Understanding Clinical Research

Abstract

With the explosion of new oral drugs and insulins to treat diabetes, a recent correspondence to the journal Diabetes Care from David S.H. Bell, MD, was thought-provoking.1 His argument was that placebo-controlled trials to assess new oral therapies are unethical because we now have proven and safe therapies. Dr. Bell reasons that because existing therapies have proven risk-to-benefit ratios, a more appropriate course would be to compare the investigational agent against an existing drug—in other words, an “active placebo.” He argues further that by using inactive placebos, we are exposing study subjects to unnecessary hyperglycemia, even if for relatively short periods of time. Currently, pivotal trials for Food and Drug Administration (FDA) approval of diabetes agents last 6 months. Does 6 months of hyperglycemia using an inactive placebo contribute to an adverse effect on quality of life and microvascular complications, as Dr. Bell argues? This topic has concerned me for a long time. Part of the problem is the types of end points we measure. For FDA approval, end points include fasting plasma glucose and HbA1c levels. As an aside, there has been much controversy and confusion about how to best express these data. Measuring the difference from baseline can be very different from measuring the difference versus placebo, depending on the direction of movement of the placebo group. For example, if drug X lowers HbA1c concentration by 1% from baseline over the past 6 months, but placebo Y results in a 0.5% HbA1c increase, the improvement of HbA1c compared …