Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘Another advantage of uncontrolled trials is that, in certain situations, uncontrolledtrials might be the only study design allowable given a set of ethical considerations.For example, it is unlikely that patients who experienced a cardiac arrest would berandomized to resuscitation versus no intervention to evaluate the efficacy ofresuscitation, since untreated patients would certainly die. Similarly, if the newtreatment involved a surgical procedure involving general anesthetic it might beunethical to perform a ‘sham’ operation given the risk of the anesthesia.Limitations of uncontrolled trialsA major limitation of uncontrolled trials is the absence of a randomly selectedcomparison group, making these trials unsuitable for fully evaluating the efficacyof a new drug. For instance, uncontrolled trials would be inappropriate forevaluating whether a particular cholesterol-lowering drug reduces the risk ofcoronary events since it would require studying a comparable untreated group(eg, a placebo control group). The use of a control group would ensure that thelowering of cholesterol is attributable to the drug itself and not to some othercause, such as changes in diet and exercise patterns.Investigator biasAnother limitation is that, compared with controlled trials, the results ofuncontrolled trials are more likely to lead to enthusiastic results in favor of thetreatment. This specific form of study bias is known as investigator bias [6].For example, suppose that an investigator wishes to conduct a new clinical trial insearch of a promising new therapy. However, desire for the drug’s success drivesthe investigator to unconsciously recruit a healthy group of individuals into thestudy. These individuals are likely to do well simply from being in the trial itself(ie, through a placebo effect), biasing the results in favor of therapy. Had theinvestigator chosen to include a control group in the study, it is likely that theresults of the study would not have shown an advantageIn general, uncontrolled trials are more likely to lead to positive results comparedto trials using appropriately selected controls [6]. For instance, case series andobservational studies have found corticosteroids to be beneficial in patients withhead trauma. However, a randomized clinical trial was terminated early becausepatients randomized to corticosteroids experienced a significantly greater risk ofdeath compared to patients in the placebo group [7]. Thus, it is possible that overinterpretationof the results of uncontrolled trials prior to the publication of therandomized clinical trial led to numerous excess deaths resulting from inappropriatesteroid prescription [8]. This example illustrates that over-interpreting the resultsof uncontrolled trials can have significant adverse public health consequences.19