patients with refractory partial epilepsy

These trials are conducted in hospitalized patients

undergoing video-EEG recording for presurgical as-sessment [19]. Given that in these patients baseline

AEDs are discontinued for diagnostic purposes, this

situation is exploited to test how the patients� seizuresrespond to the investigational drug compared with a

low-dose active control or even placebo. The use of

placebo, though criticized, has been justified by some

investigators in view of the intensive monitoring situa-

tion, which reduces the patient�s risks, and the addedusefulness of recording more seizures for the presurgical

evaluation. In these trials, study drugs are ‘‘loaded’’ and

the double-blind evaluation lasts 7 to 14 days. The main

objective is to compare time to exit due to fulfillment of

one of the exit criteria. The expectation is that patients

randomized to the high dosage of the investigational

agent are less likely to experience seizures than those

receiving a low-dose/placebo treatment.

6.1. An example

Arroyo et al. [23] reported on a multicenter, double-

blind, randomized, placebo-controlled, parallel-group

trial where patients were randomized to receive either

intravenous MHD (the active monohydroxy derivative

of oxcarbazepine) (2400mg/day) or placebo. The studyconsisted of a 48-hour baseline and a 7-day double-

blind treatment phase. Patients had to have 2 to 10

partial seizures during baseline and the trial was

completed either after 7 days of treatment or after

meeting one of the exit criteria (three partial seizures,

one new-onset secondarily generalized seizure, serial/

prolonged seizures, or status epilepticus). The per-

centage of patients meeting an exit criterion was theprimary efficacy variable. Of 107 randomized patients,

79.4% completed the trial and 20.6% were prematurely

discontinued; significantly more patients completed the

7-day assessment period in the MHD arm than in the

placebo arm (47.1% vs 9.8%). The main reason for

premature discontinuation was the occurrence of ad-

verse events (25% in the MHD group vs 7.3% in the

placebo group).

6.2. What can we learn from this type of trial?

The presurgical design is even less informative for

clinical practice than the outpatient conversion to

monotherapy trial. Because patients are withdrawn

from baseline medications very rapidly, this trial may

test primarily efficacy against drug withdrawal seizuresrather than spontaneously occurring seizures, a con-

sideration that reduces substantially the value of this

design even from the regulatory viewpoint. Other

shortcomings include (1) the very short time of as-

sessment, which is of no relevance to the routine use of

a drug in clinical practice; (2) the use of dosages and

rates of drug titration that are far from optimal; (3) the

possible confounding effect of pharmacodynamicinteractions resulting from carryover effects of the

discontinued medications; and (4) inclusion of a trial

population that is poorly representative of the type

of patients most commonly encountered in routine

practice.

7. Superiority monotherapy trial in newly diagnosedepilepsy

Superiority trials in patients with untreated, usually

new-onset, epilepsy use a multicenter, randomized,

double-blind, parallel-group, dose-controlled design,

i.e., a comparison of a low dosage with a high dosage.

Target dosages may be reached after an appropriate ti-

tration, and patients experiencing adverse effects duringtitration may be allowed to step back by one dose level.

Similar to the conversion to monotherapy designs, these

trials require patients to exit the study after meeting

specific criteria (e.g., occurrence of one or two seizures

after reaching the target dosage). Evidence of efficacy is

provided by the demonstration that patients randomized

to the high-dosage group remain in the trial for a longer

Controversies in Epilepsy and Behavior / Epilepsy & Behavior 4 (2003) 457–463 461

period than those randomized to the low dosage. Forpatients not meeting exit criteria, follow-up periods can

be extended for up to 1 year or longer. The typical total

sample size required to achieve adequate statistical

power in these studies may be on the order of 300 to 500

patients.

7.1. An example

Arroyo et al. [24] reported on a multicenter double-

blind trial in 470 patients with newly diagnosed (6 3

months) epilepsy or epilepsy relapse. Patients were

required to have had one or two partial-onset or gen-

eralized tonic–clonic seizures in a 3-month retrospective

baseline. They were randomized to topiramate at target

dosages of 50mg/day (low-dose group) or 400mg/day

(high-dose group). The primary efficacy parameter (timeto first seizure) significantly favored the high dose. A

secondary efficacy outcome measure included the

seizure-free rate at 6 months, which was 83% in the high-

dose group versus 71% in the low-dose group, a statis-

tically significant difference. Seizure-free rates at 1 year

(76 and 59%, respectively) also differed significantly

between groups. In terms of seizure-free rates, the dif-

ference between groups became statistically significantas early as Day 14, when patients were receiving only 25

and 100mg/day, respectively.

