What’s a control group in an experiment?

When designing a clinical trial, several parameters are considered to correctly evaluate the effects of the drug being tested, as well as to measure its efficacy and safety. These include the patient population to be studied, the drug being tested, the objectives of the study, and so on. In many clinical trials, the participants or population are divided into two separate groups, the experimental group, and the control group. The experimental group being those who receive the drug being tested, and the control group receiving the comparator. These types of clinical trials are known as comparative studies.

What is a control group and why is it important?

In comparative studies, we are looking to contrast the effects of the investigational drug (the one being tested) to something (the comparator drug). We can either analyze it in relation to no treatment, to a placebo, or to a similar drug that is already available on the market. In these studies, participants are divided into two treatment groups: the experimental group that will receive the drug being tested, and the control group that will receive comparator. 

When setting up the groups, we need to verify that both groups have similar characteristics. By doing this, we ensure that any differences we see in the results between the two groups are due to the drug being tested, and not due to other factors. In randomized studies, computerized systems, or tables of random numbers are used to determine which group each participant will be allocated to. This process is known as randomization and is a good way of creating similar groups.

The use of control groups is an important part of testing new drugs, which allows us to see if the drug works, and how well it works compared to other options or situations. It also lets us differentiate a drug related outcome from an outcome caused by other factors or bias. Without a control group, we would not have anything to measure the new drug’s results against.  

What are the 5 types of control groups?

Studies that use at least one control group are known as controlled trials. There are many different trial designs, and types of control groups. The most common ones are:

  • Concurrent placebo control: one group receives the study drug, the other a placebo.
  • Concurrent dose-comparison control: two different doses of the same drug are given, and each group receives a different dose. 
  • No treatment concurrent control: only one group receives the study drug, and the other does not receive anything.
  • Concurrent active treatment control: one group receives the study drug, and the other group receives an existing therapy known to be effective.
  • Historical control: in this case, participants are not put into a control group. The information or the control group is not obtained during the study, but from historical data from patients who were previously treated or treated in a different setting. This type of design has an advantage when studying rare conditions where it is difficult to find many participants for the trial.

The type of control group used depends on the study design, the type of drug being studied, the disease being treated, and the type of patients being treated. 

Placebo control group

First, let us define what a placebo is. It is an inactive substance, or other intervention, that has the same appearance and is administered in the same way as the active drug or treatment being tested. 

When a study has a placebo control group, it will usually also be a blinded study. Blinding in the context of clinical trials is when the patient does not know if they are in the experimental group, or the control group. By comparing the results from both groups, we will know what the true effects of the study drug are. 

A placebo can also be used to facilitate the blinding process of a clinical trial. In a trial where you are comparing two drugs that are obviously different (one is a pill and the other is an injection, for example), the participant is going to know which drug they are being given. However, by giving those in the pill group and placebo injection, and those in the injection group a placebo pill, all participants will be getting both a pill and an injection. You can now have a blinded study, because the participants will not know if the pill or the injection they are getting, is the active drug.

Blinding can be done at many levels, so that just the participant (single blind); the participant and the investigator (double blind); or the participant, the investigator and the person analyzing the results (triple blind), do not know which group each participant is in. It is also used to minimize the possibility of bias and to maintain equality between groups from the beginning to the end of the study.

While blinding is a great way to avoid bias, it is not always possible, or necessary, and the trial can be open label. In these studies, the participant, investigator, and analyst know which group the participant is in. 

Why use a placebo in clinical trials? 

So, isn’t getting a placebo the same as not getting any treatment? Why bother with giving patients a placebo?

When you use a placebo, you are not giving a treatment, this is true, but by using a placebo in a comparative study, you can measure how much of the effect seen in the patients taking the study drug is due to the drug, and how much is due to the placebo effect

The placebo effect is when a person’s physical or mental health appears to improve after taking a placebo or “dummy” treatment. It can be a positive or negative effect, all triggered by a person’s beliefs. This effect only happens when the person taking the placebo believes they are being given the real drug. Therefore, a placebo must look, taste and be administered the same way as the study drug.

Although comparative studies using a placebo can be useful when developing a new drug or treatment, there is a lot of controversy over whether it is ethical or appropriate to give participants a placebo when there are other valid treatment options available

It has been accepted worldwide that the use of placebo instead of an existing treatment is acceptable in the certain situations, as long as its use does not pose a risk to the participant, and when treating diseases that are not life-threatening: 

  • When an effective treatment does not exist.
  • When placebo is only given for a short amount of time. 
  • When it does not add risks unrelated to their underlying disease.

The Declaration of Helsinki, is a set of ethical principles for medical research on human subjects, including clinical trials. It states that the “benefits, risks, burdens and effectiveness of a new method should be compared with the best existing methods of prevention, diagnosis and treatment”. Therefore, the design of a modern clinical trial should include control groups that represent the latest “standard of care”, based on the evidence available at the time. 

The “standard of care” is a guideline for the adequate treatment of a disease based on the agreement of medical experts; in other words, this treatment is considered as the best way to treat this disease. Depending on the disease being treated in the clinical trial, the standard of care is usually used to treat the control group. That means that the patients included in the control group will receive the usual standard treatment, according to the standard of care at the time. In this way, the results obtained with the experimental group are compared with the existing treatment.

Non-inferiority, superiority, and bioequivalence studies

In clinical research there are some types of trials that use a standard therapy as a control group, to demonstrate whether the investigational treatment is non-inferior, superior, or equivalent to the standard. We will try to develop these approaches in a simple way.

On one hand, there are the non-inferiority clinical trials, the main purpose is to demonstrate that the new drug is as effective as the control, as well as other potential advantages, such as greater safety, shorter treatment duration, better route of administration or lower cost, among others. This type of trial is usually performed when an effective treatment for a pathology already exists. 

On the other hand, there are the superiority clinical trials, in which the main objective is to demonstrate that the experimental treatment is more effective than the comparator. 

Lastly, there are bioequivalence clinical trials,which are needed to be able to launch a generic drug. The generic drug would contain the same active ingredient, dosage, and form of administration as the reference drug. For a generic drug to be approved, it must be bioequivalent to the reference drug, meaning that it is absorbed at the same rate and at the same amount into the bloodstream. With this type of study, we can confirm bioequivalence, and show that the generic drug has the same efficacy and safety as the marketed drug or reference drug. This trial would be based on previous experiences and studies of the reference drug, which is why, compared to clinical trials of new investigational drugs, bioequivalence trials are easier to perform, have lower costs and shorter duration, as it only requires one phase of clinical trials. 

Overall, when testing a drug, we sometimes need to be able to compare our results to a control, to ensure the new drug is effective and safe, making control groups a key part of drug development and clinical trials.