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When two or more pharmaceutical agents are being compared, masking may be achieved by ensuring that all treatments appear identical; neither the patient nor the investigator is informed as to the identity of the preparation that a patient is receiving. If the objective is to evaluate a new drug in comparison with no treatment, a placebo is used for the comparison group. A placebo is an inactive agent made to seem identical to the active agent in terms of appearance and mode of administration.

The use of placebo is rare outside of clinical trials for pharmaceutical agents. For example, in evaluations of new surgical procedures, it is more difficult (and ethically questionable) to apply sham surgeries. Thus, masking in such settings may be limited to the individuals who are assessing the outcome. For example, in a clinical trial of eye surgery in which visual acuity is the outcome, the technician measuring visual acuity would be masked as to treatment assignment to avoid bias in administration of the visual acuity test.

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