Biomarker context-of-use: how organizational design can impact the implementation of the appropriate biomarker assay strategy.

Since 2011, the European Bioanalysis Forum has been discussing the topic of context-of-use for biomarker assays, in support of a cross-industry implementation of its principles. The discussions have led to the acknowledgement of the challenges that we face as an industry in implementing these principles. In addition to scientific recommendations, the European Bioanalysis Forum has addressed these challenges by providing recommendations on organizational design, and what works in both sponsor and contract research organizations, to support and enable context-of-use across biomarker strategies. Here, we highlight the key considerations for organizational design to help ensure that biomarker assays are characterized and validated according to the right context-of-use, to ensure that the right decisions based on the biomarker data can be made during drug development.

Relationships of circulating CD4+ T cell subsets and cytokines with the risk of relapse in patients with Crohn's disease.

Background and aims: We aimed to analyze circulating CD4+ T cell subsets and cytokines during the course of Crohn's disease (CD). Methods and results: CD4+ T cell subsets, ultrasensitive C-reactive protein (usCRP), and various serum cytokines (IL-6, IL-8, IL-10, IL-13, IL-17A, IL-23, TNFα, IFNγ, and TGFß) were prospectively monitored every 3 months for 1 year, using multicolor flow cytometry and an ultrasensitive Erenna method in CD patients in remission at inclusion. Relapse occurred in 35 out of the 113 consecutive patients (31%). For patients in remission within 4 months prior to relapse and at the time of relapse, there was no significant difference in Th1, Th17, Treg, and double-positive CD4+ T cell subsets co-expressing either IFNγ and FOXP3, IL-17A and FOXP3, or IFNγ and IL-17A. On the contrary, in patients who remained in remission, the mean frequency and number of double-positive IL-17A+FOXP3+ CD4+ T cells and the level of usCRP were significantly higher (p ≤ 0.01) 1 to 4 months prior to relapse. At the time of relapse, only the IL-6 and usCRP levels were significantly higher (p ≤ 0.001) compared with those patients in remission. On multivariate analysis, a high number of double-positive IL-17A+FOXP3+ CD4+ T cells (≥1.4 cells/mm3) and elevated serum usCRP (≥3.44 mg/L) were two independent factors associated with risk of relapse. Conclusions: Detection of circulating double-positive FOXP3+IL-17A+ CD4+ T cell subsets supports that T cell plasticity may reflect the inflammatory context of Crohn's disease. Whether this subset contributes to the pathogenesis of CD relapse needs further studies.