Trials Of Antiepileptic Drugs Research Articles

Predicting outcome of initial treatment with carbamazepine in childhood focal epilepsy

We developed a model to predict the outcome of treatment with carbamazepine in children with newly diagnosed focal epilepsy of presumed temporal lobe origin, using data available at the time of diagnosis. Eligible children observed at The Children's Hospital of Philadelphia during 1999 were identified. Data were abstracted on four potential predictor variables for carbamazepine success or failure. A total of 149 patients completed an adequate first antiepileptic trial. Carbamazepine was the initial drug used in 129 (87%) patients. Forty-one of these 129 patients (32%) had persistent seizures. Significant predictors of initial carbamazepine failure were as follows: early risk factor for epilepsy (risk ratio = 3.1 [95% confidence interval 1.6, 4.0]) and temporal lobe abnormality on magnetic resonance imaging scan (risk ratio = 3.1 [1.7, 4.2]). The outcome of the initial carbamazepine trial was correctly classified in up to 78% of patients. Accurate prediction of initial carbamazepine failure was as high as 0.67 (0.53, 0.79). Accurate prediction of initial carbamazepine success was as high as 0.87 (0.77, 0.94). In this study, standard clinical data were less than adequate for predicting response to the initial trial of carbamazepine, with prediction of carbamazepine failure being particularly difficult. Better markers of antiepileptic response and nonresponse are required to guide optimal therapy in patients with epilepsy.

Special considerations in treating the elderly patient with epilepsy.

Epilepsy in elderly patients, compared with the younger adult population, differs in etiology, clinical presentation, and prognosis. Challenges in the pharmacologic treatment of epilepsy in the elderly include the following: the physiologic changes associated with aging; adverse events to which the elderly are especially vulnerable; the increased risk for these patients, who are often taking multiple medications; and toxicity from drug-drug interactions. This article presents data on efficacy and safety from clinical trials of newer antiepileptic drugs (AEDs) in elderly patients compared with older AEDs. We discuss the implications of the findings using newer-generation AEDs in the Veterans Affairs Cooperative Study (VACS) #428 in order to educate physicians involved in choosing appropriate AEDs for older patients. In the elderly patient population, an optimal treatment outcome of seizure control with minimal or no adverse events is dependent on the well-informed choice of an AED by a physician.

Treatment of partial seizures in childhood : an overview.

The treatment of partial seizures in children is based on the use of first generation and recently introduced antiepileptic drugs as well as nonpharmacological treatments such as the ketogenic diet, vagus nerve stimulation and surgical therapy. The present review discusses the efficacy and tolerability of different treatment options for partial seizures in childhood. Few adjunctive or monotherapy, placebo-controlled or comparative trials of the first-generation antiepileptic drugs and some of the more recently introduced antiepileptic drugs have been performed in children. This can be explained by the fact that it is only relatively recently (1989) that the International League against Epilepsy proposed that randomised, controlled trials be included among the required criteria for assessing the efficacy and tolerability of an antiepileptic agent. This led to controlled, comparative trials among older antiepileptic drugs (phenobarbital, phenytoin, carbamazepine and valproic acid), both in adults and in paediatric patients, being performed relatively 'late', based on when these drugs were first introduced. Carbamazepine and valproic acid may still be considered as first-line antiepileptic therapies for children with partial seizures. Phenobarbital and phenytoin are mostly considered as last choice drugs because of their adverse event profiles. The new generation of antiepileptic agents has added to the first- and second-line treatment options for paediatric partial seizures. To date, there are sufficient data to support the clinical use of some of the recently introduced antiepileptic drugs (e.g. oxcarbazepine, topiramate, gabapentin and lamotrigine) as adjunctive or first-line monotherapy. Because of the risk of visual field constriction with vigabatrin, the use of this drug is currently limited to patients refractory to other medications. Tiagabine, felbamate, levetiracetam and zonisamide have been shown to be effective in adults with partial seizures; however, at present there are not yet enough data on the efficacy of these drugs in children to support consideration of their use as either first-line or add-on therapy in this patient population, although controlled studies are expected shortly. Furthermore, the use of felbamate is considerably limited by rare, but severe, hepatic and haematological toxicity. Controlled trials for paediatric partial seizures are still lacking for the ketogenic diet and vagus nerve stimulation, though they may represent, in given patients, useful adjunctive alternative treatments for refractory partial seizures. In conclusion, further trials are needed to determine an optimal sequence of first- and second-line therapies and to establish whether other newer antiepileptic drugs merit consideration as initial therapy in children with partial seizures.

