Principles of designing a clinical trial: optimizing chances of trial success

Clinical trials are essential to advance health care and develop new therapies. In this review we discuss the underlying principles of clinical trial design with an emphasis on assessing design risks that lead to trial failure as well as negative trials. While of general interest, this is perhaps particularly timely for the neuromodulation community, given the paucity of well-designed trials in the field. We give some examples from the phantom limb pain (PLP) literature.

It is critical to gather as much preliminary data as possible and to know how to interpret it in order to choose an appropriate trial design. Therefore, the investigator needs to effectively assess the likely trial design risk/benefit ratio with a view to maximizing the chance of a meaningful outcome, whether this outcome rejects or fails to reject the null hypothesis. This analysis is especially important in a complex and heterogeneous disorder such as PLP, which has had many negative trials.

We discuss the factors pertaining to a strong trial design benefit/risk assessment, how late trial phases require greater support from preliminary data, how to design trials to minimize risks, maximize benefits, and optimize internal validity as well as the chances of a positive outcome. We highlight the need for investigators to incorporate best practice in trial design to increase the chances of success, to always anticipate unexpected challenges during the trial.