7.2. What can we learn from this type of trial?

This type of trial demonstrates that a high dose of an

AED is more efficacious than a low dose. Moreover,

long-term double-blind follow-up allows identificationof efficacy and tolerability profiles in relation to the

dosages used. Although the population involved in these

trials may be representative of patients who require

initial monotherapy in routine clinical practice, this is

not necessarily true. In the above study, for example, the

patient population was highly preselected in that seizure

frequency at baseline had to remain within a narrow

range.The main problem with this design is that dosages are

selected to maximize the probability of identifying a

difference and, therefore, may overestimate (high-dose

group) or underestimate (low-dose group) the optimal

dose range. Since dosages in these trials are not adjusted

according to clinical response, the optimal dose range

may not be identified, leading to labeling specifications

that may not reflect the optimal mode of use of the drug.The trial described above, for example, identified

400mg/day topiramate as an efficacious daily dosage for

initial monotherapy. Such a dose is likely to be consid-

ered by many clinicians as unnecessarily high based on

safety concerns, however (19% of patients withdrew

from the high-dose arm). This dose was derived from a

noninferiority study suggesting good responses at lower

doses [25]. Although in the superiority trial a dose of100mg during the titration phase was significantly more

effective than 25mg (and may therefore represent a more

appropriate initial target dosage), a comparison of the

100- and 25-mg doses was not the primary aim of the

study and, therefore, it may not be necessarily taken into

consideration by regulatory authorities in determining

the approved dose range.

8. Noninferiority monotherapy trials

Noninferiority monotherapy trials are multicenter,

double-blind, randomized, parallel-group studies where

the investigational drug is compared with an established

treatment at dosages likely to produce similar efficacy

outcomes. In these trials, patients with new-onset epi-lepsy are randomized to receive two or more study

treatments, and duration of follow-up is generally on the

order of 1 year. According to EMEA guidelines, the trial

should allow comparison of the investigational agent

and the reference treatment at flexibly adjusted, opti-

mized dosages. In many of the trials conducted to date,

however, the degree of flexibility has been limited. Pri-

mary endpoints in these studies typically include a pureefficacy measure (e.g., 6-month seizure-free rates) and a

combined measure of efficacy and tolerability (e.g., re-

tention of patients on the allocated treatment).

In noninferiority trials, sample size should be suffi-

cient to demonstrate, based on confidence limit analysis,

that response rates on the investigational drug are not

clinically significantly lower than those observed for the

reference (established) treatment. However, most trialsconducted to date with second-generation AEDs have

been statistically underpowered [27].

8.1. An example

Brodie et al. [26] reported on a double-blind, ran-

domized, parallel-group comparison of lamotrigine and

carbamazepine in 260 patients with newly diagnosedepilepsy who experienced partial or primarily general-

ized tonic–clonic seizures. Although this comparison

was nominally designed as a superiority trial, predicted

differences in responder rates used for calculation of

sample size were unrealistically high, and the authors

claimed to have demonstrated a similar efficacy of the

two treatments. The trial had a 48-week duration: after a

4-week fixed-dose escalation, doses were adjusted ac-cording to efficacy, adverse events, and plasma concen-

trations. The primary outcome measure was the

proportion of patients maintained seizure-free during

the last 24 weeks of treatment and was no different be-

tween the two groups (39% lamotrigine, 38% carbam-

azepine). Lamotrigine, however, appeared to provide a

better safety profile as fewer patients withdrew because

462 Controversies in Epilepsy and Behavior / Epilepsy & Behavior 4 (2003) 457–463

of adverse events (15% vs 27% on carbamazepine).Significantly more patients on lamotrigine than on car-

bamazepine (65% vs 51%) completed the study.

8.2. What can we learn from this type of trial?

The greatest appeal of these trials is that they are, or

appear to be, close to routine clinical practice. Dose

flexibility should allow optimal treatment in both studyarms, theoretically allowing a realistic estimate of the

relative efficacy and tolerability of the AEDs being

compared. For these reasons, these trials may provide

useful information that is relevant in the day-to-day

practice, and not surprisingly, they have considerable

influence on prescribing patterns. The specific trial de-

signs, however, need to be scrutinized very closely, be-

cause methodological problems and potential bias mayhave a profound effect on clinical outcome and invali-

date some of the claims made on the basis of the findings

presented.

