6b.1 - Control Groups

Placebo-Control

Placebo-controlled trials typically provide an unambiguous statement of the research hypothesis: either we want to show that the experimental treatment is superior to placebo (one-sided alternative) or as is more often the case, we want to show that the experimental treatment is different than placebo (two-sided alternative). For this reason, we frequently refer to a placebo-controlled trial as a confirmatory trial, or in the most recent language, it is called a superiority trial (even if we are using a two-sided alternative).

Active Control

Active control groups are often used because placebo control groups are unethical, such as when:

1. the disease is life-threatening or debilitating, and/or
2. an effective therapy already exists and is considered standard-of-care.

Investigators can use an active control group in a superiority trial, an equivalence trial, or a non-inferiority trial. The new treatment may be preferred due to less cost, fewer side effects, or less impact on the quality of life. Or the new treatment may have superior efficacy.

Equivalence trials and non-inferiority trials have different objectives than superiority trials. The objective of an equivalence trial is to demonstrate that a therapy is “equivalent” to the active control (it is not inferior to and not superior to the active control). Equivalent might not be the best word choice for this type of trial as we will see later. The objective of a non-inferiority trial is to demonstrate that a therapy is not inferior to the active control, i.e., it is not worse than the treatment.

There are a number of issues related to the design and analysis of equivalence and non-inferiority trials that are not well understood by clinical investigators. We will examine these issues using examples of such trials in this lesson.