What is Active Control in a Clinical Trial?

Active control (or Active Comparator) means that an already known, effective treatment (unlike a placebo) is being compared to an experimental treatment. In other words, every participant in an active control clinical trial is given a treatment that actually works (or potentially works) instead of some receiving an inactive treatment (placebo).

Studies that compare an experimental treatment with an ineffective placebo are the “gold standard” for drug testing and provide valid, reliable results. However, there are instances when giving patients a placebo treatment is morally unacceptable. For example, giving a cancer patient no treatment is unethical. This is when active controls are used.

Although it may seem reasonable to give some treatment to all participants (instead of no treatment to some), trials that use active controls are very difficult to design, implement, and interpret.

The use of control groups in clinical trials is important for differentiating patient outcomes caused by experimental treatments from those caused by other factors, such as natural disease progression.

Reasons for Using Active Controls in Clinical Trials

Trials Involving Serious Outcomes

In trials involving serious outcomes such as mortality, it is morally unacceptable to use a placebo when active treatments are readily available.

Trials Where Benefits Need to be Tested

Clinical equipoise, referring to the state of true uncertainty about the relative benefits of alternative treatments under the "null" hypothesis to be tested, is an ethically necessary condition in all clinical research.

Trials to Demonstrate the Efficacy of a Drug That May Have Large Placebo Effects

Active controls are sometimes used to demonstrate the efficacy of a drug that may have large placebo effects. Active controls are also used to compare experimental treatments with alternative treatments. Active control trials aim to demonstrate that treatments of interest have either superior effects or similar effects to the control.

Trials Offering Important Advantages Over Currently Available Standard Treatments

Our interest usually lies in demonstrating that a particular new treatment can be recommended as being better than existing treatments. Such trials are known as superiority trials, where we seek sufficient evidence to reject the hypothesis that "the two treatments have equal effects" in favor of the superiority of the new treatment. However, failure to observe sufficient evidence for rejecting the null hypothesis does not necessarily suggest the equivalence of the two treatments.

Use of Active Controls

Active-control equivalence trials can be informative and have been used successfully and appropriately in many therapeutic areas where assay sensitivity is not in doubt. These trials are often credible and have been widely used in areas such as treatment for cancer, infectious disease, and some cardiovascular conditions (for example, acute myocardial infarction treated with thrombolysis). In general, the larger the effect size, the less study-to-study variability in outcomes, and the fewer instances of unexplained failure of the control agent to show superiority to a placebo in well-controlled studies, the more persuasive the case for using this design. Investigators who intend to perform an active-control equivalence trial (ACET) will therefore need to review previous placebo-controlled trials of the control agent to see whether it can be persuasively shown that such information exists. The ACET should be as similar as possible to the past placebo-controlled trials regarding patient selection, dose, endpoints, assessment procedures, use of concomitant therapy, and other pertinent study design characteristics.

Given the inevitable residual uncertainty about the assay sensitivity of a trial that does not contain an internal standard, reliance on ACETs may also require more evidence of replicability than would be needed for trials intended to show differences. It should be appreciated, however, that even if assay sensitivity can be assumed, the effect that the active control can be presumed to have had under the study conditions will often be relatively small. In such cases, large sample sizes will be needed to provide the narrow confidence interval needed to ensure that the new drug is not inferior to the control by more than that amount.

Assessment of Effectiveness with Active Control Trials

Because of deficiencies in study design or conduct, clinical trials that are unlikely to provide scientifically valid and clinically meaningful results raise their own ethical concerns.

Difference in Interpretation of Trial Results

The results from an active control (active comparator) trial need a different interpretation than a placebo control trial.

In placebo-controlled trials, a difference in the results between the experimental group and the control group indicates the new treatment may be potentially effective. For example, if an experimental drug prevents headaches 90% of the time and a placebo treatment prevents headaches 10% of the time, that difference indicates that the experimental drug is working.

With an active control trial, the research team is not looking for a difference in results; They're looking for no difference. In theory, a "no difference" finding can indicate that the experimental drug is equally effective as the comparator. For example, a well-known headache drug prevents headaches 80% of the time, and an experimental drug also prevents headaches with the same frequency. There's no difference—the drugs are equally effective, so the trial is a "success." In practice, active control trials are very difficult to interpret. A "no difference" finding in one of these trials can mean many different things:

• The experimental drug and the active comparator are equally effective.
• Both drugs are not effective.
• The study could not tell the difference between the 2 drugs (i.e., it was poorly designed or administered).

One way to make sure that the results are valid is to prove that the active control is superior to the placebo. This may require a separate trial. In some cases, prior knowledge about the comparator's effectiveness—perhaps from prior studies or other clinical data—can validate results from an active control trial.

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At Santos Research Center, Corp., we have completed over 400 clinical trials. We use efficient and reliable systems to plan and manage quality medical research studies.

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