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Controlling or crossing over randomized clinical studies
Experimental studies are interventional. Investigators control as many aspects of the study as is reasonable to determine cause and effect in an experimental study. Experimental studies are randomized to provide a better statistical foundation for analysis. Randomization “evens out” factors that can potentially confound the study, because these factors are symmetrically assigned during the randomization process. Randomized studies include randomized controlled clinical trials and randomized crossover clinical trials.
When properly executed, randomized controlled clinical trials provide the strongest clinical evidence. Randomized controlled clinical trials are prospective, which means the study moves forward in time, as opposed to retrospective (looks backward in time). Eligibility criteria ensure that study subjects are similar by including or excluding subjects who exhibit specific physiological characteristics. Eligibility criteria serve as additional safeguards against potentially confounding factors that can interfere with the accurate interpretation of study results. Eligible subjects are then randomized to treatment groups, or treatment arms. After intervention, or drug administration, the clinical investigator follows up on subjects in each treatment arm. Data generated during the clinical study are analyzed, and conclusions about clinical evidence are drawn.
In a randomized controlled trial, one arm serves as the control arm, against which experimental arms, or treatment arms, are tested. The control arm may be placebo-controlled or may receive an active control based on an agreed-upon treatment standard. A placebo-controlled arm can check for “placebo effects” in the experimental arm. The placebo effect is an observable and measurable improvement in a subject’s condition that is not attributed to the intervention or treatment, and it can interfere with accurate data interpretation.
A placebo-controlled arm contributes to the robustness of empirical evidence generated in the study, but can have considerable drawbacks. In certain diseases for which there is no cure, the use of a placebo-controlled arm may be unethical. A placebo control may also be difficult to formulate, as interventions may not all assume the form of an oral pill with convenient dosing. In disease areas where patients represent the majority of clinical trial subjects (for example, oncology), placebo-controlled clinical trials can interfere with clinical trial participation. Patients fear that they may be assigned to a placebo arm and not receive treatment.
When placebo-controlled arms are unethical, a randomized controlled trial will test the study drug against the current “gold standard” using an active-controlled arm. Unfortunately, an active-controlled study may not accurately pinpoint the true cause-and-effect of an intervention because each drug can work through divergent pathways that yield similar results. These divergent pathways, in turn, can generate differences in long-term safety and efficacy. In addition, when comparing a test drug against the gold standard, dosing becomes an issue. Criticisms of many head-to-head clinical trials center on suboptimal dosing of the active control. This opens the door for debates in the medical community about whether the test drug is truly more efficacious than the current gold standard and whether results would remain comparable if the dosage of the active control were increased.
Parallel or crossover?
When subjects in a randomized controlled clinical trial stay within their respective treatment arms for the duration of the study, that study has a “parallel study design.” Parallel study designs can require a large patient population to adequately compare treatment arms. However, parallel studies allow for comparison of additional treatments in each treatment arm. If, at any time, the subjects in one treatment arm of a randomized trial begin receiving the treatment of the other treatment arm, the subjects have “crossed over” to the other treatment arm, and the study is called a randomized crossover clinical trial.
Randomized crossover clinical trials are prospective studies that randomize subjects to one of two treatment arms. After a treatment period, subjects in each arm go through a washout period and are assigned to the other treatment arm. Crossover studies require a smaller sample size than randomized controlled clinical trials, and the crossover reduces intergroup variations. However, bias can be carried over from the original treatment. Crossover studies require a stable chronic condition and may take longer to complete than randomized controlled clinical trials. The crossover study design can introduce additional confounding factors from stability variations in a chronic condition and the washout period.
Experimental studies are preferred over observational studies in generating clinical evidence, based on more objective interpretation of study data and a reduction of confounding factors. Controlled trial and crossover trial designs present inherent advantages and disadvantages with regard to the objectivity and economics of results. Next month, we will look at selected types of observational studies.
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