Proof of principle trials: exploratory open studies

The aims of the observational, early phase IIa studies are usually several in number and often competing, and therefore the priorities should be clearly defined. The preclinical data, particularly the mode(s) of action of the drug and the results on experimental models, can help to build hypotheses on the agent's potential efficacy for individual seizure types and syndromes. For ethical reasons, the population selected for the initial clinical trials of antiepileptic drugs (AEDs) should be patients with continuing seizures (e.g. no less than two to four partial seizures/month) in spite of several therapeutic attempts using other appropriate AEDs, taken in monotherapy and in various combinations. Although the inherent bias in open, observational studies has limited their use in comparing treatments in epilepsy, they have several advantages over controlled trials, including lower cost, greater timeliness and inclusion of a broader range of patients. Observational, open studies with well-chosen patients and an adequate design tailored to answer precise predefined questions (including go/no go criteria) are most valuable for experienced clinicians in determining the clinical benefit of the drug, and for the pharmaceutical company in assessing the commercial merit of proceeding with further clinical testing.