The Design and Analysis of Pivotal Proof of Efficacy Trials in the Development of Drugs to Treat Panic Disorder

US Federal Regulations require at least two pivotal proofs of efficacy clinical trials (typically Phase III) to support approval of a drug for a specific indication. In the clinical development of drugs to treat panic disorder, one of these trials may incorporate a forced titration design while the other may incorporate a flexible titration - according to response design. Standard analysis approaches include treatment group comparisons at each follow-up visit in terms of variables reflecting domains of the panic condition. Such designs pose challenges as to: (1) characterizing the dose response profile across both studies; {2) characterizing duration of effect; (3) characterizing withdrawal effects; and (4) the choice of appropriate statistical analysis methods. Standard approaches to meeting these challenges, as well as reasonable alternatives are presented.