Epilepsy: A Comprehensive Textbook
2nd Edition

Chapter 140
Clinical Trials of Antiepileptic Drugs in Adults and Children
Jacqueline A. French
Tracy A. Glauser
Bernd Schmidt
The modern age of drug testing was ushered in in 1962 by the passage of the Kefauver-Harris amendments to the Federal Food, Drug, and Cosmetic Act.25 This act required for the first time that a drug be proven effective prior to marketing and sale. In most countries, extensive efficacy and toxicity testing is required before a new antiepileptic drug is approved for general use, supervised in the United States by the Food and Drug Administration (FDA) (Chapter 142) and in Europe by the European Agency for the Evaluation of Medicinal Products (EMEA) (Chapter 143). This information is obtained by performing clinical trials. These trials are of great significance for two reasons. The first is that if trials fail to demonstrate efficacy to the satisfaction of registration boards, a potentially useful drug may not emerge on the market. The second is that at the time that a drug is approved for clinical use, all that is known about its efficacy and toxicity derives from information obtained through clinical trials. Improper trial design or inadequate analysis of results may lead to misinformation and misuse of the drug. It is of vital importance that these trials be performed in a logical and comprehensive manner. This chapter will explore aspects of antiepileptic drug trials, including design issues, different types of trials, ethical issues, special populations, and analysis of results.
Phases of Testing in Humans
After a drug has undergone extensive in vitro experiments and testing in animal models of seizures and epilepsies and there is preclinical evidence of efficacy and safety, an investigational new drug application will be obtained from regulatory agencies indicating that the drug is ready to be tested in humans. Before efficacy can be assessed, the drug must be evaluated in volunteers (phase I testing). Phase I testing is performed for evaluation of safety, pharmacokinetics, and human metabolism. Initially, single rising doses will be administered to healthy volunteers in order to determine the dose at which toxicity will emerge, and to make preliminary assessments of pharmacokinetics; these studies expose approximately 20 subjects. Single-dose studies will be followed by more chronic administration studies. Again, toxicity and pharmacokinetics are assessed, including determination of drug half-life, clearance, volume of distribution, time to maximum serum concentration, and presence or absence of nonlinear pharmacokinetics. Metabolites and means of elimination are identified.13 An important determination from these studies is maximum tolerated dose. Phase I may also include studies of special populations who may be at particular risk from a given drug. For example, a drug with renal metabolism may be tested in patients with renal failure.
Obtaining quality information during phase I is critical for proceeding to phase II trials. The first testing of epilepsy patients will usually occur during phase II, which includes initial efficacy and safety testing in the population of interest, and usually also includes the first large multicenter safety and efficacy trials. The earliest trials are usually what is called “proof of principle.”64,65 These trials are performed to get a first impression of whether the drug will be antiepileptic in humans. Based on this trial, a “go–no-go” decision may be made by the company testing the drug. In other words, the company will decide whether an investment in larger, more expensive testing is warranted. One example of a common proof-of-principle trial is a study in photosensitive epilepsy patients. Photosensitivity studies are ideal as an early trial, as they can usually be performed with a range of single doses. The fact that an investigational drug can be shown to reduce or eliminate the photoepileptiform response can be taken as an indication that it has passed the blood–brain barrier and may have an antiseizure effect, demonstrated on the surrogate marker of the photoparoxysmal response. Efficacy in this model is also often taken as an indication that the drug may have activity against a broad spectrum of seizure types.11,64 Early trials may also include a maximum tolerated dose (MTD) study in epilepsy patients, as tolerated doses are known to differ significantly between normal volunteers and patients. Early trial results may also give a first indication of potential pharmacokinetic as well as pharmacodynamic interactions.65 Several large phase II trials have failed because the dose has been poorly chosen.
Phase III testing includes continuation of safety and efficacy testing as well as trials for specific indications, or in special circumstances. Monotherapy studies and studies in patients with distinct epilepsy syndromes such as the Lennox-Gastaut syndrome might be included in phase III testing plans. When the drug is approved, trials frequently continue during phase IV or postmarketing studies with the aim to define the drug’s optimal use in a general clinical practice population and to broaden the well-documented safety database. Other pivotal phase III trials for extended indications such as pediatric use, primary generalized seizure types, or a monotherapy indication may be pursued either before or after initial approval. Postmarketing surveillance is also done, looking for rare adverse events, pregnancy outcomes, and other information that might not be obtainable in preapproval data.
Efficacy Trials
As noted above, efficacy trials are usually performed as part of phases II and III. These pivotal trials are designed to definitively determine whether a drug has antiepileptic potential in humans. Trial design and implementation is driven by several

independent and potentially conflicting needs. These include the need of a pharmaceutical company to find out whether a compound is worth developing, in the least expensive way possible; the need of the company to demonstrate efficacy and safety to registering agencies (e.g., the FDA and EMEA); and, lastly, the need of physicians to know the potential utility of a new drug in the treatment of patients with epilepsy. It is frustrating to clinicians that the last need, which they may see as the most vital, may have the least influence on trial design. Unfortunately, if the first two needs aren’t met, the drug may never come to market. Only after the drug is registered may there be the “luxury” of determining its clinical properties.
The fact that many efficacy trials are registration driven explains why trial design is very different in different countries. In Europe, active-control monotherapy trials are considered acceptable, and crossover designs have been more common in the past. Both these design elements are seen as problematic by the FDA, and are rarely or never used in the United States. As development programs have become global programs aiming at one dossier used for filings around the world, study designs are fairly standardized nowadays.
