Placebo-controlled studies in neurology

In this issue of Neurology, Schachter et al.1 report a double-blind, randomized, placebo-controlled study of oxcarbazepine in what has been termed a “presurgical” antiepileptic drug (AED) study of patients with refractory partial seizures. The study randomized 102 patients to treatment with oxcarbazepine (2,400 mg/day) or placebo. To enter the study, patients had to have experienced—during a period following withdrawal of their usual AEDs—between 2 and 10 partial seizures within the preceding 48 hours, at least one of which was a complex partial seizure and of which no more than 2 evolved into secondary generalized tonic-clonic seizures. Patients completed the study at day 10 or by experiencing a fourth partial seizure, 2 secondarily generalized tonic-clonic seizures, serial seizures, or status epilepticus after randomization. Thus, during the course of inpatient assessment, patients might have experienced between 6 and 14 complex partial seizures, or 0 to 4 tonic-clonic seizures, before their usual AEDs were recommenced. Forty-seven percent of the oxcarbazepine-treated group met one of the premature exit criteria compared with 89% of the placebo group, a difference that was highly significant. The study was undertaken to support an application for a monotherapy license for oxcarbazepine to the Food and Drug Administration (FDA), and in this respect the study is highly supportive. The study does, however, raise two fundamental questions: Is it ethically acceptable? And, linked to this, what is its clinical value? The study illustrates starkly that the questions that some regulatory agencies and the pharmaceutical industry ask are diverging considerably from questions that are relevant to doctors and their patients. The study involves epilepsy, the most mature of neurologic therapeutic areas; however, the principles involved are important to other neurologic areas in which there are effective treatments. In epilepsy there is considerable evidence that the occurrence of seizures is associated with …