Ethical issues in antiepileptic trials: old issues in a new world.

Clinical trials of new antiepileptic drugs and therapies raise a number of challenging issues. Some would call them methodological issues. Others would call them safety issues. Still others would focus on ethical issues. Taking them altogether, they should be called responsibility issues. Responsible conduct of human studies of epilepsy, its pathophysiology, and its therapy, as in any clinical condition, must, of course, consider study design, procedures, safety, and ethics. These essential components cannot be separated, nor can the responsibility for ensuring that all studies are sound in all respects. The goals of scientists, of their subjects, and of society are ultimately shared goals; there may be differing emphasis and competing interests, but all parties to the research mission share common goals and share a common responsibility to ensure that studies are properly designed and conducted with all these elements in mind. At least four perspectives must be considered in human trials: those of the investigators, the sponsors, the subjects, and the research ethics review board (RERB), which used to be called the institutional review board, or IRB. Traditionally, the interests of sponsors and investigators have been aligned and linked together, as are those of the subjects and IRBs. These pairings have contributed to a confrontational environment, one that began with the imposition on the scientific and corporate communities of regulations for protection of human subjects in research, an environment that has existed for the past three decades. This paradigm pits the interests of those who want to do research against those on whom it will be done. Consider, for example, a 15-year-old female patient with a history of grand mal seizures since 2 years of age. She has taken four different drugs over the years, is now stable, has been without seizures for >1 year, and is succeeding in school. Her medication is reasonably well tolerated, except for severe gingival hyperplasia. This has been on her mind lately as she is getting ready to attend her junior prom.

Antiepileptic drug development for "therapeutic orphans".

Epilepsy is the most common serious neurological disorder among children. Excluding the elderly, the incidence of epilepsy is highest among children. About half of children with epilepsy have epilepsy syndromes that have unique onset in childhood. Clinical drug trials of antiepileptic drugs (AEDs) among children have been primarily performed using drugs developed for the larger adult partial epilepsy market. The current AED drug development system essentially renders children with epilepsy "therapeutic orphans" who can only benefit from AED development if a drug developed for adult partial epilepsy happens to also be effective for a pediatric epilepsy syndrome. The rapid evolution of different seizure types and childhood epilepsy syndromes, and rapid changes in baseline neurological status, make distinguishing clinical changes due to study drugs in clinical trials and the natural history of the epilepsy syndrome difficult. Unique ethical issues (e.g., informed consent), practical and logistical issues (e.g., serum AED level monitoring with microassay methods), as well as major financial and regulatory disincentives for the pharmaceutical industry are additional barriers to need-based AED development for children. A government-funded pediatric epilepsy group or consortium to conduct clinical trials similar to the successful Children's Oncology Group (COG) and regulations plus financial incentives that encourage the pharmaceutical industry to develop AEDs specifically for children are needed.

Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy.

Results from add-on antiepileptic drug (AED) trials performed in patients with chronic refractory epilepsy cannot be directly extrapolated to newly diagnosed patients because of fundamental differences in disease characteristics between the two patient populations. This article reviews the results of randomized, controlled trials of AEDs as monotherapy in newly diagnosed patients, focusing on the newer drugs. None of the newer AEDs has shown superior efficacy when tested against established agents for the treatment of partial seizures and generalized tonic-clonic seizures, the most common seizure types. Some of the newer drugs have shown good tolerability, resulting in better overall effectiveness in the case of lamotrigine over carbamazepine and oxcarbazepine over phenytoin, whereas vigabatrin and remacemide were demonstrated to have inferior efficacy compared with carbamazepine. The difficulty in detecting differences in efficacy among the AEDs might be attributed to the strategies underlying their development and the characteristics of the patient population under investigation. A better understanding of the pathophysiology of seizures and its relationship to epileptogenesis, and the use of more innovative strategies to identify new molecular targets, are needed for the development of a new generation of more effective AEDs that are not merely antiseizure but will hinder or reverse the deleterious processes that underlie the genesis of refractory epilepsy.