Trial Design
Need for Blinding and Control Groups
Efficacy trials must compare two treatment groups in a blinded fashion. It is not typical to use a population as its own control, comparing a baseline pretreatment epoch with an epoch after treatment has been initiated, because of placebo effect. In other words, patients who have an expectation that they may improve will demonstrate improvement with or without new treatment.
Physicians may have difficulty accepting the reality of the placebo effect in intractable epilepsy patients, who have been switched from treatment to treatment without benefit, yet time and again patients in the placebo arm of multicenter epilepsy studies will demonstrate a substantial seizure reduction. The degree of placebo effect will vary from study to study for unclear reasons. In recent studies, 0% to 36.5% of patients in the placebo arm of blinded trials showed a 50% or greater seizure reduction over a standard 3-month exposure period.14 The degree of a placebo effect also varies between regions and individual centers within one large multicenter trial.
Active Versus Placebo Comparisons
For some purposes it is considered acceptable or even desirable to choose two active treatment arms as blinded comparison groups. Some of the best early examples of this type of trial were two VA cooperative studies,46,47 which randomly assigned patients with newly diagnosed seizures to different antiepileptic drug therapies. This allowed direct comparison of these drugs in terms of both efficacy and safety. A large number of active control comparison trials have been performed in the last decade, comparing standard drugs such as carbamazepine and phenytoin to the newer drugs.10,12,15,17,18,39,41,55,68 This type of trial may be extremely informative for clinical purposes. In Europe, they have contributed to the registration of a number of new antiepileptic drugs (AEDs) as monotherapy. In the United States, however, the FDA does not accept active controlled trials as proof of monotherapy efficacy.43 These active-control trials, including the VA cooperative studies, were able to demonstrate equivalence between drugs. In order for the FDA to accept a trial as proof of efficacy, superiority of the new drug must be demonstrated.
Adjunctive Versus Monotherapy Trials
There are inherent disadvantages to adjunctive, or add-on, trials in which active treatments or placebo is added to the patient’s baseline antiepileptic drugs. It is more difficult to prove efficacy in a patient who is already partially treated. Side effects may be magnified by combining drugs, and pharmacokinetic interactions may alter baseline or experimental drug levels. Despite these drawbacks, most efficacy trials use an adjunctive therapy design because of the ethical issues raised by monotherapy parallel trials involving placebo in patients with epilepsy. New trial designs were developed in the 1990s that attempted to circumvent ethical issues and permit monotherapy studies. The two most popular designs were described by Pledger and Kramer.53 The first, which involves randomization to drug or placebo in inpatients who have had their background antiepileptic drugs withdrawn for presurgical evaluation, has been deemed too short to be used for registration purposes and not relevant for extrapolation to a general clinical population, and is now used primarily for a proof-of-principle trial.13,28,63 A second design is performed in outpatients.8,29,38,53,60,62 Patients are randomized to treatment with an experimental drug or placebo, after which baseline therapy is withdrawn over 2 to 8 weeks. A modified, or “ethical,’’ placebo is utilized rather than a true placebo to reduce the likelihood of status epilepticus or secondary generalization. This can consist of a minimally effective dose of either the same investigational drug or of any other therapy presumed to be less effective than the test drug. A starting dose of valproic acid (15 mg/kg) has been employed in a number of trials for this purpose. Outcome is assessed in terms of “failures’’ and “completers.’’ Failure is determined on the basis of escape criteria, such as doubling of seizure frequency, occurrence of generalized tonic–clonic seizures, or increase in seizure severity. If more patients receiving the experimental drug at a therapeutic dose in monotherapy can complete the trial, without fulfilling escape criteria, than patients receiving modified placebo in monotherapy, the treatment is considered effective in monotherapy. This trial design has been successfully used to obtain a monotherapy indication from the FDA for oxcarbazepine and lamotrigine (withdrawal to monotherapy in refractory patients). A drawback of this design is that antiseizure effects are evaluated in an AED withdrawal situation only.
Two other monotherapy designs have been employed to gain FDA monotherapy approval. These have been performed in patients with newly diagnosed epilepsy. One study compared oxcarbazepine to placebo in patients having frequent seizures (average 5.5 per month) at baseline.59 The end-point was time to third seizure. Another study compared 50 mg of topiramate to 400 mg in newly diagnosed adolescents and adults with partial-onset seizures.1 Outcome measures included time to first seizure as well as seizure-free rate at 6 months and 1 year. Although all these monotherapy trials led to registration of at least one AED as monotherapy, the trials continue to raise ethical as well as pragmatic issues. For this reason, efforts are under way to devise new methods to perform monotherapy trials.30,34
Parallel Versus Crossover Designs
In parallel trials, patients are randomly assigned to one of two treatment groups for a period of time. Their seizure frequency during the treatment period is compared to a pretreatment baseline. Seizure outcome is compared between the two groups. In a crossover design, patients are also randomly assigned to two treatment groups, but after a period of time each group is crossed over to the other treatment, usually after a washout period. Outcome as compared to baseline is determined for each treatment. There are some advantages to a crossover design. Far fewer patients are required to perform the trial, provided

that the subjects complete all required crossover periods, including the washouts. Also, if two active treatments are used, this trial design is more like clinical practice, in which patients are usually crossed from one treatment to another. Each patient will receive both treatments, allowing more direct comparison of efficacy and tolerability. The disadvantages of a crossover trial include a much longer duration, risk of patients dropping early, and, more importantly, a potential unblinding of the trial. This is of the utmost concern in a trial that compares placebo to active drug. Patients may be able to discern a difference in side effects when switching from placebo to drug, or vice versa. There may be carryover effects of a drug, which would impact the initial portion of the second treatment phase. For these reasons, the FDA and the EMEA do not favor such trials.
