Clinical Trials

❘❙❚■ Chapter 23 | Subgroup Analysisstrategy is that the treatment itself can influence how the subgroup is formed.An example of this effect is given below.Example 3Consider a study that shows a new treatment to be beneficial overall, and that theresults are even stronger in younger patients. The trial coordinators state that thetreatments work even more effectively in younger patients. However, the reasonthat these results may occur is because older patients may not be able to toleratethe side-effects of the drug and therefore might withdraw early from the study,making it appear that the benefits are greater in young patients. The statementthat the treatment is not beneficial in older patients may also be made. In truth,the effect is not dependent on age but rather the ability of patients to tolerateside-effects. Therefore, neither statement about the young or old subgroups isentirely correct. If we had predefined that we would review the effect oftreatments in older and younger patients, we would have aimed to balance thegroups during recruitment and would soon have spotted that the groups do notremain balanced after randomization. We would, therefore, have seen the effectof drug side-effects on compliance from older patients.4. Reviewing existing data to seek support for the subgroup resultsMore credibility is given to subgroup analysis results if they are supported bysimilar results from previous independent trials or systematic reviews such asmeta-analyses (see Chapter 38).What factors should be considered when planninga subgroup analysis?If the primary outcome of the trial is related to factors other than the treatmentstrategies, such as age and gender, then these and other subgroups of interestfrom previous studies should be prespecified in the protocol with some biologicalrationale to support their choice. Stratifying randomization and analysis will helpreduce imbalance between the subgroups, thereby improving the accuracy ofsubsequent observations. However, if the size of the study is fixed, it might only bepossible to stratify randomization by a small number of characteristics, whichlimits the number of subgroups that can be predefined. The analysis shouldexamine the relationship between the primary outcome and only these fewprespecified subgroups. Subgroup analyses with outcomes occurring with a highfrequency in the study will also be more reliable than those investigatingrare events.270