William L. Slone, Ph.D., Assistant Director, Clinical Research Methodology; Melissa Vadnais, VMD, Ph. D., Clinical Trial Methodology Fellow; Andrew Kuhlman, Medical Writer; Michael F. Murphy, MD, Ph. D., Chief Medical & Scientific Officer
As discussed in Part 1 of this series (EXTERNAL CONTROLS IN CLINICAL RESEARCH (PART I): THE CLINICAL IMPERATIVE), regulatory concepts referable to the creation of an external control group have long been noted and occasionally implemented, particularly for diseases with severe morbidity, mortality, and unmet medical need. As defined in Guidance for Industry: E10 Choice of Control Group and Related Issues in Clinical Trials (2001), “an externally controlled trial is one in which the control group consists of patients who are not part of the same randomized study as the group receiving the investigational agent.” 1 Though simple in definition, implementation of external controls into a development program for product registration must navigate a number of strategic options and design methods.
Given that these programs immediately become “non-traditional,” positioning an external control so that it can successfully address industry and regulatory scrutiny requires informed choices at each point in the development process. The discussion below outlines the potential benefits and disadvantages of using an external control within a program and the key criteria from representative programs that have successfully passed industry and regulatory muster to use external controls in registrational programs.