Part 9. Conclusions
Baruch Spinoza wrote "demonstrations are the eyes of the mind"[1]. By demonstration he meant something close to rigorous reasoning. Add "validated", making it rigorous and validated reasoning, and the aphorism, which was also the rule of his own life, can be read as: models are the eyes of the mind. Everything above makes that version acceptable, at least intuitively. Our eyes and our brain transmit to our mind models of reality that help us understand it and act on it. This document set out to justify that aphorism in therapeutic research, and to show how to put it into practice.
In silico clinical trials, MIDD, and M&S mark a new R&D paradigm. By accounting for the complexity of normal biology and disease pathophysiology, and for intra- and inter-patient variability, it allows systematic exploration of virtually every hypothesis that cannot be tested in vivo or in vitro. It addresses many of the questions current clinical development methodology leaves out, and it helps tailor therapies to patients. Grounded in the Effect Model law, the methodological standard for in silico clinical trials, the paradigm has two important consequences. First, critical decisions about a drug development program rest on a prediction of clinical benefit rather than on intuition, serendipity, and trial and error. Second, in vitro and in vivo trials confirm in silico findings rather than explore a necessarily limited number of hypotheses. Proofs of concept exist and regulators are progressively paying attention, which points to wider adoption. In silico clinical trials could become the cornerstone of clinical development in place of phase 3 trials, with the role of phase 3 shifting from exploring clinical efficacy to confirming the clinical outcomes predicted in silico.
Nova's approach also addresses a feasibility problem in rigorously evaluating therapy benefit and risk, noted decades ago for care practices that were not yet established: "The number of medical practices that are candidates for RCTs far exceeds the research community's capacity to perform them"[2].
1. The full quotation is “demonstrations are the eyes of the mind, by which the mind sees and observes things" (Ethics, V, p23S). Spinoza was also a physicist - he collaborated with Christiaan Huygens - and a mathematician: he worked on what later became the theory of probability. ↩︎
2. Kahan JP, Neu CR, Hammons GT, Hillman BJ. The Decision To Initiate Clinical Trials of Current Medical Practices. Rand Corporation, 1985 ↩︎