Preliminary efficacy of levetiracetam in children

ABSTRACT Treatment of seizures in pediatric patients is complicated by the fact that the etiology of the disorder and the pharmacokinetics, efficacy, and safety of antiepileptic drugs (AEDs) may differ from that in adults. With few controlled clinical trials of AEDs in children, the selection of agents to treat pediatric patients must be made on the basis of information from small uncontrolled studies or the extrapolation of clinical trial results in adults. Data from a large number of children with a wide range of seizure disorders who were treated in small‐scale prospective studies, or whose records were retrospectively evaluated, indicate that levetiracetam reduces the frequency of seizures in pediatric patients. Available data also indicate that levetiracetam is well tolerated in pediatric patients, with a safety profile similar to that in adults, a low potential for behavioral disturbances, and no reported idiosyncratic adverse reactions. As with other AEDs, children metabolize and clear levetiracetam more rapidly than adults, and somewhat higher doses (based on body weight) are needed to achieve desired plasma concentrations. Several ongoing studies will provide further information on the pharmacokinetics, efficacy, and safety of levetiracetam in this patient population.

Leukoencephalopathy and Cortical Laminar Necrosis Associated with Intrathecal Methotrexate and Cranial Irradiation

Leukoencephalopathy and Cortical Laminar Necrosis Associated with Intrathecal Methotrexate and Cranial Irradiation

Measuring the efficacy of antiepileptic drugs

Clinical trials of new antiepileptic drugs (AEDs) include regulatory studies aimed at demonstrating efficacy and reasonable safety, post-marketing open-open label studies and longer term outcome studies. Regulatory trials involve a carefully selected population of patients and are conducted under rigorously standardised conditions. Data from such studies cannot often be translated into clinical practice. Pragmatic post-marketing studies using flexible dosing schedules allow clinicians to better judge the utility of the new drug in a wider population of patients with epilepsy and decide the most appropriate dosing schedules. This paper discusses some of the issues surrounding the measurement of efficacy of new AEDs in both pre- and post-marketing phases of their development. All of the newer AEDs are initially used in patients with refractory partial seizures as adjunctive treatment. These trials are generally parallel-group studies although cross-over designs have been employed. The use of placebo-control is uncontroversial in this type of study. Efficacy endpoints are generally manipulations of seizure frequency on study drug compared to control. Global outcome measures and health related quality of life scores can also be used to measure efficacy. As the standard AEDs are associated with a high rate of seizure remission in patients who receive them as monotherapy, demonstration of superior efficacy of a new agent in a comparative trial will require large numbers of patients in a design that takes into account the natural history of treated epilepsy. Comparing investigational agents to a standard AED in an ‘active-control’ study with demonstration of equivalent efficacy would seem to be an acceptable way of assessing efficacy of new AEDs in this population. Some regulators, however, do not accept equivalence as proof of efficacy and insist on demonstration of superiority compared to a control. The use of placebo alone in the control group is ethically dubious. Several innovative study designs have, therefore, been used to satisfy regulatory requirements, while maintaining patient safety including withdrawal to monotherapy using high versus low dose comparators. Observational outcome studies provide the best opportunity of exploring the long-term utility of individual AEDs. Such studies largely follow standard clinical practice and need considerable time and resources. They can, however, yield valuable information about the effectiveness of AEDs in everyday clinical practice. Data from regulatory trials should be complemented by postmarketing studies and longer term studies of outcome to help clinicians decide the best way of utilising new AEDs and establishing their role in the therapeutic armamentarium.

Epilepsy surgery, delays and referral patterns—are all your epilepsy patients controlled?

