When a computational model aims to be adopted beyond research purposes, e.g. to inform a clinical or regulatory decision, trust must be placed in its predictive accuracy. This practically translates into the need to demonstrate its credibility. In fact, prior to its adoption for regulatory purposes, an in silico methodology should be proven credible enough for the scope. This has become especially relevant as, although evidence of the safety and efficacy of new medical products or interventions has been traditionally provided to the regulator experimentally, i.e., in vivo or ex vivo, recently the idea to inform a regulatory decision in silico has made its way in the regulatory scenario. While a harmonised technical standard is currently missing in the EU regulatory system, in 2018 the ASME issued V&V40-2018, where a risk-based framework to assess the credibility of a computational model through the performance of predefined credibility activities is provided. The credibility framework is here applied to Bologna Biomechanical Computed Tomography (BBCT) solution, which predicts the absolute risk of fracture at the femur for a subject. BBCT has recently been the object of a qualification advice request to the European Medicine Agency. The full implementation of ASME V&V40-2018 framework on BBCT is shown. Starting from BBCT proposed context of use the whole credibility plan is presented and the credibility activities (Verification, Validation, Applicability) described together with the achieved credibility levels. BBCT risk is judged medium, and the credibility levels achieved considered acceptable. The uncertainties intrinsically present in the material properties assignment affected BBCT predictions to the highest extent. This work provides the practical application of the ASME V&V40-2018 risk-based credibility assessment framework, which could be applied to demonstrate model credibility in any field and support future regulatory submissions and foster the adoption of In Silico Trials.

In Silico Trials methodologies will play a growing and fundamental role in the development and de-risking of new medical devices in the future. While the regulatory pathway for Digital Patient and Personal Health Forecasting solutions is clear, it is more complex for In Silico Trials solutions, and therefore deserves a deeper analysis. In this position paper, we investigate the current state of the art towards the regulatory system for in silico trials applied to medical devices while exploring the European regulatory system toward this topic. We suggest that the European regulatory system should start a process of innovation: in principle to limit distorted quality by different internal processes within notified bodies, hence avoiding that the more innovative and competitive companies focus their attention on the needs of other large markets, like the USA, where the use of such radical innovations is already rapidly developing.

At present, the current gold-standard for osteoporosis diagnosis is based on bone mineral density (BMD) measurement, which, however, has been demonstrated to poorly estimate fracture risk. Further parameters in the hands of the clinicians are represented by the hip structural analysis (HSA) variables, which include geometric information of the proximal femur cross section. The purpose of this study was to investigate the suitability of HSA parameters as additional hip fracture risk predictors. With this aim, twenty-eight three-dimensional patient-specific models of the proximal femur were built from computed tomography (CT) images and a sideways fall condition was reproduced by finite element (FE) analyses. A tensile or compressive predominance based on minimum and maximum principal strains was determined at each volume element and a risk factor (RF) was calculated. The power of HSA variables combinations to predict the maximum superficial RF values was assessed by multivariate linear regression analysis. The optimal regression model, identified through the Akaike information criterion (AIC), only comprises two variables: the buckling ratio (BR) and the neck-shaft angle (NSA). In order to validate the study, the model was tested on two additional patients who suffered a hip fracture after a fall. The results classified the patients in the high risk level, confirming the prediction power of the adopted model.

Principal components analysis is a powerful technique which can be used to reduce data dimensionality. With reference to three-dimensional bone shape models, it can be used to generate an unlimited number of models, defined by thousands of nodes, from a limited (less than twenty) number of scalars. The full procedure has been here described in detail and tested. Two databases were used as input data: the first database comprised 40 mandibles, while the second one comprised 98 proximal femurs. The “average shape” and principal components that were required to cover at least 90% of the whole variance were identified for both bones, as well as the statistical distributions of the respective principal components weights. Fifteen principal components sufficed to describe the mandibular shape, while nine components sufficed to describe the proximal femur morphology. A routine has been set up to generate any number of mandible or proximal femur geometries, according to the actual statistical shape distributions. The set-up procedure can be generalized to any bone shape given a sufficiently large database of the respective 3D shapes.