Efficiency of Clinical Trials: Selective Inclusion of Study Subjects

The object of an experimental clinical trial is to assess whether a new agent is superior to a placebo or standard treatment and to measure the magnitude of its effect in the most efficient way. However, at the present time, clinical trials of caries prophylactic agents are usually conducted with less than optimum efficiency and are in consequence unduly costly. One reason is that large numbers of participants are often used to overcome the variability among factors which affect the subjects' response to a new treatment. This situation arises from confusion over the aim of the experimental trial, which should be so designed that the conditions give a promising new agent the best chance of demonstrating a clinical effect, and the community trial, the purpose of which is to ascertain the cost-effectiveness of a clinically tested agent when used routinely by a population sample.1 Thus, in clinical trials so far conducted, sample sizes have been inflated in an attempt to construct a population sample and achieve the objectives of both the experimental and community trial at one and the same time. Many individuals have been included who would be unlikely to show a treatment effect even if the agent was really of value. As a result, such trials have provided inefficient tests of the agents while also failing, because of the artificial conditions imposed, to demonstrate their cost-effectiveness on a public health basis. In other fields of medical research, it is common practice to carry out experimental trials of new therapeutic agents using only groups of individuals at high risk to the disease of interest. In caries research, it is also usual to preselect subjects to an extent in so far as most trials are conducted on children who are entering a period of high caries activity. However, selective inclusion could be carried a stage further if it were possible to distinguish readily individuals in a susceptible age group likely to show a consistently larger, more significant treatment response than their peers. By restricting inclusion in an experimental trial to such individuals, sample sizes might be reduced without loss of power, and experimental efficiency thereby increased. However, a positive response on such a group would then call for a community trial of the agent on a population at risk. To examine the possibility of improving efficiency through selective inclusion of trial subjects a two-stage study was carried out. First, groups of participants showing a considerable treatment effect in clinical trials were investigated in an attempt to discover possible criteria for preselection. In the second stage, the data from subjects meeting the selected criteria were analyzed separately and the minimum sample sizes required to reject null hypotheses were computed. The variables chosen for study were initial measurements which could either be obtained easily or were already made routinely. Thus, in the preliminary investigations, sex, initial DMFS, and tooth surfaces at risk of caries attack were considered. Oral cleanliness, a further variable of possible interest, was examined but disregarded for while subjects with good oral cleanliness at the conclusion of one trial have demonstrated a greater caries reduction than those with poor oral cleanliness,2 the treatment response was shown to be unrelated to this factor at the beginning of the study. There is evidence that sex is important in determining treatment response. For example, girls have usually demonstrated a larger, more significant effect than boys in fluoride dentifrice trials in the United Kingdom.3-5 due possibly to their oral condition being more favorable, their more effective use of the dentifrice or their earlier tooth eruption times giving the agent longer time