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1.
Monotherapy trials in epilepsy are confronted with a dilemma: either they are in conflict with ethical requirements, or they are scientifically not meaningful. Monotherapy trials, which are performed as controlled studies randomizing patients to ineffective (pseudo)placebo treatment, are incompatible with the Helsinki Declaration. On the other hand, equivalence or noninferiority studies using an active-control design do not permit valid conclusions on the efficacy of the test drug. Therefore, they do not fulfill scientific requirements for trials on new drugs. As an alternative approach, a monotherapy trial design for epilepsy patients undergoing presurgical evaluation was outlined. During presurgical evaluation, antiepileptic drugs are routinely tapered down for seizure recording. This situation is used for a placebo-controlled short-term monotherapy trial. Four trials according to this design have been completed so far. Recently, several points of concern have been raised against this design, especially for matters of ethics and external validity. In the present article, these objections are outlined and discussed. In the proposed modification the randomization and the titration of the test drug or control begins prior to the presurgical investigations. The advantages are: the test drug does not have to be titrated quickly, pure monotherapy conditions are achieved, and the subjects do not have to experience more seizures than are required for the presurgical evaluation.  相似文献   

2.
R K?lvi?inen 《Epilepsy research》2001,45(1-3):75-8; discussion 79-80
It is difficult to design valid and well-controlled monotherapy trials that satisfy regulatory requirements and, at the same time, demonstrate the usefulness of a new drug in clinical practice. The conversion design is a drug-substitution trial in which patients with uncontrolled seizures are assigned to add-on treatment with an investigational drug and, usually, an appropriate control, after which pre-existing treatment is gradually discontinued. In the most utilised design, patients are randomised to receive a high dose versus low dose of the new drug, while concomitant medication is gradually discontinued. Exit criteria are predetermined to prevent excessive deterioration of seizures, and treatment retention time is used as the primary outcome variable to measure the effectiveness of the allocated treatments: the goal is to demonstrate higher retention rates in the high-dosage group. Conversion studies may help to fill some gaps in knowledge regarding efficacy and tolerability as monotherapy before larger-scale de-novo studies are started. In the de-novo design, newly diagnosed patients are randomised to receive the investigational drug or an active control. In equivalence (or non-inferiority) trials, the active control is usually an established antiepileptic drug (AED) such as carbamazepine or valproate, and outcome parameters may include proportion of patients achieving a predefined (for example, 6-month) seizure remission or the proportion of patients remaining in the trial (retention rate, a combined measure of efficacy and tolerability). In regulatory trials designed to show a difference, newly diagnosed patients are randomised to a high versus a low dose of the investigational drug, and exit criteria are again predetermined for patients whose seizures are not adequately controlled. In this case, outcome parameters may include time to first seizure in addition to retention in the trial. Comparative monotherapy trials in newly diagnosed patients are relevant to approximately 50% of the patients who develop epilepsy and can be satisfactorily managed with a single drug. These trials allow direct head-to-head comparisons and avoid the confounding effects of baseline drugs and co-medication withdrawal present in conversion studies. Long-term follow-up of patients who are receiving a drug in monotherapy at adequate doses gives the most clinically relevant answers regarding the usefulness of a new drug. It is concluded that the de-novo design is the gold standard when studying AEDs as monotherapy, but the conversion-to-monotherapy design can be used before starting the de-novo program in order to obtain estimates of efficacy and tolerability of the AED as monotherapy in a population of difficult-to-treat patients. With both designs, the use of suboptimal comparators incorporated into some of the regulatory trials is a cause of ethical concern.  相似文献   

3.
Innovative Designs of Controlled Clinical Trials in Epilepsy   总被引:2,自引:2,他引:0  
Summary: Uncontrolled noncomparative clinical observations of investigational antiepileptic drugs (AEDs) often lead to overoptimistic efficacy results and are therefore of very limited value for clinical AED development. The classic add-on trial with placebo as control treatment, in contrast, has provided unequivocal evidence of the efficacy of classic and new AEDs and has also identified less useful AEDs. Drug interactions, carryover effects, difficulty in analyzing individual drug action, and the recognition that monotherapy is by far the more common way of prescribing AEDs have led to the development of classic active control monotherapy trials. A major problem of these trials is a no-difference outcome, which allows no useful interpretation. Recently, two alternative monotherapy designs have been developed to avoid the deadlock of a no-difference outcome. In these designs the active control drug is administered in an attenuated form (low dosage or low concentration) or a placebo control is used when standard treatment is discontinued during presurgical evaluation. Both designs have produced unequivocal evidence of the efficacy of the investigational AED during monotherapy. Ethical concerns are minimized by the introduction of preset escape criteria for patient protection. These designs are valuable new supplements for the clinical development of investigational AEDs for monotherapy in epilepsy. In our opinion, alternative monotherapy designs should be preceded by more than one pivotal add-on, placebo-controlled trial.  相似文献   

