External Controls In Clinical Research (Part I): The Clinical Imperative

By William L. Slone, PHD, Assistant Director, Clinical Research Methodology and Michael F. Murphy, MD, PHD, Chief Medical And Scientific Officer

In situations where patient populations are rare or increasingly niche, where costs associated with large patient pools are prohibitive, or where patient/ advocacy groups demand greater proportions of patients on potentially active investigational treatment, the prospect of removing a concurrently randomized placebo group and relying instead on external controls has obvious allure. Equally compelling may be the arguments against use of external controls due to bias, methods of analysis, and selection of an appropriate external control population. Although these considerations weigh heavily in investigations that may be considered potentially pivotal registration studies, they are of equal importance in early phase clinical research – given that decisions for subsequent development must be based on trial data, which neither inappropriately rejects nor accelerates continued development.

To understand when, how, and whether to factor external controls into a program scenario, sponsors and trialists must consider what constitutes external controls and how they may be applied in terms of data collection and analysis for specialized clinical investigations. Additionally, sponsors and trialists must also weigh the potential benefits against the potential risks that may affect both trial methods and operations.

To help shed light on these evolving issues, this paper examines what constitutes external controls and considers the general benefits and risks associated with their use.