In silico assessment of biomedical products: the conundrum of rare but not so rare events in two case studies

In silico clinical trials, defined as “The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention,” have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients’ phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern

Human cortical bone: the SINUPROS model.

International audienceSeveral modelizations have been investigated on human cortical bone in our team and we have often observed that the introduction of a new geometrical parameter induces significant perturbations on the numerical values obtained with previous models. We have therefore decided to take into account the totality of all possible parameters in a modelization which is physically and physiologically plausible. In order to do this, we have analyzed the architecture of cortical bone and exhibited all parameters that occur. To determine physical properties at each architectural level, the best adapted tool is without any doubt the mathematical theory of homogenization. All the necessary algorithms have been implemented into SINUPROS software (websites of the Universities). Its main interest is the evaluation of macroscopic physical properties for a given configuration. It can also be used to seek, by successive tests, configurations corresponding to properties experimentally measured. Computation time being too high (10 to 45 minutes according to tested configurations), a fast version based on approximation theory has been developed and thus the obtaining of the results is immediate. The researched configuration being thus obtained, it has then to be validated by the original version

Human cortical bone: the SiNuPrOs model. Part II--a multi-scale study of permeability.

International audienceCortical bone is more and more considered as a porous medium and this induces the necessity of the determination of the physical properties associated with such a concept: the porosity and the permeability. If porosity does not present a major problem, at least for the order of magnitude, there is a difficulty for the permeability. According to experimental sources, values vary between 10(- 13) and 10(- 23) m(2): it seems obvious that the same entities have not been measured. This article proposes a new vision of the permeability based on a concept of multi-scale medium corresponding to the scales already introduced in the SiNuPrOs model which has been developed for cortical bone. According to this model, several architectural levels are proposed and a mathematical development based on the homogenisation theory, which can be applied to each of these levels, allows a numerical computation of the permeability tensor coefficients. A comparative analysis of our simulations and some experimental results (already published) shows a good accordance with the literature