Rationale : Epilepsy surgery is a standard of care in the treatment of medically intractable epilepsy, but is underutilised. We describe the results of epilepsy surgery and the referral patterns at a referral epilepsy programme. Methods : We reviewed the outcome of epilepsy surgery performed at the University of South Florida and Tampa General Hospital epilepsy programme for the years 2000 and 2001. The typical presurgical evaluation included clinical evaluation, EEG-video monitoring, MRI with dedicated epilepsy protocol, PET, SPECT, neuropsychological testing and Wada testing. We used the Engel outcome classification, and focused on the referral information to determine how and when in the course of their illness patients arrive at a referral epilepsy centre. Results : In the 2-year period (2000–2001), a total of 36 epilepsy surgeries were performed. Twenty-nine temporal lobectomies, six extratemporal resections and one corpus callosotomy. Ages varied from 17 to 65 years. Overall results were: 30 (83%) seizure-free [class I], 5 (17%) rare seizures or almost seizure-free [class II] and 1 no improvement. Of the 29 temporal lobectomies, 27 (93%) are completely seizure-free [class I] and 2 (7%) are >90% improved [class II]. Duration of seizures before being seen at the epilepsy centre averaged 18 years (range 2–58 years). Twenty-two (61%) were sent by their neurologists, while 14 (39%) came self-referred without having discussed surgery with their neurologists. Five (14%) were specifically advised by their neurologist to not consider surgery. Two had participated in clinical trials of antiepileptic drugs (AEDs) before being seen at the epilepsy centre. Conclusions : Epilepsy surgery has high efficacy and very low morbidity. Yet, there continues to be a long delay in the referral of patients to the epilepsy centre, suggesting that surgery for epilepsy is underutilised.

Help-seeking patterns for children with epilepsy in rural India: implications for service delivery.

Most people in the world with epilepsy are untreated with antiepileptic drugs (AEDs). In some developing countries, this is because treatment facilities are unavailable or difficult to access. It has even been suggested that indigenous health systems threaten the prospect of the global control of epilepsy with AEDs. We have investigated patterns and costs of help seeking for children with epilepsy in a region of rural India where only 12% of children with epilepsy were in treatment. Our objective was to find out (a) whom families had consulted; (b) if nonconsulting families differed in demographic or child medical factors; (c) if indigenous treatment was taken, exclusive of allopathic treatment; and (d) the direct and indirect cost of various providers. We conducted a cross-sectional interview study in a community-based program for childhood epilepsy in rural West Bengal, India. We interviewed parents of 85 children aged 2 to 18 years with untreated epilepsy who had entered a clinical trial of AEDs during 1995 through 1996. Eighty percent of families had sought some help in the past: 62% with an allopathic practitioner, 44% with traditional practitioners. Primary health centres (PHCs) and quacks were not popular. Twenty-four percent of families never sought help of any kind, and this was unassociated with sex, income, maternal literacy, or medical variables. There was evidence of both exclusivity and pluralism: 42% of families first consulting allopathic practitioners also visited traditional practitioners, whereas 30% of families first consulting traditional practitioners also went to allopathic practitioners. One visit to a physician cost a median of 9-13% of monthly income and 5-12 person-hours; the cost of visiting indigenous providers was negligible. Most families sought some form of help and were motivated to spend large amounts of money and time for allopathic treatments from qualified practitioners. The typical cost of allopathic treatment was unsustainable in the long term. Medical pluralism is common and does not adversely influence use of allopathic treatment. The phenomenon of nonconsulting merits further study. Traditional practitioners play a complementary role and might become involved in community treatment programs. Low-cost, local treatment is essential to the public health control of epilepsy.

