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.

System-based approaches as prognostic tools for glioblastoma

“…A key idea is the shift from real-world clinical trial testing a single treatment option on many, mostly unselected, patients to first test in silico several treatment options, both approved or repurposed, for each individual patient. Importantly, mathematical models can also optimize the dosage and scheduling of the selected treatment [141, 162, 164–166].…”

The Role of Eryptosis in the Pathogenesis of Renal Anemia: Insights From Basic Research and Mathematical Modeling

“…Individual patients were represented by a patientspecific parameter set (RBC life span, ESA half-life, endogenous Epo levels, and effective parameters accounting for the ESA's effect on erythroid progenitor apoptosis and maturation velocity) capturing their erythropoiesis-related physiology (Fuertinger FIGURE 5 | Estimation of physiological parameters in a HD patient population using a physiology-based model of erythropoiesis (Fuertinger et al, 2013). Shown are relative frequencies of estimated RBC life span (left) and endogenous Epo levels (right) obtained from patient-individual model adaptations to hemoglobin and ESA administration data of 6,659 HD patients, resulting in a virtual patient population (Fuertinger et al, 2018b) (see the main text for details).…”

“…10.2 U/L, 21.1 U/L). The relative frequencies of estimated RBC life spans and endogenous Epo levels among the population of virtual patients reported in Fuertinger et al (2018b) are shown in Figure 5.…”

“…This model explicitly represents the proliferative hierarchy of erythroid progenitor populations in the bone marrow including the dynamics of cell birth, maturation, differentiation, and apoptosis; in this modeling scheme, Epo acts as a regulator of apoptosis of the colony-forming unit-erythroid (CFU-E) and erythrocyte populations. Previously, this model has been adapted on a patient-individual level to a large population of HD patients treated with methoxy polyethylene glycol-epoetin beta (6,659 patients randomly sampled from a U.S. HD population comprising over 37,000 patients) ( Fuertinger et al, 2018b ). These model adaptations were carried out such that previously recorded hemoglobin responses to ESA therapy for the specific patient were described by the model within a predefined accuracy.…”

“…These model adaptations were carried out such that previously recorded hemoglobin responses to ESA therapy for the specific patient were described by the model within a predefined accuracy. Individual patients were represented by a patient-specific parameter set (RBC life span, ESA half-life, endogenous Epo levels, and effective parameters accounting for the ESA’s effect on erythroid progenitor apoptosis and maturation velocity) capturing their erythropoiesis-related physiology ( Fuertinger et al, 2018b ). Although iron availability is not an explicit part of the model, its effects are implicitly present in the effective bone marrow-related parameters.…”