Patient Issues
Overall trial makeup is influenced as much by the population chosen for the trial as by the trial design. Trial populations may differ in terms of epilepsy syndrome, as well as disease severity.
Epilepsy Syndrome Selection
The majority of phase II and phase III AED trials are performed in patients with partial epilepsy, specifically with complex partial seizures. These patients comprise the majority of adults with uncontrolled seizures, and the pharmaceutical companies need an indication from registering bodies to treat partial seizures, for market share. With rare exceptions, a drug that is unable to treat such patients would not be profitable to develop. Recently, there has been discussion regarding bringing drugs forward for niche indications or for orphan diseases such as Lennox-Gastaut syndrome. Nonetheless, to date no new AEDs have been approved without a partial seizure indication.
When a partial seizure indication has been obtained, further studies may be performed to assess efficacy in other syndromes. Studies in different syndromes offer their own potential obstacles and may impact trial design. One example can be seen in the Lennox-Gastaut population. Initially, it was felt that seizures in these patients were easily recognizable, and that placebo effect would not be an issue in this severely impaired population. Therefore, open trials were undertaken in patients treated with cinromide, a drug that was in development. The results were very promising, demonstrating a >50% response. However, when the study was repeated with a placebo control, it was found that the entire treatment effect could be attributed to a placebo response.23 It was felt that this reflected not only a bias in parental observation, but also a difficulty in differentiating between seizures and abnormal behaviors, common in this population. As a result, subsequent trials incorporated video-electroencephalographic (V-EEG) monitoring to train parents on differentiating seizures. In addition, the primary outcome variable was reduction in motor (tonic, atonic, and generalized tonic–clonic) seizures, which are the most recognizable. This led to a successful trial design, and ultimately to approval of three of the new AEDs (felbamate, lamotrigine, and topiramate) for use in the Lennox-Gastaut syndrome.26,49,61 This and other examples of potential populations, study limitations, and ways of circumventing them are given in Table 1.
Seizure Severity
Another patient characteristic that may impact AED trials is disease severity. It cannot be taken for granted that a drug that has been proven to be highly effective in intractable, severely affected patients will also be the most ideal drug for new-onset patients. It is feasible that some drugs may work preferentially in refractory patients, due to specific pathophysiologic alterations that are found in these patients. One possible example of this relates to the antiepileptic drug vigabatrin. This drug exhibits retinal toxicity in selected populations and is not available in the United States, but is approved in Europe. In placebo-controlled add-on trials in refractory patients, this drug appeared to be more potent than almost any other available antiepileptic drug.31 However, when tested in a head-to-head fashion against carbamazepine, it was not as effective.16
Once a drug has been proven safe, trials in new-onset patients are frequently performed. These trials have usually been performed as active-control comparisons, in which an investigational agent is compared to a standard agent, with the exception of oxcarbazepine, which was tested against placebo.59 Both placebo control and active control may have drawbacks to confirm the efficacy of AEDs in newly diagnosed patients. Placebo-controlled trials are short by necessity, and only prove that a drug is better than “nothing.” On the other hand, if the population for an active-control equivalence trial is chosen poorly, if the trial is not designed properly, or if the sample size is not sufficient to have the power to show a difference when one exists, then equivalence may be demonstrated between two drugs for which there actually exists a clinically meaningful difference in efficacy or safety.34
Women of Childbearing Age
Women of childbearing potential also bear further consideration. In earlier epilepsy trials, women were only included in studies if they were postmenopausal or had undergone surgical sterilization. Recently, there has been pressure to include more women in trials at an earlier point in development.42 In order to do this, it is necessary to expose women of childbearing potential to drugs that do not have established efficacy and safety. Most protocols lay out strict guidelines for contraception that is considered acceptable during a trial based on potential hormonal interaction data. Occasionally, contraception will fail and a pregnancy will ensue. It is often the policy at present to discontinue the investigational drug immediately in such a situation. This may not always be the safest course for the mother or fetus, particularly if the individual had a very significant seizure reduction from that drug. Postmarketing pregnancy registries by sponsor companies and academic consortia have been set up to better investigate the comparative teratogenicity of AEDs.
Clinical testing of antiepileptic drugs considers children separately because of the age-related changes in both brain and overall physiologic and biochemical status that occur during childhood along with the age dependency of certain seizure types and epileptic syndromes. Most studies on AEDs have considered “children” to be those younger than 12 years of age, and have included those aged 12 years and over in trials designed primarily for adults. The population of patients younger than 12 years is often subdivided into neonates (<1 month postnatal age); infants (1 month up to 2 years), and children (from 2 years up to 12 years). The children group can be further subdivided into preschool (2 to 5 years) and school age (5 to 12 years). This last division is not arbitrary; there are differences in the type of epilepsies likely to present before and after 5 years57 and there are different methods and scales used to monitor behavioral and cognitive side effects between these two age groups.
