Clinical Trials

❘❙❚■ Chapter 5 | Patient SelectionIntroductionThe aim of a clinical trial is to investigate the efficacy of an intervention in patientswith a particular disease or condition. When performing a trial, it is impossible toenroll every patient with the particular disease or condition – instead, a sample ofpatients is selected that represents the population of interest. It is thereforeessential that the selected sample truly reflects the population it represents, andthat the eligibility criteria are not so restrictive that they hamper recruitment orlimit the generalizability of the findings. Essentially, the findings from the trialshould have relevance to patients in future clinical practice, ie, the study shouldhave external validity or generalizability. In order to ensure generalizability, it isessential to have an understanding of the disease and its current treatmentoptions. However, eligibility criteria also serve the function of choosing a samplewho can tolerate being in a trial and those in whom there are less co-morbiditiesthat might dilute the effect of the intervention. Also, for clinical safety it isworthwhile selecting a sample who are less likely to have adverse effects (not theelderly or those on multiple co-therapies).ExampleDuring the planning of the CHARM (Candesartan in Heart failure – Assessmentof Reduction in Mortality and morbidity) trial, it was already known thatangiotensin-converting enzyme (ACE) inhibitors are beneficial to patients withsevere heart failure. Since the pharmacological targets of candesartan and ACEinhibitors are related, it seemed unethical to stop ACE inhibitor treatment inpatients already receiving this medication unless they were experiencing negative,drug-related side-effects. However, at the same time, it seemed valid to include agroup comprising patients with less severe heart failure who were not receivingACE inhibitors, since candesartan was expected to have some effects in patientswith preserved heart function. Therefore, the CHARM program consisted ofthree trial subpopulations [1] These subpopulations contained patients with:• severe heart failure on ACE inhibitor therapy (CHARM-Added)• severe heart failure who had ceased previous ACE inhibitortherapy due to side-effects (CHARM-Alternative)• heart failure despite preserved heart function (CHARM-Preserved)In this way, any benefit of candesartan could be demonstrated to be broadlygeneralizable to patients with heart failure, whilst ensuring that usefulcomparison groups for other specific situations were chosen.48