ReviewMeasuring outcomes of treatment with antiepileptic drugs in clinical trials
Introduction
The US incidence of epilepsy is estimated at 200,000 cases per year[1]. Epilepsy imposes a considerable burden on patients and society. Some patients may be cured with surgery, and others, particularly children, may enter remission; however, others often require life-long treatment with antiepileptic drugs (AEDs). Despite pharmacological treatment, more than one third of individuals will continue to have seizures [1]. The patient burden associated with recurrent seizures includes negative effects on physical, mental, and behavioral functioning as well as stigmatization [2], [3].
Guidelines published by the International League Against Epilepsy (ILAE) state that the goal for patients requiring AEDs is improved quality of life (QOL) without seizures, if possible, and minimal impact from adverse medication events [4]. Patients who become seizure free at low AED doses show improvements in QOL [5], [6]. QOL may also improve for patients with refractory seizures; in such patients, the correlation between QOL and treatment-related adverse effects is much stronger than that between QOL and seizure frequency [7]. Thus, the balance between AED efficacy and adverse effects is an important determinant of QOL in patients with drug-resistant seizures. As rates of adverse effects are high with some AEDs due to suppressive influences on the central nervous system and frequent use in combination therapy, clinicians must critically consider AED tolerability when making treatment decisions.
Most newly diagnosed patients can be treated successfully with a single AED; however, patient-specific variables, seizure type, efficacy, and pharmacokinetic and tolerability profiles must be considered [8,9]. Seizures in approximately 40% of patients will not respond to initial therapy and may require polytherapy. Each switch to another AED may increase the likelihood of treatment failure, relapse, and new or worsened adverse events [8], [9], [10]. Thus, AED data based on clearly defined and consistently applied outcome measures are needed. Ideally, AED study design should be relevant to real-world settings, providing comprehensive measures of efficacy, tolerability, and QOL with reliable and valid assessment tools. This requirement is usually not met by regulatory trials, which focus on efficacy and dose response in refractory patients.
Given the numerous treatment options and the limited amount of clinically relevant information from fixed-dose regulatory studies, the American Academy of Neurology (AAN) and the ILAE Commission have recommended the conduct of more meaningful long-term comparative trials that better resemble actual clinical practices[8], [11], [12]. This leads to questions regarding what the “right” clinical endpoints of a trial should be. Here, we discuss optimal trial designs and review endpoints for measuring treatment success. The concepts of efficacy, effectiveness, tolerability, retention, and compliance are defined and reviewed.
Section snippets
Optimal trial design and the need for improved studies of AEDs
The AAN and ILAE indicate that it is critical not only to know whether an AED will control a patient's seizures, but also to understand long-term treatment outcomes [8], [11], [12]. Results of 3- to 6-month clinical trials are difficult to apply to general practice, because that time frame may not be sufficient to establish a drug's usefulness for the course of the disorder. Furthermore, short-duration trials do not enable observation of natural patient discontinuation patterns, which may be
Categorization of outcome measures
In the assessment of the usefulness of outcome measures, it is helpful to consider the definitions of the categories of outcome measures (Table 2). Efficacy is defined as a reduction in seizure frequency and/or severity directly attributable to treatment, with the most important outcome being prolonged periods of remission from seizures [17]. Efficacy differs from clinical effectiveness, which is a composite of efficacy and tolerability. Tolerability is measured in terms of the number,
Relationships among outcome measures
Compliance is a clinical outcome related to efficacy, effectiveness, and retention. Since retention reflects the effectiveness of a drug, and effectiveness is a composite of efficacy and tolerability, it is expected that efficacy will have an impact on retention. For example, mild to moderate adverse events may not be acceptable to patients if they do not feel that the drug's efficacy makes them worthwhile. Conversely, patients may be willing to tolerate mild, moderate, or even certain severe
Recommendations
From the above discussion, it is clear that many factors must be considered in the design of clinical trials of new AEDs. As most regulatory trials focus on the efficacy of add-on therapy in patients with refractory epilepsy, endpoints most applicable to this trial type and population are likely not the same as those most applicable to monotherapy trials in patients with new-onset epilepsy. Both types will require demonstrations of efficacy and tolerability, and a more uniform use of specific
Conclusion
Accurate information regarding long-term outcomes with AEDs is necessary to make decisions to minimize the risk of treatment failure due to lack of efficacy, poor tolerability, safety risks, or poor compliance. When evaluating the results of AED clinical trials, the real-world relevance of the trial design, such as duration, patient population, and outcome measures must be considered. Regulatory trials, which are usually add-on studies of patients with drug-resistant seizures of a relatively
Disclosure Statement
Dr. Ben-Menachem in the past three years has received honoraria: Eisai, Cyberonics, UCB; research support: UCB, Ortho-McNeil, Esai, Bial, Pfizer, Cyberonics; and consultation: UCB, Ortho-McNeil, Bial, Eisai, Cyberonics, BioMas, Lundbeck, Ovation.
Dr. Sander has received honoraria for consulting and for membership of Speakers' Bureau from UCB, GSK, Eisai, Janssen Cilag. His department has received research grants and support: UCB, Esai, Pfizer, Sanofi-Aventis. He has been a Board Member for
Acknowledgments
Editorial support for the writing of this manuscript was provided by Nancy Bella, PharmD, of MedErgy Scientific.
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2022, Epilepsy ResearchCitation Excerpt :The most common serious TEAE in patients with prior surgery was seizure, reported by 6 patients, which is not unexpected given the treatment-refractory seizures in this patient group. Treatment retention rates are an indicator of overall treatment satisfaction, including efficacy, safety, and tolerability, as each patient decides whether to continue treatment (Ben-Menachem et al., 2010; Chung et al., 2007). The high retention rate of 76.5 % for patients with prior surgery indicates cenobamate was an effective and tolerable treatment over a treatment period of up to 43 months.