4.
Measuring the efficacy of antiepileptic drugs.   总被引:4,自引:0,他引:4  
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.  相似文献   

5.
Until recently, the gold standard for assessing the efficacy and effectiveness of new medications has been the placebo-control randomized clinical trial (RCT). However, there are serious ethical concerns about placing patients on a placebo when effective treatments exist. Further, if a new agent is tested only against a placebo, there is no guarantee that it is more effective, or even as effective, as an existing agent. For these and other reasons, ethicists and regulatory bodies have said that, under these circumstances, new drugs should be tested against an active agent. There are three types of such trials: superiority, equivalence, and non-inferiority. In superiority trials, the goal is to establish that the new drug is better (i.e., more effective, or with a more benign side-effect profile) than the standard. Because such trials require much larger sample sizes than placebo-control studies, and are rarely required to bring a drug onto market, they are rarely done. In equivalence trials, the aim is to show that the new and standard agents have similar degrees of effectiveness or adverse events. Due to sample size requirements, most studies of new drugs are non-inferiority trials, in which it is sufficient to demonstrate that the new drug is not significantly worse than the existing ones. However, there are methodological concerns with equivalence and non-inferiority trials, including (a) an inability to determine if the drugs were equally good or equally bad; (b) poorly executed trials with low power can be mistaken for "proving" equivalence or non-inferiority; (c) the equivalence interval is arbitrary; (d) successive non-inferiority trials may lead to a gradual reduction in effectiveness; and (e) often larger trials are necessary. The paper also discusses "add on trials." It is recommended that, even when existing drugs exist, trials should consist of at least three arms, one of which is a placebo. This paper briefly considers the ethics of placebo, and conditions are stated under which such studies can be conducted.  相似文献   

6.
Gamma Vinyl GABA: Current Role in the Management of Drug-Resistant Epilepsy   总被引:2,自引:2,他引:0  
David M. Treiman 《Epilepsia》1989,30(S3):S31-S35
Summary: The goal of management in epilepsy is to make patients completely seizure-free without side effects. Currently, this goal can be achieved fully in only about one-half of the 50,000,000 people in the world with epilepsy. Epilepsy is not a benign condition. Uncontrolled epilepsy produces significant morbidity and mortality. Even infrequent seizures put a patient at risk of sudden death and compromise employability and other social functions. The potential risk of a new antiepileptic drug has to be weighed against the potential risk of continuing seizures and the potential for the new drug to control those seizures. Vigabatrin (gamma vinyl GABA, GVG) is one of the promising new antiepileptic drugs now under development. In four large clinical trials half of the patients in each trial had a ≥ 50% reduction in seizure frequency when GVG was added to existing antiepileptic drug. This represents a significant response rate in add-on trials, which are a severe test of a new antiepileptic drug. Although microvacuoles have been seen in the white matter of the brains of rats and dogs treated with GVG, such pathological changes have not yet been observed in humans. Evoked potential studies have failed to reveal any evidence of microvacuolization in humans. Because of the potential efficacy of GVG in controlling previously therapeutic-resistant seizures and of the absence of evidence of significant toxicity in humans, carefully monitored clinical trials of GVG in therapy-resistant patients with epilepsy should continue.  相似文献   

7.
Beghi E 《Lancet neurology》2004,3(10):618-621
BACKGROUND: Until the early 1990s six major compounds (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid) were available for the treatment of epilepsy. However, these drugs have pharmacokinetic limitations, teratogenic potential, and a negative effect on cognitive functions that impairs the quality of patients' lives and limits the use of these drugs in some patients. In addition, 20-30% of patients are refractory to these drugs. RECENT DEVELOPMENTS: The development of ten new antiepileptic drugs (vigabatrin, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin) has expanded treatment options. The newer drugs may be better tolerated, have fewer drug interactions, and seem to affect cognitive functions to a lesser extent than old drugs. Guidelines on the use of new antiepileptic drugs have been developed in the USA and in the UK. Both guidelines offer a clear picture of the efficacy, safety, and tolerability of the new antiepileptic drugs and agree on their use as add-on treatment in patients who do not respond to conventional drugs. The guidelines differ in the type and strength of recommendations. Whereas the US guidelines recommend treatment in newly diagnosed epilepsy with a standard drug or a new drug depending on the individual patient's characteristics, the UK guidelines recommend that a new antiepileptic drug should be considered only if there is no benefit from an old antiepileptic drug, an old drug is contraindicated, there is a previous negative experience with the same drug, or the patient is a woman of childbearing potential. WHERE NEXT: The limited amount of information on the new antiepileptic drugs may explain the discrepancies among the two guidelines and between these and other recommendations. Comparative, pragmatic, long-term and open trials should be done to show long-term efficacy and comparative features of the new antiepileptic drugs, and to better assess the effect on quality-of-life, cost-effectiveness, tolerability, and teratogenic potential. In addition, the conflicts should be resolved between the needs of the regulatory bodies and those of the treating physicians. Finally, there is a need for trial designs to be standardised.  相似文献   