Table 1 Epilepsy Syndromes and Potential Obstacles They Present
Epilepsy syndrome Potential obstacle Solution
Partial seizures Simple partial seizures may be subjective and difficult to count Count only observable simple partial or complex partial seizures
Primary generalized epilepsy (absence, myoclonic and tonic–clonic seizures) Seizures usually well controlled on currently marketed medications
Absence seizures may not be clinically apparent
Perform add-on study in refractory patients, using minor seizures such as myoclonus as end-point
Perform inpatient monitoring, measuring spike-wave on EEG for absence
Lennox-Gastaut syndrome Too many seizures to count accurately; in severely retarded subjects, abnormal behaviors may not be distinguishable from seizures Use videotape to train parents to distinguish seizures from behaviors Use tonic–atonic seizure frequency as an independent outcome variable (less frequent and easily countable)
Neonatal seizures Difficult to count clinically Difficult to do add-on, but placebo control raises ethical issues Use video-EEG to count events Perform short placebo-controlled trials
Status epilepticus Difficult to obtain informed consent Convulsive and nonconvulsive status have different prognoses Obtain waiver of consent Carefully define clinical status syndromes, and randomize to different groups
EEG, electroencephalogram.
Trials targeted at resistant partial seizures in adults can be relevant to the same type of disorder in childhood. However, the spectrum of childhood treatment-resistant epilepsies is different than those in adulthood, and it should not be assumed that AEDs effective in adults will be appropriate for

the resistant epilepsies special to childhood. In the infant, early myoclonic encephalopathy and early infantile epileptic encephalopathy51 respond only rarely to established AEDs. West syndrome, severe myoclonic epilepsy in infants, myo-clonic astatic epilepsy, and Lennox-Gastaut syndrome, although responsive to some of the more recently introduced AEDs, remain difficult to treat in at least half of affected children. Epilepsies with cognitive symptomatology, such as acquired epileptic aphasia (Landau Kleffner syndrome) and epilepsy with continuous spikes and waves during slow sleep, are rare, with difficult-to-quantify clinical features making these patients challenging subjects for AED trials. Although these syndromes are relatively rare in adults, epilepsies with features of Lennox-Gastaut and West syndromes may persist beyond childhood. Children with these epilepsies deserve to have closely monitored trials designed to specifically address their needs.
The patterns of seizures and the designations of epileptic syndromes may evolve throughout childhood; these transformations are probably related to maturational features in the brain. For most circumstances, it is not known whether this, of necessity, means that the newly acquired state is likely to be more or less responsive to AEDs. However, the researcher must appreciate that alterations in seizure type during a trial can be due to evolution of the epilepsy, rather than the AED. For example, about one third of patients with an initial presentation of early infantile epileptic encephalopathy (EIEE, with suppression burst on the EEG) can progress to West syndrome (with hypsarrhythmia on EEG) and later appear to have Lennox-Gastaut syndrome (with diffuse slow spike-wave on EEG). Alternatively, some infants with initial EIEE later have focal spikes, having, in some cases, had hypsarrhythmia as an intervening stage.50 Children with West syndrome often have resistant partial seizures later. Another transformation that would be problematic for the AED trialist occurs with severe myoclonic epilepsy in infants. Predominantly clonic, often lateralized, seizures occur in the first year of life, followed by myoclonic jerks and partial seizures during the second year, accompanied by the development on the EEG of generalized spike and polyspike waves, photosensitivity, and focal abnormalities.24 Even in noncatastrophic epilepsies transformation can occur. For example, although childhood absence epilepsy is not accompanied by other seizure types in 60% of cases, generalized tonic–clonic seizures or progression to juvenile myoclonic epilepsy may occur in others.
The majority of inborn errors of metabolism of which seizures, particularly myoclonic seizures, are symptomatic present in childhood, particularly in infancy. Consideration of whether such an underlying condition could be present but unrecognized must always be an important feature of the assessment of suitability for AED trials. Alternatively, knowledge of the specific biochemical defect and the mode of action of the new AED might allow prediction of success or eliminate the likelihood of precipitation of adverse biochemical states. Maximal understanding of the biochemistry and pharmacology of new AEDs is essential before they are used for childhood seizures.
Drug Issues
In order to design and successfully implement a clinical trial with a given drug, a significant amount should be known about that drug’s unique characteristics. Every trial design will not work for every drug, and innovative alterations may be necessary in a standard design, due to specific drug properties. Failure to fully explore drug–drug interactions early on can lead to problems in a phase II trial. For example, in an early phase II trial, felbamate was used as adjunctive therapy in patients taking carbamazepine as a baseline drug.70 This trial failed to demonstrate efficacy against placebo, in part because felbamate caused a reduction in carbamazepine levels, possibly leading to seizure exacerbations. Felbamate is also known to increase phenytoin levels by 20%. When felbamate was tested in a Lennox-Gastaut protocol, all patients had to have phenyt-oin doses reduced by 20% prior to the baseline period.26 If this had not been done, the increased phenytoin levels in the treated group could have lead to toxicity, and the study could have been unblinded. Similarly, since valproic acid doubles the half-life of lamotrigine, patients on valproic acid were excluded from blinded trials with that drug.6,40,45,48 Pharmacodynamic

interactions may also confound a trial. In the only adjunctive trial of oxcarbazepine in adults with partial seizures, the dropout rate in the high-dose group was >70% in the absence of pharmacokinetic interactions,5 despite this dose having been very tolerable in a monotherapy trial.9 It is felt that the high dropout rate was due to pharmacodynamic disturbances when oxcarbazepine was added to other AEDs, coupled with a relatively rapid titration. Knowledge about the tolerability of rapidly titrating an AED may be important for other reasons. Inpatient monotherapy trials require rapid titration of study drug, as the treatment period is usually 2 weeks or less. Drugs that need a slow titration would not be suitable for this type of trial.
