In a clinical trial that tests the safety and efficacy of a drug or vaccine, the drug or vaccine being tested is always compared to a group called the control group that does not receive the drug or vaccine. When preparing for a study, scientists randomly select participants for either the vaccine or a control group. The control group either receives:

1. A placebo
2. An active control

Placebos are substances used in clinical trials to understand the safety and efficacy of a new drug or vaccine that have no active properties. Often designed to look very much like a real drug or vaccine, placebos are usually made of inactive substances like saline solution, starch or sugar. Placebos are the gold standard for studying how safe and effective a drug or vaccine is in a trial because it provides the most control. 

An active control is a known, safe and effective vaccine or drug that is used to compare against the vaccine or drug being tested. This design helps examine differences in efficacy and safety between two shots, and the safety and efficacy of the new drug or vaccine being tested overall. Active controls are often used in more complex ethical situations. For instance, if a cancer treatment is being studied, it would be unethical to give a cancer patient a placebo (no treatment at all). As a result, an active control would be used. 

Active controls can also make sure participants remain unaware of whether they received the vaccine or the control. This is important for getting unbiased data from trial participants. For instance, in the trial of the AstraZeneca vaccine, the University of Oxford used a vaccine for meningitis and septicemia as a placebo in some of their trials, since it provokes side effects at the site of injection that are similar to the AstraZeneca vaccine. 

This approach helps to “blind” participants so that they don’t know whether they received the vaccine or the control. When participants are not “blinded,” it can influence their behavior after vaccination or treatment, and could bias results of the study. For instance, if someone knew that they received the vaccine, they might be more likely to report side effects; or on the other hand, if someone knew that they received the control, they might be less likely to report side effects. This “blinding” is another major reason why active controls are sometimes used, in addition to ethical concerns.

Not all clinical trials explicitly state the composition of the placebo used, but there is a growing consensus that effective standards must be set for reporting placebo controls. Additionally, the World Health Organization provides guidelines on the ethical principles that should be considered for the use of inactive or active placebos, as well as the use of placebo controls in vaccine trials.

Vaccines go through several stages of clinical trials before they are deemed safe and effective for public use. During these trials, the safety and efficacy of a vaccine is tested against a control which is generally an inactive substance (a placebo). In some cases, to ensure that the trials are truly “blinded” (i.e. participants are unaware of whether they received the vaccine or placebo), or because of ethical concerns, an unrelated vaccine may be used in place of a placebo (an active control).  In these cases, a vaccine or treatment that is already approved by regulators and is considered safe is used in place of the usually inactive placebo. Government regulators and the World Health Organization lay out clear ethical guidelines for when and if such substitutions can be made to ensure that the vaccine trials are safe and elicit the data needed for regulators in their assessments.