8.
Clinical trials of new antidepressants usually compare a new drug to a reference antidepressant and to a placebo. The placebo is intended to validate the trial in the case of a no-difference outcome, i.e., it helps in assessing equivalence. The aim of the present paper is to test whether placebo has indeed helped establish equivalence of effect in comparative trials of new antidepressants. We carried out an example of sample size determination first in a trial to show a difference between the new and control drug, and second in a trial to assess equivalence between two competing drugs. Finally, we retrospectively calculated the maximum difference accepted as equivalence of effect in published trials of new antidepressants. Assuming a response rate to antidepressants of 70%, 294 subjects for each treatment group are needed to show a 10% difference between two antidepressant drugs and more than 1,300 to assess equivalence at a 5% level of delta, the maximum difference acceptable as equivalence of effect. The level of delta in published trials of new antidepressants ranges between 12 and 43%, suggesting they cannot claim to demonstrate equivalence of effect. Therefore, the presence of a placebo arm for comparison didn't help establish whether both drugs really worked the same way. Comparative trials of new antidepressants should adopt a two-arm design, a suitable number of patients and a high standard in the experimental design in order to minimise possible control-event rate variation.  相似文献   

9.
G Pledger 《Epilepsy research》2001,45(1-3):67-71; discussion 73-4
Presurgical evaluation of patients with refractory partial seizures provides a unique opportunity to perform a placebo-controlled, monotherapy trial. Some patients undergoing presurgical evaluations must have all of their antiepileptic drugs (AEDs) tapered in order to induce seizures and therefore such patients are possible candidates for a placebo-controlled monotherapy trial. Often, EEG monitoring is continued throughout the trial period, thus patients either receiving placebo or whose seizures do not completely respond to the active drug are still evaluated to determine whether or not surgery is feasible, supporting the validity of a trial in this setting. In addition, all patients are, in general, eligible to receive the study drug after the blinded period of the trial, and can therefore be assured of the possible therapeutic benefits of the study. Presurgical inpatients studies have been carried out using felbamate, gabapentin and oxcarbazepine. All patients randomised in these trials were refractory to previous treatment and the studies themselves were short-term and placebo-controlled. These presurgical studies are designed to elucidate AED activity and show statistically significant differences between active and control treatments during short-term therapy, and are therefore of use in fulfilling regulatory requirements. However, these measures of efficacy are distinctly different from those determined during chronic treatment and are therefore not necessarily predictive of clinical usefulness.  相似文献   

10.
Perucca E  Tomson T 《Epilepsy research》1999,33(2-3):247-262
Traditional randomized clinical trials for the monotherapy assessment of antiepileptic drugs (AED) involve allocation of newly diagnosed patients to long-term treatment with different AEDs in order to determine remission rates and side effect profile. Apart from being time-consuming, however, these trials are unlikely to show significant differences in seizure control between the various drugs, which may lead some regulatory agencies to argue that remission rates could be related to the natural history of the disease rather than to efficacy of the administered drugs. To circumvent this problem, a number of innovative designs for the monotherapy assessment of new AEDs have been developed in recent years. They all share the common feature of being aimed at demonstrating a difference in response rate over a short treatment period between a high dosage of a new AED and some form of suboptimal treatment (placebo or low-dose active control). Patients allocated to suboptimal treatment show unacceptable seizure control more rapidly than patients on high-dose active treatment and therefore they exit the trial at a faster rate: evidence of antiepileptic activity is therefore based on demonstration of differences in rate of deterioration rather than improvement. These trials are conducted with titration schedules, dosages and durations of treatment which are totally unrelated to optimal use of the same AEDs in routine clinical practice. No comparative data with an established reference agent are provided, and allocation of patients to suboptimal treatment raises serious ethical concerns. For these reasons, justification for the continued implementation of these trials is questionable. Randomized long-term comparative trials should be considered the gold-standard for the monotherapy assessment of new AEDs. A review of the literature, however, reveals that long-term trials with new AEDs completed to date had significant shortcomings in their design, including excessively rigid or inappropriate dosing schedules, enrollment of patients with heterogeneous seizure disorders, low statistical power and insufficient duration of follow-up. Because these studies are usually aimed at addressing regulatory requirements, the information obtained cannot be meaningfully applied to routine clinical practice. Large longer-term randomized comparative trials using more pragmatic approaches are highly needed to determine the real value of first-line therapy with new AEDs in patients with well defined seizure disorders.  相似文献   

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