Epilepsy surgery in children

Many treatment options exist for adult patients with epilepsy; somewhat fewer exist for pediatric patients. In most cases, physicians attempt pharmaceutical therapy to alleviate or control seizures before embarking on the more permanent course of surgery as a treatment, and surgery is performed only after patients have failed multiple trials of antiepileptic drugs (AEDs). Information has come to light, however, that questions this norm. At the very least, new information demands increased awareness about the “whens,” “whys,” and “hows” of surgical management when it is under consideration as an option for patients with intractable epilepsy. At best, the information may be signaling that the time has come for clinicians to start thinking about surgical interventions sooner in the course of a patient’s disorder. According to information reported about long-term outcomes of patients undergoing pharmaceutical treatment for new-onset epilepsy, physicians should consider surgical management as the next step in therapy when the patient has not responded to two different monotherapies with AEDs. Kwan and Brodie1 followed 525 patients (9 to 93 years of age) with new-onset epilepsy for a median follow-up period of 5 years. Ninety percent of the patients were followed for more than 3 years. Participants entering the study were not taking AEDs at time of entry, although they were not excluded if they had received previous treatment with AEDs. Although no difference in response was found between patients receiving older AEDs and those receiving therapy with more recently developed AEDs, the study authors noted a statistically significant relationship between the number of seizures experienced and the response to AEDs. Specifically, the prevalence of persistent seizures was higher in patients who had experienced more than 20 seizures versus patients with 20 or fewer seizures before entering the study (51% versus 29%; p < 0.001). In addition, the prevalence …

Response to first drug trial predicts outcome in childhood temporal lobe epilepsy.

To construct a clinical prediction model for the early identification of children destined to develop refractory temporal lobe epilepsy (TLE) 2 years after epilepsy onset. Patients with TLE between 1 and 18 years old seen in the Division of Neurology at Children's Hospital of Philadelphia during 1999 were identified through billing records and chart review. Data were abstracted independently on 5 candidate predictor variables for refractory TLE and on seizure frequency outcome at 2 years after epilepsy onset. One hundred twenty patients met inclusion criteria and had at least 2 years of follow-up. Forty-five of 120 patients (37.5%) had refractory TLE at 2 years after onset, and 75 of 120 (62.5%) were seizure free. Three significant predictors of refractory TLE were found on bivariate analysis: an early risk factor for epilepsy (risk ratio = 3.5 [95% CI 2.2, 5.6]), temporal lobe abnormality on MRI scan (2.9 [95% CI 1.9, 4.6]), and failure of the first antiepileptic drug (AED) trial (16.5 [95% CI 6.3, 43.9]). Logistic regression indicated that the best model to predict refractory TLE contained only the variable "failure of first AED trial," with a positive predictive value of 0.89 (95% CI 0.76, 0.96) and negative predictive value of 0.95 (95% CI 0.87, 0.99) to predict "refractory TLE" at 2 years. Failure of first AED trial accurately predicts refractory TLE at 2 years after onset, based on retrospective cohort data in children. If verified prospectively and with longer follow-up, this finding should support earlier consideration of surgical options.

Efficacy of lamotrigine add‐on therapy in severe partial epilepsy in adults with drop seizures and secondary bilateral synchrony on EEG

ABSTRACT Objectives To evaluate the efficacy of lamotrigine (LTG) add‐on therapy in drug‐resistant, partial epilepsy with epileptic drop attacks (EDA) and secondary bilateral synchrony (SBS) on EEG. Methods We carried out a single‐center, open‐label, prospective study on a restricted group of patients experiencing an EDA frequency of at least one/month during the previous year regardless of multiple antiepileptic drug (AED) trials. Study design consisted of three phases: a 3‐month baseline period, a 4‐month period in which LTG was titrated and a 9‐month maintenance dose observational period. LTG add‐on therapy depended on valproate (VPA) association, with a maximum of 200 mg/day with VPA and 600 mg/day in the absence of VPA. Every three months, patients underwent clinical, hematological and EEG evaluation including plasma level of AEDs. To assess the efficacy of LTG add‐on therapy, patients were required to keep a detailed seizure diary throughout the study. Results Fourteen patients (nine men and five women), aged from 21 to 51, were included in the study. All of them had complex partial seizures (CPS), besides EDA, and half of them had secondarily generalized seizures (SGS). Two of the 14 patients had to stop LTG due to side effects, although one of them was seizure‐free after LTG. Twelve patients completed the study. The improvement was more than 50% for every type of seizure. SGS disappeared in three cases and improved by more than 50% in another three cases. EDA disappeared in six patients; and improved with more than 50% EDA reduction in five patients. CPS disappeared in two patients and improved by more than 50% in eight. EEG improved in nine cases, with SBS disappearing in six patients. Conclusions We have demonstrated a good efficacy of LTG adjunctive therapy on EDA. Results include control of SGS and improvement of EEG tracing.

