The control group provides the essential reference point against which the effects of an investigational treatment are measured. Without a properly designed control group, researchers cannot distinguish whether observed outcomes result from the treatment itself, from natural disease progression, from participant expectations, or from regression to the mean. The choice of control is one of the most fundamental decisions in trial design, directly affecting the scientific validity and ethical acceptability of the study.

Several types of control groups are employed depending on the research question and therapeutic context. Placebo controls use an inactive substance to isolate the true pharmacological effect of the investigational product. Active controls use an established therapy as the comparator, appropriate when withholding proven treatment would be unethical. Historical controls compare trial participants to previously treated patients, though this approach is susceptible to bias. No-treatment controls simply observe participants without intervention, suitable when the placebo effect is minimal and observation alone poses no ethical concerns.

The selection of an appropriate control must balance scientific rigor with ethical obligations to participants. Active-controlled trials may be required when effective therapies exist and participants would be harmed by receiving placebo. Non-inferiority designs comparing investigational treatments to active controls have become increasingly common, demonstrating that new therapies are not substantially worse than established options while potentially offering other advantages such as improved safety or convenience. The protocol must clearly justify the chosen control and demonstrate that the design will yield clinically meaningful results.