Monotherapy clinical trials of new antiepileptic drugs: Design, indications, and controversies

The focus in assessing new antiepileptic drugs (AEDs) varies with the needs of the assessor. Patients and doctors seek evidence-based clinical information, regulatory agencies look for efficacy and safety, and the health-care industry demands data on the risk-benefit ratio attached to a product. The pharmaceutical companies attempt to satisfy the interests of all parties involved. Most new AEDs obtain a first license based on placebo-controlled, randomized clinical trials as add-on therapy in patients with chronic refractory partial epilepsy, a method which, in fact, explores the efficacy of different drug combinations rather than measuring the efficacy of the new drug itself. Although that methodology satisfies the requirements of the licensing authorities, it fails to provide the clinical community with the information necessary to make rational treatment decisions, as would be derived from monotherapy studies. This article reviews controversies surrounding monotherapy studies and the design of comparative monotherapy clinical trials. A persuasive argument can be made that the goal of clinical trial design should be ethically acceptable, clinically meaningful studies in which new AEDs are compared with optimal doses of standard AEDs to inform clinical practice, meet licensing requirements, guide reasonable marketing efforts, and allow appropriate reimbursement.