One general problem with these studies is their lack of

assay sensitivity, defined as the ability to detect a

meaningful difference between treatments if such a dif-

ference existed. The issue of assay sensitivity has differ-

ent facets. First, as discussed above, experience hastaught us that variation in responder rates to established

and suboptimal treatments (including placebo) in dif-

ferent trials has been so wide that a finding of no dif-

ference does not really exclude the possibility that the

two treatments were equally ineffective under the con-

ditions in which they were tested [7,15]. Second, it must

be ascertained whether the study had sufficient power to

exclude a clinically significant difference. In the trialdiscussed above, for example, confidence limits for

outcome measures were so large that major differences

in efficacy, though not seen, could not be excluded [26].

Third, the maximal difference that is assumed to be

clinically irrelevant should be scrutinized. For example,

in a recent noninferiority trial comparing lamotrigine

and gabapentin in newly diagnosed epilepsy [28], it was

assumed that a difference in retention rate 6 20% be-tween the two treatments (e.g., a 45% retention rate on

the investigational drug vs a predicted 65% retention

rate on the reference drug) would be clinically irrelevant,

which is surely debatable. Fourth, it is important to

confirm that the selected outcome measures were not

suboptimal in terms of assay sensitivity. In the lamo-

trigine-versus-gabapentin comparison [28], for example,

the primary efficacy endpoint (time to exit due to inef-ficacy at the highest tolerated dose) was probably an

insensitive measure for the following reasons: the pro-

tocol required stepwise dose increments after any sei-

zure; the trial duration was only 30 weeks; and the

seizure frequency at baseline could be as low as one

seizure during the previous 12 months. (Not surpris-

ingly, of 299 patients included in the trial, only 5 exited

due to inefficacy!) Finally, it must be realized that assaysensitivity and statistical power can be weakened

through inclusion of heterogeneous patient populations.

In both trials discussed above [26,28], patients had both

partial and generalized epilepsies, which may respond

differentially to the administered drugs. Although simi-

lar efficacies were claimed for both types of epilepsy, the

subgroups were too small to allow meaningful conclu-

sions. For example, only 58 of 299 patients included inthe gabapentin-versus-lamotrigine trial [28] were diag-

nosed as having generalized epilepsy.

Another important shortcoming of some noninferi-

ority trials relates to the possibility of flaws in study

design which, at times, introduce bias in favor of the

sponsor�s product [18]. Many noninferiority trials com-

pleted to date have concluded that the sponsor�s productis similarly effective but better tolerated than an estab-lished older-generation AED. However, this conclusion

often was not supported by confidence limit analysis,

and in any case, it would be valid only for the dosing

regimens that were selected for those studies. The lam-

otrigine-versus-carbamazepine comparative trial de-

scribed above [26], for example, may have been biased

by the fact that both drugs were administered twice

daily, which is appropriate for lamotrigine but poten-tially suboptimal for the immediate-release carbamaze-

pine formulation used in that trial [29]. Likewise, an

excessively fast titration schedule may have contributed

to an unusually high withdrawal rate (27%) due to ad-

verse effects in the carbamazepine group.

In another trial comparing vigabatrin with carbam-

azepine, the dosage of vigabatrin could not exceed a

predefined limit (3000mg/day), whereas carbamazepinedosage had to be increased until seizures were controlled

or toxic effects had appeared [10]. This may explain why

in that study vigabatrin was not only better tolerated, but

also apparently less efficacious. In many trials in which a

new agent was reported to be better tolerated than an

established AED, it is not possible to exclude that such a

tolerability difference would have vanished, without

necessarily loss of efficacy, if the established agent hadbeen used at lower dosages [4]. Another shortcoming of

many trials conducted to date is that duration of follow-

up was relatively short, usually 1 year or less, which may

be insufficient for adequate optimization of dosage and

assessment of long-term efficacy and tolerability.

9. Conclusions

New AEDs should undergo monotherapy testing to

have an appraisal of their efficacy and tolerability profile

in this situation. However, the applicability of the in-

formation obtained in these trials to day-to-day clinical

practice may be minimal, especially with conversion to

monotherapy designs. Clinical trials in newly diagnosed

Controversies in Epilepsy and Behavior / Epilepsy & Behavior 4 (2003) 457–463 463

patients, particularly those allowing dose flexibility, of-

fer more useful information, but a close scrutiny of

several methodological issues is required to avoid mis-

interpretation of the findings. In many instances, the

neurologist has a drug with a label, but critical infor-mation on optimal titration rates, optimal target and

maintenance dosages, response rates in populations with

different epilepsy syndromes, different age ranges and

comorbidities, and long-term safety data will eventually

become available only through general clinical experi-

ence, well-designed phase IV studies, and postmarketing

surveillance.

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