Methodologies to Avoid the Enrollment of Ineligible Patients in Clinical Trials

Abstract

As the authors point out, failed psychopharmacologic randomized controlled trials are common but poorly understood. In the companion article,2 the authors describe the analyses from computer-based assessments to examine the impact of eligibility criteria in more detail. The major finding was that, on the basis of computer assessments, nearly two-thirds of randomized subjects failed to meet at least 1 protocol-specified eligibility criterion. As the authors indicate, the enrollment of ineligible subjects may contribute to the failure of acute psychopharmacologic efficacy studies. Computer assessments may no doubt not only control rater bias but also influence the responses of subjects of investigation. As the authors recognize, the study does not measure the benefits of the site monitoring system nor does it establish that computer assessments of any of the eligibility criteria are superior to those of a well-trained site-based rater. A key message is that we need to improve the validity and reliability in the way we establish eligibility criteria and symptom severity. Possible solutions to this problem include improving the training of site raters and using central raters through videoconferencing or with the assistance of computer-generated ratings. The authors’ results provide valuable information to improve the design of clinical trials. The fact that, according to the computer assessment, close to two-thirds of patients did not meet eligibility criteria for diagnosis and symptom severity is concerning—such a large proportion of subjects in any study would lead to biased assessments. Failing to find a difference when one exists or finding spurious differences is concerning. The presented data suggest that a better signal detection will be reached when the eligibility of subjects is established with highest possible confidence, which, in this case, was achieved with the help of computer-administered assessments. Advantages of computer-administered ratings may include consistency of metrics across subjects of investigation and sites, but this system may also miss information that can be captured only by well-trained clinician raters. To summarize, we applaud the publication of negative/ failed data, but, more importantly, we value the attempt to find solutions to deal with challenges that contribute to the failure of clinical trials with psychotropic agents. By improving our clinical trial methodology, we will be able to find better and safer treatments for our patients.