Cognitive and behavioural assessments in clinical trials: what type of measure?

This paper provides an overview of the types of neuropsychological and behavioural measures used in randomised controlled trials (RCTS) of antiepileptic drugs (AEDs) in patients with epilepsy. The results of previous systematic reviews are reported in respect of the methods used in clinical trials to assess cognitive and behavioural effects of AED treatment. There were 46 trials incorporating behavioural measures and 40 trials incorporating neuropsychological measures. The evidence supporting the choice of test, and their reliability, validity, and sensitivity to change was minimal. It is concluded that poor reporting of methods and a plethora of both neuropsychological and behavioural measures make it difficult to provide any meaningful comments about the effects of AED treatment. A much more standardised approach to assessing these effects is necessary.

Proof of efficacy trials: cross-over versus parallel-group

In recent years, most of the published trials of new antiepileptic drugs (AEDs) have had a parallel-group design rather than cross-over. Nevertheless, in some situations the cross-over trial does have advantages, and therefore, its role needs re-appraisal. The crossover design requires a much smaller number of patients for a similar statistical power because patients act as their own controls, which is a particular advantage when the type or severity of epilepsy varies widely in the patients recruited. As a result, the financial cost is smaller and fewer patients are exposed to the new agent, perhaps with ethical arguments in favour of this type of design in proof-of-efficacy trials. Within-patient analysis also makes the detection of drug interactions more robust. On the other hand, there is a theoretical risk that the beneficial effects of the first treatment (or conversely, withdrawal seizures on stopping it) might carry over into the second treatment period and thereby confound the detection of treatment effects. The parallel-group design is more versatile in that a stable disease state is not a pre-requisite, and therefore, trials in newly diagnosed patients are possible. Multiple treatment limbs are also more practical. The duration of a parallel-group trial may be shorter because only one treatment period is involved, although this may be offset by the much larger number of patients needed to be recruited and the time involved in doing so. Parallel-group trials almost always require a multicentre approach, with the inevitable logistic problems involved. It is argued that proof-of-principle and add-on proof-of-efficacy trials of a new drug are more efficiently undertaken using a cross-over design but that subsequent evaluation will require the versatility of trials with a parallel-group design.

Monotherapy trials: endpoints

Monotherapy antiepileptic drug (AED) trials can optimally provide information concerning efficacy and tolerability of one drug compared with placebo, as well as to different doses or rates of administration. Commonly, a drug is compared with one or more other drugs. The outcome measures will be dictated by the questions being asked. In most comparative studies, the single overall result that best defines success or failure is time of continuation on drug as expressed in a life table. Discontinuation before planned completion of the study implies insufficient efficacy or unacceptable adverse effects. A statistically significant difference between treatments provides important support for recommending the drug or dose with the best outcome. The criteria for continuation/discontinuation are defined in the design based on the expected outcome. The outcome of primary importance is efficacy in prevention of seizures or a decrease in severity. Complete control for the duration of the study is the ultimate goal but in some populations may not be possible. The number of subjects entering remission gives further information about long term outcome. Time to first ( nth) seizure provides similar evidence of efficacy. Seizure rates allow comparisons of subjects retained for different lengths of time in the trial. Differences in seizure severity may be of clinical importance and multiple efforts have been made to develop instruments to accurately measure this outcome. Adverse effects of the drugs are the second major outcome. These can be expressed as incidence and/or prevalence. The presence and frequency of side effects will depend on how the study is designed and whether these effects are specifically sought by the investigators. Serious systemic safety outcomes are monitored, but the relative infrequency of occurrence and number of subjects in the trials usually do not provide enough power to detect statistically significant differences except for rash. Tolerability is more easily documented but is difficult to access accurately in the absence of placebo controls. Frequency, severity and persistence are measurable. Specific unwanted types of drug effects can be specifically studied using detailed neuropsychological test batteries. Some information concerning pharmacokinetic properties may be obtained but are better assessed in other types of trials. A final important outcome is the effect of drug therapy on quality of life. Although a favorable finding in this outcome is most desirable, the measures used are much less precise than those for efficacy and adverse effects.

