LAUSR

World Psychiatry 22:1 February 2023 adequate and well-controlled clinical investigation, and specifically mentions other types of controls – such as active treatment concurrent control and no treatment concurrent control – in addition to placebo concurrent control. Placebo-controlled trials are often favored and chosen by sponsors because they typically produce the most readily interpretable results. Regarding generalizability of clinical trial results, Correll et al note that many “real world” patients would not qualify for pharmaceutical trials because of comorbidities. Sponsors should be prepared to justify their exclusion criteria, focusing on comorbidities that are expected to complicate interpretation of the study or decrease the likelihood of detecting an effect (e.g., active substance use disorders). The paper suggests requiring post-marketing studies to examine drug efficacy in “real world” patients; however, the FDA does not have the statutory authority to require such studies. Correll et al describe scenarios in which rapid recruitment may impact study quality. Baseline symptom inflation and diagnostic imprecision may speed recruitment but will also make demonstrating efficacy more difficult. Although small sites may be a source of heterogeneity, they may simply be recruiting judiciously. Therefore, we recommend caution regarding the suggestion to drop poorly recruiting sites early in the study. We agree that some new technologies might have the potential to improve assessments; however, before incorporating novel assessments (e.g., digital endpoints), we recommend that sponsors submit supportive evidence that the technology is fitfor-purpose. For example, a computerized system for assessing patient speech may seem to be an improvement on established subjective clinician ratings. However, it is the subjective clinical ratings which would have been tied to dysfunction and prognosis. Unless the computerized system also reflects dysfunction and prognosis, it may not be fit-for-purpose. Additionally, sponsors should ensure that including technology does not discourage or prevent certain groups from enrollment or introduce unanticipated biases. Sponsors should discuss novel statistical approaches with regulatory authorities prior to starting clinical trials. Regarding the suggestion to use an endpoint that reflects symptom course over time (rather than at discrete time points), this may or may not be acceptable for a given trial. Such averaged endpoints may reflect improvement at the start of a trial that is lost as the trial progresses, leading to questions about the durability of effect. Before attempting something novel in a development program, sponsors should meet with regulatory authorities, which can often refer companies to pertinent publi shed guidances, help think through regulato ry requirements, and use experience from other programs to offer recommendations.