Controlled and Uncontrolled Clinical Trials

As mentioned in our publication Types of Clinical Trial Design, one of the designs is based, on the inclusion or not, of a control group to compare the effects of the investigational treatment. Trials that do not include it are called uncontrolled trials and those that do are called controlled trials.

Uncontrolled trials

Uncontrolled trials are those that do not include a control group. A control group is made up of a group of patients that do not receive the investigational drug, but instead take the standard treatment, approved for the disease on which the study is being carried out, or takes a placebo, which is a simulation of the investigational drug, but has no activity on the studied pathology.

Uncontrolled trials are often used in the early phases of drug research, phases I and II, to determine pharmacokinetic properties or to investigate tolerated dose ranges. They can also be useful to study side effects, biochemical changes in long-term therapies, tolerance, interactions or efficacy of drugs.

It is known that uncontrolled trials produce higher estimates of the mean effect than those obtained in a controlled trial, since by not having a control group acting as a reference, they can induce erroneous impressions about the results of the investigated drug. As they can generate a certain bias, the results of uncontrolled trials are considered less valid than those of controlled trials. The results obtained are usually compared with those obtained in previous studies or that have been published by other researchers.

Controlled trials

The design of these trials includes at least one study group that is compared with a control group. The control group can receive placebo or another effective treatment. Both groups are studied simultaneously, except when historical data are used as a control. These types of trials are the most common in Phase III of drug research. Controlled trials allow the patient's outcome to be discriminated from an outcome caused by other factors, such as the natural history of the disease or the expectations of the patient or the investigator.

The controls that are usually used are:

• Placebo control: using an inert substance or an intervention designed to simulate investigational medical therapy, but have no effect on the pathology under investigation. The placebo should have the same appearance and dose frequency as the active drug. This design is used to demonstrate superiority or equivalence and should only be used when there is no effective treatment. Placebo should only be used if no permanent harm (death or irreversible morbidity) occurs by delaying available active treatment for the duration of the trial, being preferable for a short-term, minimal risk study.
• “No treatment” control: patients in the control group are not given any intervention or treatment. The disadvantages of this design are the potential bias of the observer due to the difficulty of blinding and the possible ethical implications.
• Active treatment control: This design involves comparing a new drug with a standard drug or comparing the combination of new and standard therapies versus standard therapy alone. This design can be used to demonstrate equivalence, non-inferiority, and superiority of a treatment. This design is more ethical, provided that approved drugs are available for the disease under study.
• Control with dose comparison: different doses or regimens of the same treatment are used as active arm and control arm. The purpose is to establish a relationship between the dose and the efficacy / safety of the intervention. This design can include active and placebo groups in addition to the different dose groups. This design may be ineffective if the therapeutic range of the drug is not known.
• Historical control (external and non-concurrent): in this design, the information from the controls is not obtained during the study, but is from patients who were treated at an earlier time or in a different setting. This type of design has an advantage when studying rare conditions where it is difficult to generate a sample size. On the contrary, it has many disadvantages such as that randomization and blinding is not possible and that the comparability of the current intervention with the historical control is difficult and the differences in the baseline characteristics of the subjects in the research group versus the historical group.