Selecting the appropriate dose range is essential for running a successful trial. In most circumstances, a dose approaching the maximally tolerated dose should be selected. If too high a dose is chosen, there will be excessive patient dropouts from toxicity. If, on the other hand, too low a dose is selected, efficacy may not be demonstrated. Overall perceptions about a drug may be predicated on the dose chosen for phase II studies. For example, initial adjunctive studies with topiramate (see Chapter 159) were performed at or near the maximally tolerated dose. This produced the appearance of a very potent drug, with a high side effect profile. In contrast, trials with lamotri-gine (Chapter 150) and gabapentin (Chapter 149) were performed at lower doses, resulting in an appearance of only moderate potency but good tolerability. If different doses had been selected, the results may have looked quite different.
The pharmacokinetic differences between children and adults cannot be ignored during drug evaluation. Most drugs administered orally are absorbed by passive diffusion in the small intestine. Multiple age-related factors affect the rate and extent of oral medication absorption, including gastric pH (reaches adult values by 2 to 3 years), gastric acid secretion (adult values by 3 months), gastric emptying (adult values by 6 to 8 months), and intestinal motility (variable in neonates, unknown when it reaches adult values). Oral absorption of phenobarbital and phenytoin are reduced in neonates compared to older children. Similar problems exist with intramuscular absorption in neonates; at this age the rectal route is probably the most reliable, provided a suitable formulation can be obtained. In contrast, in infants and children, drugs given orally or intramuscularly are absorbed more rapidly than in adults.
Age-dependent distribution factors (e.g., changing body composition, variable degree of protein/tissue binding) combine with physiochemical properties of the drug to determine a drug’s distribution characteristics. Body composition changes markedly from newborn to adult. For example, a newborn’s brain mass and skeletal muscle mass is 12% and 25% of its total body weight compared to 2% and 40% in adults, respectively. Acidic drugs are less well bound to plasma proteins in neonates and infants than in older children. Weak bases are also less well bound in neonates, but binding may be increased in infants and children.
In the absence of exposure to enzyme-inducing drugs in utero, metabolic degradation of AEDs is very slow during the first 2 weeks. A rapid increase in metabolic rate occurs for the next 2 years, after which the rate gradually declines to adult levels. Renal excretion of drugs is very slow in the neonate, but is comparable to that of the adult by age 6 to 8 months. The highest relative capacities to excrete AED are found in infants aged 1 to 13 months.
Some drug-specific pharmacokinetic phenomena, such as whether a drug undergoes linear or nonlinear metabolism, is constant across all ages. Information obtained in adults on this type of AED property is relevant to all ages. Compared to adults, children tend to receive more short courses of other types of drugs (e.g., antibiotics); it is important that interactions, and particularly effects on pharmacokinetics of a trial AED, are explored and recognized. Febrile illnesses, which may affect drug elimination, are common in young children. Should fever occur during an AED trial, its presence should be noted, both as a possible adverse reaction and as a potential influence on pharmacokinetic parameters.
Analysis of Results: Standard Measures
The standard measure used in analysis of AED trials is seizure frequency. Typically, different seizure types are counted separately. For example, for a trial evaluating patients with partial seizures, simple partial, complex partial, and secondarily generalized seizures would be analyzed separately.
Choosing an Outcome Variable
In every trial, a primary outcome variable must be chosen in advance. This is to prevent an ineffective drug from appearing effective because there was a chance reduction in seizure frequency for one seizure type out of many. Typically, reduction in complex partial seizures is chosen as the primary outcome variable. It is much more difficult to demonstrate reduction in simple partial seizures, because they are more variable and subjective, and in secondly generalized seizures, because only a fraction of enrolled patients will have this seizure type.
Handling Seizure Data
There are intrinsic problems inherent in analyzing seizure data. One can get a good understanding from an example given by Gordon Pledger.54 Two patients are enrolled in a trial. One has a baseline seizure rate of 50 per month, the other 100 per month. Both patients have a reduction of 50 per month. Whereas one has a 50% reduction in seizure frequency, the other has a 100% reduction. Has the drug been equally effective in both patients? In another example, how do two patients compare when one who has gone from three to two seizures per month, and the other has gone from 30 to two per month? Seizure data are nonparametric. One way of handling this problem is to normalize the data prior to applying a statistical treatment. Another is to use an analysis that is suitable for nonparametric data. Since there are so many ways to handle the data, a statistical treatment must be chosen in advance. Unfortunately, not all of the statistical treatments are intuitively comprehensible to a clinician who is trying to review the data. For example, the multicenter gabapentin trials were analyzed using response ratio.35,36 This consists of the difference between the treatment and baseline seizure rates divided by the sum of the two rates; for clinicians, this ratio has no obvious clinical meaning. The other problem with the vast array of methods of analysis is that results from different trials are not easily compared.
Intent to Treat
All drug study outcomes are evaluated by “intent to treat” analysis. This means that all randomized patients are entered in the analysis, even if they drop out early on. Using the last-observation-carried-forward (LOCF) approach, the last obtained seizure frequency count will be used as outcome, even if the patients did not complete the exposure required by the protocol. The impact of dropouts on a trial may vary based on the chosen outcome variable as well as the trial design. Dropouts are often “censored” from the results at the time of dropout. This is why in a trial of oxcarbazepine in which over half the patients dropped out of the 2,400-mg arm, the

50% responder rate could still be 50%.5 On the other hand, in some circumstances, dropouts will reduce the likelihood of a significant outcome. For this reason, investigators must make a determined effort to enroll only patients who are likely to complete the trial.
