Workflow structure
The reproducible pharmacometric workflow was designed in consensus between the pharmacometricians, clinicians, and data managers within the project, and is shown in Fig. Overview of the pharmacometric reproducibility workflow. Clinical operations were the initial start of the workflow, but because of its circularity, and ongoing clinical operations throughout the trial parallel to the data processing, the workflow was performed repeatedly. The black boxes represent the clinical team, purple boxes represent the data management team, magenta boxes represent the pharmacometric team, and orange box represent the independent data safety monitoring board (DSMB). All processes were blinded until the end of the clinical trial, after which the data report per arm and the DSMB contained the unblinded data. eCRF = electronic case report form, QC = quality control.After resolving all queries, the pharmacometric processing script produced two types of output. Firstly, the script automatically generated two data reports for frequent review; an aggregated report and a per-arm closed report. The aggregated data report, with treatment arms combined to prevent investigator unblinding or bias, was presented to the data safety monitoring board (DSMB) during the open session of their meeting, where the clinical team was present. The closed data report for the DSMB conversely showed the clinical trial data separated per arm but still blinded during the trial. Second, the pharmacometric processing script prepared for the different pharmacometric analyses, by graphical exploration of the data and data parsing to datasets for non-linear mixed effects modelling, of which the results were also presented to the clinical team and the DSMB. Collaboration on, and interoperability of, the pharmacometric processing script was essential between the different members of the pharmacometric team, which are working on the same reporting and analyses in parallel. To facilitate coding within the same script, the members of the pharmacometric team worked together in a private Github repository through Github Desktop (v.2.9.4) which at the same time ensured the script’s version control.