Randomization

The controlled clinical trial (CCT) is the scientific tool for demonstrating causality. Two essential elements characterize the CCT: (a) it contains a control group and an experimental group; (b) with the exception of treatment, all other conditions and procedures to which the subjects are exposed during the trial are constant. These two characteristics of the CCT enable the researcher to establish a causal relationship between treatment and the outcome of the trial. The tool for standardizing the trial is the study protocol, the document defining the subjects eligible for inclusion in the study, the study procedures and schedules.

A key element is the method of allocating subjects to the treatment groups. Subjects may possess a variety of characteristics that could influence their response to treatment. These could be related to the subjects' demographic background, such as age, sex and ethnic origin, genetic disposition or other prognostic variables. The method of allocating subjects to treatment must make sure that the resulting treatment groups are balanced with respect to such factors. The most effective way to achieve this is by randomization, i.e. assign each subject to a treatment group using a chance mechanism. Of course, one could achieve the desired balance by using a systematic, non-random allocation scheme that will force the balance. Randomization, however, has some important advantages. Any non-random method inevitably involves a decision by the individual making the allocation. This potentially could result with the preference of a certain type of subject for one of the treatments that may not be reflected as an imbalance in any of the identified prognostic variables. Furthermore, there might be some other variables which affect the response to treatment, which are either unrecognized as such at the time the study is planned, or are impossible to balance for logistical reasons. A random allocation, at least in large trials, can typically protect the investigator against such problems.

The most common method of randomization is by using randomized blocks. Let us illustrate this for a trial with three treatment Groups: A, B and C. Blocks containing the letters A, B, and C in a random order, with each letter repeated the same number of times, are generated. Such a block of length 6 might look like B, B, A, C, C, A. The requirement that each letter appears in the block as frequently as any of the other two letters implies that the length of the block must be a multiple of 3. Thus, for the case of three treatment groups, the block size must be either 3, 6, 9, etc. The number of such random blocks generated must be such that the number of letters in the resulting string equals or exceeds the number of subjects to be enrolled in the trial. Subjects are then assigned sequentially to the treatment group corresponding to the next un-assigned letter in the randomization string. Because each individual block contains the same number of each of the letters, the treatment assignment sequence obtained from the randomized blocks method is not exactly a sequence of random numbers. However, the method has the advantage that it guarantees a maximum balance in the resulting sizes of the treatment groups. This is a desirable feature because it increases the efficiency of the statistical analysis tools.

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