Other Analysis Problems
Many patients with epilepsy have seizures in clusters. This can cause problems in analysis in situations when seizures are so frequent during a cluster that they seem to blend together. It may be impossible for an observer to separate or count the seizures. This problem is particularly troublesome in Lennox-Gastaut trials. Enrolling patients who do not have epilepsy at all would cause serious problems in data analysis. To prevent this, some trials require electrographic evidence of epilepsy in the form of an interictal abnormality, although this is becoming less frequent due to the problems it causes in recruitment. The presence of such an abnormality may also be helpful in correctly classifying patients.
Noncompliance is another serious potential problem. A drug cannot be effective if the subject is not ingesting it. Because of intent-to-treat analysis, even patients in whom there is evidence of noncompliance will be included in analysis. Patients with known noncompliance must be excluded as subjects, and compliance must be monitored during the trial by pill counting or other means.
Nonstandard Outcome Measures
Seizure frequency may be a crude measure of antiepileptic drug effect. Unquestionably, patients may receive substantial benefit from a drug without any change in seizure frequency. Recently there has been renewed interest in exploring novel outcome measures.
One such outcome measure is seizure severity. After receiving a new drug, a patient might experience a significant reduction in falling and injury with seizures, or postictal period may shorten, without any reduction in seizure frequency. Several seizure severity scales have been developed to objectively assess changes in seizure severity.2,3,4,19,20 The scales may incorporate information obtained by questionnaire from both patients and observers. One such scale has been used successfully to evaluate outcome in a trial of lamotrigine.67 At the present time these data are considered purely elective and cannot be used in isolation for drug approval.
Quality-of-life scales are another way of assessing outcome from clinical trials. These scales attempt to combine efficacy, tolerability, and safety in an overall measure. Information is again obtained from questionnaires filled out by patients and significant others. The most frequently used scale is the QOLIE (quality of life in epilepsy). More information about these scales can be obtained in Chapter 100. Although these scales are certainly valuable, they have been criticized because they cannot distinguish the various factors that may go into “feeling better.” For example, if a drug had antidepressant properties, patients’ quality-of-life scores might improve substantially, and yet the drug may have no antiepileptic effect whatsoever.
Another method that has been used to assess overall outcome is time on the drug. If patients or their physicians are dissatisfied with either efficacy or tolerability of a drug, they are likely to implement a change to another agent. In an early VA cooperative study, four antiepileptic drugs were compared in new-onset patients.47 Although there was no significant difference in efficacy, patients discontinued phenobarbital and pri-midone earlier than phenytoin and carbamazepine, due to side effects. Many of the newer AEDs have also demonstrated longer time on a drug when compared to older AEDs in active-control equivalence trials, and this has always directly related to better tolerability.10,12,17,18,21,39,58,68 However, in some of these trials, some efficacy outcome measures, such as time to first seizure, have gone in the opposite direction to tolerability outcomes, making interpretation of time-on-drug outcomes difficult.32 Complicating matters, interpretation of drug tolerability outcomes may be confounded by titration rates, selection of doses, and use of suboptimal formulations such as immediate-release carbamazepine (used in earlier trials vs. controlled-released carbamazepine formulations used in most recent studies).
Safety Trials
Safety of an investigational AED can be assessed in several ways. Phase II trials are designed to assess both safety and efficacy. In addition, some trials may be performed solely for safety evaluation. These are usually part of phase III.
Safety Testing during Phase II Efficacy Trials
Large multicenter placebo-controlled trials provide the first information about drug safety and toxicity. Even in a placebo-controlled trial, toxicity directly related to an investigational drug is difficult to determine. Most of these trials are add-on. Pharmacodynamic interactions with baseline AEDs will tend to amplify apparent toxicity from the new drug. In a study by Schmidt, toxicity developed in 90% of patients who were converted from monotherapy to polytherapy with standard agents.66 Monotherapy studies almost always demonstrate lower adverse event profiles than adjunctive studies with the same drug. It is very important to compare side effects in the placebo and drug-treated groups. Also, since this list of side effects usually includes 20 to 30 items, by chance some may have a statistically higher occurrence in the treatment group. Several trials must be performed before a clear picture of toxicity develops.
Many development plans include studies comparing multiple doses. If such information is not available, it may be very difficult to determine which side effects are dose related and which are idiosyncratic, although investigators who have participated in the study may have a sense of this from their clinical experience.
Placebo-controlled studies usually have a 3-month treatment duration and are performed in 60 to 120 patients per dose arm studied. These trials cannot assess long-term toxicity, nor will they be likely to uncover rare idiosyncratic toxicities, such as blood dyscrasias and liver failure. For this reason, studies are necessary using more chronic treatment in a large number of subjects. Part of this information will derive from subjects who choose to remain on a drug after a placebo-controlled trial is completed. To obtain broader information, a drug development plan will frequently include a safety trial, in which a large number of patients are treated for 1 to 2 years. These trials are difficult to interpret, because there is no control group. Certain adverse events, such as sudden death and psychosis, are more common in patients with epilepsy than in the population at large. The true incidence may not be known, particularly for the intractable population that are candidates for investigational drug trials. In recent years, several adverse events have been uncovered either in long-term open label studies or even when the drug has been used after approval. Significant examples include visual field defects associated with vigabatrin, glaucoma associated with topiramate, hypohidrosis associated

with both topiramate and zonisamide, and renal calculi associated with topiramate and zonisamide.27,44,56,71
Safety Issues in Children
The pediatric epilepsy population presents special safety concerns including potential effects of the investigational AED on brain growth and development, cognitive development, and physical development. Normal development of the brain and, in particular, of the neocortex has been reviewed by Evrard et al.31 The chemical factors underlying the various anatomic and physiologic stages of brain maturation remain ill understood. The neuroepithelium is derived from the dorsal midline ectoderm. Segmentation is induced by the notochord. Neuronal and glial elements are generated by the neuronal tube. During the first half of gestation, after neurulation, there is neuronal multiplication, followed by neuronal migration and, later, regional development of the cerebral vesicles. Toward term, growth and arborization of the neurons is followed by the development of synapses, myelination, and gliogenesis. In early childhood, considerable plasticity of development is present, with remodeling of synaptic connections and loss of those apparently redundant. At this stage, persistence of transmission through unwanted pathways, such as may occur in seizures, is clearly undesirable, yet it is equally important that an AED not inhibit normal synaptogenesis.
