Safety and study design

How do researchers decide which interventions are safe to test in people?

Before a clinical trial is designed and launched, scientists perform laboratory tests and often conduct studies in animals to test a potential intervention’s safety and effectiveness. If these studies show favorable results, the European Medicines Agency (EMA) or respective national competent authorities such as the Federal Institute for Drugs and Medical Devices in Germany (BfArM), or the U.S. Food and Drug Administration (FDA) need to approve the intervention to be investigated in humans, namely in clinical trials.

Controlled Clinical Trials

Controlled clinical trials consist of several treatment groups, an intervention group (investigational group) and one or more control groups. The investigational group receives the new treatment to be investigated. The control group may receive an approved standard treatment (active-controlled trial) or placebo, i.e., a treatment that does not contain a pharmacologically active substance (placebo-controlled trial).

The importance of placebo

The placebo control group receives a placebo that does not contain a pharmacologically active substance but has the same appearance as the novel comparator drug. This placebo condition is necessary to understand the real effects and side effects of the new treatment and to avoid the approval of drugs that are considered effective because of a statistical error.

Placebo treatments can make people feel better because they believe they are being treated. This is known as the placebo effect. However, people can also develop negative reactions to the placebo, such as nausea, headache, etc. most likely because they are expecting specific side effects. This is sometimes also called the nocebo effect. The placebo can be powerful. Therefore, a placebo control group prevents health authorities from approving treatments that are less effective than placebo treatment.

Blinding

Blinding is a procedure in which one or more parties in a trial are kept unaware of which treatment arms participants have been assigned to, in other words, which treatment was received. Blinding is an important aspect of any trial done to avoid and prevent conscious or unconscious bias in the design and execution of a clinical trial.

A clinical trial is called single blind when only one party is blinded, usually the participants. If both participants and study staff are blinded, it is called a double-blind study.

Randomization

Trial participants are randomly assigned to either treatment or control arms in randomized controlled trials. Randomly assigning a trial participant to treatment or control arms is called ‘randomization’. Different tools can be used to randomize (closed envelopes, computer-generated sequences, random numbers).

There are two components to randomization: generating a random sequence and implementing that random sequence, ideally in a way that keeps participants unaware of the sequence. Randomization limits the occurrence of bias and ensures that the data obtained are reliable. In clinical trials, bias refers to factors that could interfere with or distort the results.