BBCT Briefing Book Document submitted to EMA

The In Silico World consortium recently submitted a qualification advice request to the European Medicine Agency (EMA) for the so-called Bologna Biomechanical Computed Tomography (BBCT) methodology, developed by researchers at the University of Bologna.

BBCT belongs to a new category of methods referred to as “in silico trials”, where the response biomarker used to follow body processes and diseases in humans and animals is not measured but rather predicted by a computer model.

In particular, BBCT-hip predicts an Absolute Risk of Fracture at time 0 (ARF0), a surrogate biomarker of the risk of femur fracture in osteoporotic patients, which could be employed in Phase II and some Phase III Clinical Trials to assess the efficacy of new osteoporosis treatments in place of the currently used biomarker, the areal Bone Mineral Density (aBMD). Although the aBMD is correlated to the risk of fracture, it is a limited fracture predictor, and ARF0 has been shown to have better stratification accuracy.

Technically speaking, BBCT-hip simulates 1,000,000 falls of a body of height and weight equal to those of the subject. For each simulated fall the resulting impact forces on the femur are calculated. ARF0 is computed as the ratio of the number of simulated falls causing fracture and the total number of simulated falls. A fall is said to cause fracture when it exceeds the load to failure (the intensity of the force required to fracture the femur) estimated based on a patient-specific Finite Element (FE) model informed by the QCT of the patient.

The importance of this tool is twofold: on one side, osteoporosis takes a huge social and economic toll as in the EU 22 million women and 5.5 million men suffer from this disease. On the other side, we are convinced that BBCT-hip is capable of providing a surrogate of the fracture endpoint in clinical trials which is significantly more accurate than aBMD. Due to the prohibitive cost and duration of clinical trials which employ fracture as an endpoint, aBMD can be usually found in Phase II or supportive Phase III studies as the primary outcome to assess the efficacy of new drugs, despite its inability to mechanistically capture potentially important elements of bone strength.

Our consortium aims at lowering seven of the most important barriers to the wider adoption of in silico trials, and in this perspective, the project will support the trajectory of BBCT solution through the entire product lifecycle, encompassing development, validation, regulatory approval, optimisation, and commercial exploitation.

The Briefing Document submission to the Scientific Advice Working Party (SAWP) of EMA is the first step towards this ambitious goal.