Neuronal migration and its disorders are now recognized to be of major importance in the pathogenesis of epilepsy.52 Anatomic events are well described: Neuroblasts in the periventricular germinal matrix migrate to the neocortex in close attachment to specific glial cells with which they interact in a dynamic manner through cell adhesion molecules, but the underlying biochemical events remain speculative. Thus, the brain of the young child is undergoing considerable anatomic and physiologic change. This is particularly so in preterm and term neonates, and to a marginally lesser extent in the infant. By the nature of their activities, AEDs are developed for their abilities to reduce neuronal excitation. Such damping of cerebral activity might, in theory, lead to failure of development of appropriate synaptic connections, to poor perpetuation of their connections, or to early or excessive loss of synapses. It is expected that major effects on the immature brain would be identified in preclinical trials in animal models. Nevertheless, awareness of potential problems in relation to brain growth and neurologic and cognitive development is important in AED trials, especially when previously untried agents are prescribed for immature infants who, by virtue of the presence of seizures, already have abnormal brain function. Serial assessments of head circumference and neurodevelopmental status are essential in pediatric AED trials.
Some established AEDs are associated with unacceptable weight gain in childhood. It is important to closely monitor new AEDs for this effect. Established AEDs can cause alterations in blood levels of hormones, but these do not appear to be of clinical importance for height growth.69 Nevertheless, effects on height and timing of puberty need to be considered when using a trial AED.
During childhood, the liver, kidneys, and other organs are growing and theoretically could be more vulnerable to adverse effects of AEDs; their growth also may indicate a greater capacity for recovery. To date, in the absence of specific inborn errors of metabolism, nonneurologic organs are no more likely to suffer damage in childhood than in adulthood.
It is important to ensure that every pediatric subject in a drug trial has been thoroughly evaluated (prior to study entry) for an underlying metabolic or other chronic medical disorder that could worsen as a result of participation. The greatest risks lie with the severely handicapped and the very young (whose seizures may be the first signs of an underlying disorder). In general, a child with epilepsy who is otherwise healthy (e.g., normal growth and development, no history of chronic medical problems) is unlikely to have a significant underlying metabolic disorder. However, caution for all neonates, infants, and young children is appropriate both prior to entry into the trial and as they progress through the study.
Prior to commencing a trial AED, tests of renal and hepatic function, a full blood count, an electrocardiograph, and microscopy of the urine are essential. Certain biochemical tests, such as alkaline phosphatase, have different normal values in children, and these must be acknowledged. Only in exceptional circumstances is it acceptable to use a trial drug when the biochemical status is other than completely normal.
Ethical Issues
Many antiepileptic drug trials involve investigational drugs. Particularly in early stages of testing, the risks of treatment with these agents may not be known. Even in later stages of testing, in trials involving standard drugs, a rigid protocol may impose inconveniences and risks to subjects, when compared with standard clinical care. Yet, these trials are vital in the process of drug development and approval. Any patient who enrolls in an antiepileptic drug trial must be made aware of the potential risks and benefits of participation, by means of informed consent. In this respect the Helsinki-Charter and its amendments look after the patient’s best interest, and its implementation is locally supervised by institutional review boards (IRBs).
It is always difficult to determine what risks are appropriate for patients to be subjected to. Most patients enter trials with investigational drugs because they have failed all standard drugs and continue to have seizures that impair their quality of life. They may also be influenced by the promise of free medical care or free drugs, which are offered by pharmaceutical companies. Because of this, it is frequently the most severely afflicted patients who are enrolled in trials. This may affect trial outcome, as these patients may be the most difficult to treat. Whereas it may be more beneficial for drug development to enroll less severely affected patients, physicians may be constrained by the ethics of doing so. Each physician must make his or her own decisions on who they feel comfortable enrolling. The further a drug is in development, the more comfortable a physician may feel in enrolling patients who have less intractable epilepsy.
In most AED trials, the patient’s treating physician is an investigator in the study. This raises potential conflict of interest. The physician is usually paid commensurate with the number of patients enrolled. There may be circumstances in which two trials are running concurrently, one of which is more lucrative than the other. That same physician is the one who will explain options for treatment. A physician in this situation must guard against painting an overly rosy picture of an investigational drug. This is more true now than ever, as more new drugs are approved and drug study subjects become more difficult to find.
Ethical Issues in Children
The multiple ethical issues involved in research involving children are examined in detail by Grodin and Glantz.38 Some ethical issues that deserve particular mention include the need for parental written consent and, if possible, child consent or assent; the importance of considering the patient’s epilepsy

syndrome on trial suitability; the investigator’s large responsibility to properly classify the patient’s seizure type and epilepsy syndrome; and lastly, where possible, the need to take action to reduce patient pain during the trial.
