Clinical trialist perspectives on the ethics of adaptive clinical trials: a mixed-methods analysis

Abstract Background In an adaptive clinical trial (ACT), key trial characteristics may be altered during the course of the trial according to predefined rules in response to information that accumulates within the trial itself. In addition to having distinguishing scientific features, adaptive trials also may involve ethical considerations that differ from more traditional randomized trials. Better understanding of clinical trial experts’ views about the ethical aspects of adaptive designs could assist those planning ACTs. Our aim was to elucidate the opinions of clinical trial experts regarding their beliefs about ethical aspects of ACTs. Methods We used a convergent, mixed-methods design employing a 22-item ACTs beliefs survey with visual analog scales and open-ended questions and mini-focus groups. We developed a coding scheme to conduct thematic searches of textual data, depicted responses to visual analog scales on box-plot diagrams, and integrated findings thematically. Fifty-three clinical trial experts from four constituent groups participated: academic biostatisticians (n = 5); consultant biostatisticians (n = 6); academic clinicians (n = 22); and other stakeholders including patient advocacy, National Institutes of Health, and U.S. Food and Drug Administration representatives (n = 20). Results The respondents recognized potential ethical benefits of ACTs, including a higher probability of receiving an effective intervention for participants, optimizing resource utilization, and accelerating treatment discovery. Ethical challenges voiced include developing procedures so trial participants can make informed decisions about taking part in ACTs and plausible, though unlikely risks of research personnel altering enrollment patterns. Conclusions Clinical trial experts recognize ethical advantages but also pose potential ethical challenges of ACTs. The four constituencies differ in their weighing of ACT ethical considerations based on their professional vantage points. These data suggest further discussion about the ethics of ACTs is needed to facilitate ACT planning, design and conduct, and ultimately better allow planners to weigh ethical implications of competing trial designs.http://deepblue.lib.umich.edu/bitstream/2027.42/111302/1/12910_2015_Article_22.pd

Automated Quantification of Choriocapillaris Lesion Area in Patients with Posterior Uveitis.

PURPOSE To validate a custom algorithm for automated identification and quantification of clinically relevant inflammatory choriocapillaris (CC) lesions from en face swept source optical coherence tomography (SS-OCTA) images. DESIGN observational case series METHODS: : Twenty eyes of 14 patients with posterior uveitis were imaged using the PLEX® Elite 9000. The machine-generated en face OCTA CC slabs were exported to MATLAB where a custom algorithm performed unsupervised lesion boundary delineation and area quantification. Lesions identified by the algorithm (AG) were compared to those identified by two masked human graders (HG1 and HG2), using the Sørensen-Dice coefficient (DSC) and intraclass correlation coefficient (ICC). Intra-grader and intra-visit reliability were determined by coefficient of variation (CV) and DSC. RESULTS The AG demonstrated excellent agreement with both HGs in determination of lesion area (HG1 vs. AG ICC 0.92, 95% CI 0.81-0.97, HG2 vs. AG ICC 0.91, 95% CI 0.78-0.97). The AG demonstrated good spatial overlap (DSC≥0.70) with both HGs in 14/20 (70%) eyes and at least one HG in 16/20 (80%) eyes. Poor spatial overlap (DSC between 0.31 and 0.69) was associated with the presence of a choroidal neovascular membrane and low contrast lesion boundaries. Intra-visit repeatability for the AG was superior to both HGs (CV 2.6% vs >5%). CONCLUSION This custom algorithm demonstrated a high degree of agreement with human graders in identification of inflammatory CC lesions, and outperformed human graders in reproducibility. Automated CC lesion delineation will support the development of objective and quantitative biomarker of disease activity in patients with posterior uveitis