Clinical Trials

❘❙❚■ Chapter 26 | ConfoundingWhat is confounding?A confounding factor is a variable that is related to both the treatment beinginvestigated and the outcome [1,2]. Consider a hypothetical study in which drug Xproduces an overall reduction in the number of deaths of patients with hypertensioncompared with standard therapy. For screening purposes, a chest X-ray is performedbefore randomization and later it is found that half of the patients in the standardtherapy arm have lung cancer compared with none in the drug X group. On closerinspection, the rate of death in the patients diagnosed with cancer was found to befour times higher than in the group of patients without cancer. From these laterobservations, we can state that the reason that drug X appeared to do better wasbecause the patients in the standard therapy group suffered a higher rate of lungcancer deaths. Therefore, lung cancer is a confounder for the relationship betweendrug X and the likelihood of death in the study, since lung cancer (a cause ofpremature death) is unevenly distributed between the two treatment groups.Confounders are more usually a problem in observational studies, wherethe exposure of a risk factor is not randomly distributed between groups [3]. Anexample from epidemiology would be a hypothetical observational study conductedto assess the effect of the type of work undertaken by mothers during pregnancy(office or manual) on the birth weight of the baby. Let us say that the results showedthat babies born to women with manual jobs had a lower birth weight than those bornto women working in offices. However, it is also established that the type of workdone during pregnancy is associated with other maternal characteristics and thewoman’s age and nutritional status. Furthermore, these maternal characteristics arealso known to be associated with the weight of the baby. Therefore, it is possible thatour observed association between the type of work undertaken during pregnancy andthe birth weight of the baby is due to these other characteristics. These characteristicsare considered to be confounding variables if they falsely accentuate the relationshipbetween a perceived risk factor and the outcome of pregnancy.Sometimes confounders are inherent in the design of early-phase clinical trials. Forexample, dose-titration studies are used to assess the dose–response relationship indrug development [4]. In a dose-titration study, a subject will only receive the nexthigher dose if he/she fails to meet some objective response criterion at the currentdose level, such as a reduction of systolic blood pressure by a prespecified amount.The major problem in this case is that the dose–response relationship is oftenconfounded with time course – it can be argued that the relationship found in adose-titration study is not due to the dose, but rather to some other factor related tothe time course, such as the total length of time the patient is exposed to the drugirrespective of dose concentration.296