Persons below the age of 18 (or, in some societies, 16) are considered not to be competent to make their own decisions about treatment. For most children, the parent or legal guardian is considered an allowable surrogate in the matter of consent to medical treatment. This presumption is made on the basis that such a surrogate will have the child’s best interests at heart. In addition, since parents are inevitably involved in the consequences of treatment choices, they have a right to stand by their own values in relation to the child’s upbringing, and they are entitled to promote circumstances in which the family may function as an intimate unit.38 The child’s consent to such parental involvement must be assumed, but this makes it particularly incumbent on the investigator to ensure that parental comprehension of the risk–benefit ratio is maximized. Written information and written consent are essential. Clearly, in children able to understand the implications of a drug trial, information should be given to the individual involved and that individual’s written consent or assent obtained.
For many children with epilepsy, a specific syndrome can be identified. Where this is possible, a reasonably accurate prognosis can be given. The threshold for using a trial AED should be higher for those epilepsies that are likely to remit than where severe, frequent seizures are expected to persist despite optimal use of established AEDs. Thus, only if it is believed that side effects would be fewer should a trial drug be used early in its investigation for childhood absence epilepsy or benign partial epilepsy with centrotemporal spikes. On the other hand, it is justifiable to consider the early use of trial therapy in situations such as the Lennox Gastaut syndrome and seizures secondary to inoperable structural lesions.
The clinician investigator’s prime aim always must be the child’s well-being.38 The clinician investigator carries a heavy responsibility to ensure that his or her knowledge of epilepsies is sufficiently sophisticated to allow proper categorization of childhood seizures and identification of syndromes. Otherwise, children may unnecessarily be exposed to a drug that is not expected to help them.
All monitoring procedures should be conducted with as little discomfort as possible. For example, the use of anesthetic cream can minimize the pain associated with venipuncture. Neurophysiologic measurements, if indicated, should be taken, if at all possible, without the use of needle electrodes.
Applicability of Trial Data to Clinical Practice
The goal of regulatory authorities is to obtain rigorous scientific evidence that a new AED is safe and effective. The goal of clinicians is to obtain the kind of clinically relevant information about a new AED that will lead to appropriate selection of treatment for their patients, including information about how to use a drug to its maximal advantage, and data that can determine accurate risk assessment. Several areas where these two may differ have already been discussed above. For example, regulatory trials are usually short in duration, and may not supply sufficient information regarding long-term side effects of medication. This may impact the ability of the clinician to make an accurate risk–benefit assessment. Antiepileptic drugs may not necessarily undergo rigorous testing in certain epilepsy syndromes, particularly in children, that are of great interest to clinicians. Therefore, clinicians may be left to extrapolate data from the trials that have been done. Also, many randomized controlled trials of drugs in development are performed in patients with the most severe epilepsy. It is unclear whether the results can or should be generalized to the remainder of patients with epilepsy, who, by and large, do not have intractable disease. It may also be difficult to determine whether the patient with less severe epilepsy will be willing to remain on a medication with some side effects, which may seem less concerning to the patients with severe refractory epilepsy.
Efficacy Versus Effectiveness
The concept of efficacy versus effectiveness becomes even more important in an age when evidence-based medicine has become a guiding principle in clinical care. The concept of evidence-based medicine is that if clinical trial data are available, that data should be used to make treatment decisions. However, it is important to remember that clinical trials usually focus on efficacy rather than effectiveness. Efficacy can be defined as the ability to reach an end-point in the context of a clinical trial. Effectiveness is defined as the value of an antiepileptic drug in the environment of use or, in other words, its ability to benefit patients in clinical practice. Although efficacy and effectiveness are linked, they are not always the same. For example, in clinical practice, duration of titration may be guided by patient response. If the patient begins to complain of side effects, titration rates can be slowed or concomitant antiepileptic drugs can be reduced. This is usually not possible in the setting of a clinical trial, where trial methodology has to be predetermined. This may lead to an appearance of poor tolerability in a trial compared to clinical practice. Further, in a clinical trial all patients are titrated to a predetermined dose, often irrespective of tolerability. This too may impact trial outcome. Trial doses and titration rates must often be selected before ideal conditions of use have been determined. Many examples of this can be seen. As already noted above, a 2,400-mg dose was included as one arm in an adjunctive oxcarbazepine trial. This led to dropout of over 50% of patients.5 In a trial of topiramate as monotherapy in newly diagnosed patients with partial seizures, patients were randomized to either 50 mg or 400 mg. The low dose led to failure due to seizure recurrence, whereas the high dose led to a high dropout rate. The conclusion was that 400 mg was an effective dose. While this may be true, the trial could not assess whether this was the optimal dose, since only two doses were tested. More tolerable doses such as 100 and 200 mg were not included in the trial.1 Conversely, the highest dose of gabapentin tested in randomized placebo-controlled trials was 1,800 mg.33 Since no higher doses were included in this study, it is impossible to determine whether 1,800 mg was the highest optimal dose. Many such examples could be given. Clearly, in essence clinical trials may represent a “proof of principle” that a specific treatment is effective in a specific condition. However, trials may not definitively outline optimal use. There is clear need for more pragmatic trials that will provide more guidance.
Summary and Conclusions
The pathway to antiepileptic drug approval is relatively clear-cut. Trial methodology is well established for add-on efficacy and tolerability studies in patients with treatment-resistent partial seizures. These studies lead to market approval in the U.S. and Europe, but leave many important clinical questions unanswered. In addition, trial designs for monotherapy studies, studies in children, and in syndromes outside of partial epilepsy are not well characterized, and progress is needed. Also, there is a need for better early (proof of principle) studies that will identify potentially successful versus unsuccessful drugs at an earlier stage.

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