Monotherapy trials: endpoints

Prof Brodie stressed the importance of assessing the effectiveness of a new drug in addition to its efficacy. ‘Effectiveness’ is defined as the global outcome, combining both tolerability and efficacy. Global outcome measures in monotherapy trials, such as retention time, are of great importance because they are clinically meaningful. There may, however, be some problems with these global outcome measures. Retention time or time to treatment failure is influenced by both efficacy and tolerability. In comparing two treatments, it may emerge that drug A is better tolerated than drug B but is less efficacious. Therefore, as many patients may remain on drug A as on drug B. The consequence may be that the two treatments would appear to be equivalent using a global measure of outcome when, in fact, they have very different patterns of tolerability and efficacy which may be highly relevant to their use in clinical practice. It tends to be the case that drugs which are potent in terms of efficacy are less well tolerated than those of more modest efficacy, and global measures alone may lose these differences. This has been the experience of Dr Tony Marson in my Department, who has been undertaking a meta-analysis of comparative trials of antiepileptic drugs. A further global outcome measure, quality of life, might be seen as attractive in this area. However, it can be argued that if the clinical outcomes of a trial are those of genuine importance, these will, by definition, be immediately reflected by an impact on health-related quality of life. It is important to recognise that the outcome chosen for a clinical trial will be determined by whether that trial is explanatory in nature and be used for regulatory purposes, or whether it is essentially pragmatic to inform everyday clinical practice. Sometimes, these different objectives are confused. However, although global measures are important in pragmatic trials, it is important to recognise their limitations, and ensure that other secondary endpoints in a trial will assess the individual profiles of efficacy and tolerability of the drugs being investigated.

Proof of efficacy studies: endpoints

The majority of clinical trials of antiepileptic drugs (AEDs) fall into two main groups: (i) phase II and early phase III add-on studies in people with drug-resistant, chronic epilepsy, and (ii) late phase III parallel-group monotherapy studies in newly diagnosed patients. Both types of trial record the occurrence of seizures over a set period from which a large number of endpoints may be derived for analysis. Although the main objective of treatment is the suppression of seizures, other associated endpoints such as drug side-effects, quality of life, and costs are also of relevance. Within any particular trial, the required sample size will depend crucially on the characteristics of the population sampled, the type (and perhaps number) of endpoints, losses to follow-up and other deviations from protocol, as well as important statistical considerations, especially the type of design, including Type I and II error rates, and methods of analysis.

Proof of principle trials: exploratory open studies

The aims of the observational, early phase IIa studies are usually several in number and often competing, and therefore the priorities should be clearly defined. The preclinical data, particularly the mode(s) of action of the drug and the results on experimental models, can help to build hypotheses on the agent's potential efficacy for individual seizure types and syndromes. For ethical reasons, the population selected for the initial clinical trials of antiepileptic drugs (AEDs) should be patients with continuing seizures (e.g. no less than two to four partial seizures/month) in spite of several therapeutic attempts using other appropriate AEDs, taken in monotherapy and in various combinations. Although the inherent bias in open, observational studies has limited their use in comparing treatments in epilepsy, they have several advantages over controlled trials, including lower cost, greater timeliness and inclusion of a broader range of patients. Observational, open studies with well-chosen patients and an adequate design tailored to answer precise predefined questions (including go/no go criteria) are most valuable for experienced clinicians in determining the clinical benefit of the drug, and for the pharmaceutical company in assessing the commercial merit of proceeding with further clinical testing.