The Virtual Anemia Trial: An Assessment of Model-Based In Silico Clinical Trials of Anemia Treatment Algorithms in Patients With Hemodialysis

Abstract

In silico approaches have been proposed as a novel strategy to increase the repertoire of clinical trial designs. Realistic simulations of clinical trials can provide valuable information regarding safety and limitations of treatment protocols and have been shown to assist in the cost-effective planning of clinical studies. In this report, we present a blueprint for the stepwise integration of internal, external, and ecological validity considerations in virtual clinical trials (VCTs). We exemplify this approach in the context of a model-based in silico clinical trial aimed at anemia treatment in patients undergoing hemodialysis (HD). Hemoglobin levels and subsequent anemia treatment were simulated on a per patient level over the course of a year and compared to real-life clinical data of 79,426 patients undergoing HD. The novel strategies presented here, aimed to improve external and ecological validity of a VCT, significantly increased the predictive power of the discussed in silico trial.

Figure 1

Setup schematic of Virtual Anemia Trial (VIAT) 3.0. Blue boxes indicate “deterministic” modules: the simulation of hemoglobin values for each Avatar using the physiology based mathematical model and the calculation of a new dose following the anemia therapy protocol. Green boxes indicate modules of “stochastic” nature. VIAT 3.0 comprises modules simulating the (random) impact of the involved laboratory (e.g., measurement noise), physician (e.g., blood transfusion orderings), dialysis facility (e.g., nonadherence of patients to therapy), and hospital (e.g., hospital stays). ESA, erythropoiesis stimulating agent.

Figure 2

Mean absolute percentage errors (MAPE) between model simulation and individual patient data. Density of MAPE of hemoglobin levels between empirical patient data and all avatars during the model adaptation period.

Figure 3

Comparison of clinical data of the comparator group and simulations obtained from Virtual Anemia Trials (VIAT). Empirical data is shown in blue across all panels; comparisons to results from VIAT 1.0, VIAT 2.0, and VIAT 3.0 are depicted in the top, middle, and bottom row, respectively. Panels (a), (c), and (e) exhibit the distribution of empirical hemoglobin (Hgb) values routinely measured in the clinics over the course of a year (blue) and simulated Hgb values for an entire year as obtained from VIAT 1.0 (orange), VIAT 2.0 (red), and VIAT 3.0 (green). Panels (b), (d), and (f) show the corresponding frequencies of empirical (blue) and simulated (orange, red, and green) erythropoiesis stimulating agent (ESA) doses.

Figure 4

Spline curves representing the relationship between hemoglobin (Hgb) and erythropoiesis stimulating agents (ESA). Blue curves represent Hgb‐ESA splines corresponding with clinical data in both panels (a,b). Results from Virtual Anemia Trials (VIAT) 2.0 and 3.0 is overlaid in red and green, respectively, a and b. Spline curves were derived from a general additive model using the cumulative monthly ESA dose and monthly average Hgb for each patient each month.