ABSTRACT
Patients with panic disorder experience sudden, unexpected episodes of intense apprehension or terror (a panic attack) with no apparent stimulus. Typical signs and symptoms include hyperventilation, tachycardia or palpitations, chest pain, sweating, trembling, and sensations of smothering or choking. Patients with the disorder may also experience blurred vision, weakness, or feelings of unbearable dread or terror. Many become so demoralized or incapacitated they are unable to leave their homes [1]. Panic disorder may occur with or without agoraphobia. Agoraphobia is a fear of places where help may not be available-such as crowded places (movie theaters, sports arenas, malls, etc.) or remote and isolated places. Panic disorder with or without agoraphobia is common. The overall
12 month and lifetime prevalence rates are 2.1% and 5.1% [2]. It is a severe condition in those affected, often requiring visits to emergency rooms. U.S. Federal Drug Regulations require at least two pivotal proof-of-efficacy
clinical trials to support approval of a drug for a specific indication [3]. For drugs not yet approved, pivotal proof-of-efficacy trials occur in Phase III of the clinical development program. However, they may occur post marketing as Phase IV trials when a company develops evidence to support labeling for additional indications for an approved drug. For example, Klonopin, a potent benzodiazepam, was originally U.S. FDA
approved in the early 1970s for the treatment of Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. Twenty years later, the parent company, Roche, initiated a clinical trials program that led to FDA approval of an SNDA that established Klonopin as effective in the treatment of patients with panic disorder with or without agoraphobia. The SNDA clinical trials program consisted of two, pivotal proof-of-efficacy
trials [4-6]. One incorporated a randomized, forced titration dose-response design while the other incorporated a flexible titration (according to response) design. Design aspects of these trials are detailed in Section 16.2.
