Proof of Principle studies are an early stage of clinical drug development when a compound has shown potential in animal models and early safety testing. This step of proof-of-principle (PoP) or proof-of-concept (PoC) often links between Phase-I and dose ranging Phase-II studies. These small-scale studies are designed to detect a signal that the drug is active on a pathophysiologically relevant mechanism, as well as preliminary evidence of efficacy in a clinically relevant endpoint. Sponsors use these studies to estimate whether their compound might have clinically significant efficacy in other diseases states as well as epilepsy (e.g., migraine, neuropathic pain, anxiety, depression). Endpoints other than seizure frequency often reveal special characteristics of the drug. A structured dose escalation design can reveal dose-dependent effects and adverse effects, crossover studies can demonstrate change, presurgical studies can define efficacy, interictal discharges and photosensitivity models can explain changes in seizure features, transcranial magnetic stimulation evaluates hyperexcitability. PoP studies allow exploration of a wide range of potential therapeutic areas beyond epilepsy as part of an integrated CNS development plan.