Clinical Trials

Types of Trials

In experimental studies, the investigator manipulates the study factor (exposure groups) and randomly allocates experimental units to different exposure groups. An experimental study is also called a trial. A trial must progress longitudinally in time from exposure to outcome. This together with the ability to manipulate the study factor and to randomize the experimental units makes a stronger causal inference using experimental studies than using quasi-experimental studies, [Page 202]which involve manipulation of the study factor but not random allocation of experimental units, or using observational studies, which involve neither manipulation of the study factor nor randomization of experimental units. Experimental studies without control or comparison groups (e.g., Phase I/II clinical trials) are called uncontrolled trials, while experimental studies with control or comparison groups are called controlled trials. A controlled trial in which the allocation of experimental units to different exposure groups is done randomly so that all experimental units have an equal chance of being allocated to each of the exposure groups is known as a randomized controlled trial (RCT), which can be a randomized controlled clinical trial (when the unit of randomization is a patient such as the Phase III clinical trial); a randomized controlled field trial (when the unit of randomization is a normal individual, rather than a patient, such as the vitamin C trial of Karlowski et al., 1975); or a randomized controlled community (cluster—a group of people in a community) trial (when the unit of randomization is a community or cluster such as Project Burn Prevention trial of Mackay and Rothman and water fluoridation trial of Ast and Schlesinger (1956). The less common field trials and community (cluster) trials are aimed at the evaluation of primary preventives, while the more common clinical trials are used to evaluate treatment effectiveness of a disease or to find a preventive of disease recurrence or death. All randomized trials are controlled. In nonrandomized controlled trials, the groups may not be comparable due to selection and confounding biases and so estimates of effects of the intervention may not be valid without further statistical adjustments.

Clinical Trial Protocols

Researchers for each clinical trial follow a protocol reviewed and approved by an institutional review board (IRB), a separate board of scientists, statisticians, physicians, and nurses who are not associated with the clinical trial. A Clinical Trial Protocol contains a study plan that describes the organization of a clinical trial, the background, rationale, objectives, and hypotheses; how the subjects are to be selected and how data are to be collected; primary exposures and methods of their measurements (an exposure is a factor that either causes, prevents, or treats an outcome), outcomes of interest and methods of their measurements; as well as intervening variables and methods of their measurements, type of study design, method of randomization, methods to control confounding bias prior to data analysis if randomization is not used, measures of association to be used, statistical methodology and analysis, including methods to control confounding bias during data analysis, and power calculations. It may also address issues of noncompliance, dropout as well as selection and information biases, and how nondifferential misclassification may affect the interpretation of results. The protocol also states the number of participants, eligibility requirements, agents that will be used, dosages, schedule of tests, the length of the study, and the larger population to which the results can be generalized. Note that both issues of internal validity and external validity have been covered in the description of clinical trial protocol given above. This protocol will also serve as the basis for writing the final report.

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