Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘in a small subgroup of patients >80 years of age, there might be more womensince women generally live longer than men. The way to avoid both theselimitations is for investigators to calculate an appropriate sample size for the studywith well-informed predictions of the likely size of the subgroups in mind.Are there solutions to deal with the problemsof subgroup analyses?A number of solutions have been devised to overcome the problems stated above.1. Adjusting the threshold of significance for subgroup analysesOne option would be to adjust the significance level (usually a 1 in 20 chance,or P < 0.05) by the number of planned comparisons. For example, if theoverall treatment effect was significant at the 5% level and the aim was toinvestigate the subgroup effect over 20 categories (such as by study sites), thenone could divide the original significance level (0.05) by the total number ofcategories, meaning that a P-value of < 0.0025 is required to declare significancefor any one subgroup analysis. This significance adjustment is sometimes calleda Bonferroni correction.2. Using an interaction testIn addition to adjusting the significance level, a subgroup analysis should besupported by some sort of interaction test to see whether the association betweenthe treatment effect and the specific characteristic of the subset is significant.For example, let us say that a traditional subgroup analysis found a highertreatment effect in women. We could then ask the question: “Was the treatmenteffect seen in women significantly different from that seen in men?” If so, thisimplies that female gender influences treatment response.In a study of 35 trials where subgroup analyses were performed, only 15 trials usedsuch statistical tests of interaction to confirm the subgroup effect [7]. The limitationof interaction tests, as with other tests, is that with smaller populations to comparethey have less statistical power either to capture or to rule out an association.3. Avoiding bias arising from post hoc analysisSubgroup analyses are often defined after a study is complete; therefore, they arenot prespecified or predefined. The method is termed retrospective or ‘post hoc’analysis. Such an analysis should be used mainly to form ideas or proposeassociations – ie, hypothesis generating – but a large number of researchers usethe results of such analyses to support conclusions or explain results, leading toover-interpretation of the positive result. The reason that this may not be a valid269