Part 9. Conclusions

Baruch Spinoza wrote “demonstrations are the eyes of the mind"[1]. By demonstration he meant something like “rigorous reasoning”. If we add “validated”, turning the definition into “rigorous and validated reasoning'', the philosopher aphorism (and rule of his own life) can be read: “models are the eyes of the mind". All the derivations above make this new version acceptable, at least intuitively. Our eyes associated with our brain transmit to our mind models of reality that help us to understand it and take action. This document was aimed at explaining how to justify and put into practice this aphorism in the field of therapeutic research.

In silico clinical trials, MIDD and M&S mark the advent of a new R&D paradigm. Accounting for both the complexity of the normal biology and the pathophysiology of diseases as well as intra- and inter-patient variability, it will enable the systematic exploration of virtually all possible hypotheses that cannot be tested in vivo or in vitro. It will address many of the relevant questions that current clinical development methodology omits and will help to tailor therapies to patients. Grounded in the Effect Model law, the methodological standard for in silico clinical trials, this new paradigm has two important consequences: First, critical decisions about a drug development program are based on a prediction of clinical benefit rather than intuition, serendipity and trial-and-error. Second, in vitro and in vivo trials are used to confirm in silico findings rather than to explore a necessarily limited number of hypotheses in the old paradigm. Proofs of concept exist and regulators are progressively paying attention, thus indicating the potential for widespread adoption. In silico clinical trials have the potential to become the cornerstone of clinical development in lieu of phase 3 trials, where the role of phase 3 trials would change from exploring clinical efficacy to confirming clinical outcomes predicted in silico.

The NOVA approach can solve a problem with the feasibility of the rigorous evaluation of therapy benefit/risk, noted decades earlier for non established care practices: “The number of medical practices that are candidates for RCTs far exceeds the research community's capacity to perform them”[2].