The EMA (European Medicines Agency) proposed strategy on Regulatory Science to 2025 recognizes the importance of emerging technologies in general and modelling and simulation, also known as in silico methods, in particular. However, the document tends to stress the value of in silico methods almost exclusively in connection with the reduction of animal experimentation. While we agree that this is a relevant application for such methods, it is not the only one and likely not the most impactful one for the patient and for the industry. The term In Silico Trials indicates a number of use cases, not only related to pre-clinical evaluation, but also to the reduction, refinement, and in some cases even replacement of clinical trials.

The cost of healthcare is a growing problem. In higher income countries the raising costs associated with the aging population and the resulting greater expectation of care are challenging the financial sustainability of universal healthcare models. In lower income countries the accessibility to pricey new therapies is a major issue.  Everywhere, as we are successful in treating the most common conditions, the burden of disease moves to rarer conditions (rare diseases) and to subgroups within common conditions that respond poorly to the standard of care for that disease.

All these challenges are quite different from each other, but all share one common factor: the cost of innovation in healthcare is too high and the pace of medical innovation clearly too slow. This has two components: we already harvested all the low-hanging fruits, and now only very complex therapeutic targets are left, for which the traditional “trial and error” approach is falling short. The second is that growing (and fair) social pressure for safer and effective medical products is increasing the cost, complexity and duration of the regulatory process. While there is disagreement on the absolute values, all experts agree that the cost to develop and bring to market a new medical product has been raising exponentially in the last 30 years.

In every other industrial sector this problem has been solved by adopting and widely deploying modelling and simulation. From aerospace to automotive, from civil nuclear to chemical and energy industry, the safety and performance of new products, including their regulatory assessment, is done “In Silico”.  It is time we pursue the same revolution for medical products.

There is now a variety of predictive technologies for life sciences: bioinformatics, systems biology, computational biochemistry, physiology-based pharmacokinetics, physiology-based and biophysics-based mechanistic models, non-linear system identification methods, Bayesian modelling, Big Data Analytics, and analytical artificial intelligence methods, just to name a few.  Each is well suited for a specific class of problems, but all together provide a formidable set of methods, that can be used to develop “In Silico” trials, that can complement, supplement, or in some cases even replace conventional clinical trials.

In Silico Trials could radically change the regulatory process. When new evidences impose more stringent regulatory scrutiny, for example when new adverse effects and failure modes are observed clinically, adding a new safety evaluation would be less demanding than it is now: extending In Silico Trials to evaluate the risk for one additional adverse event is much simpler, cheaper and faster than doing this experimentally. During an event at the European Parliament on September 4th, 2018, the Irish based company Medtronic reported[1] that using computer models for regulatory approval enabled them to release their new pacemaker 2 years earlier, allowing them to treat 10,000 patients and saving 10 Million Euro of testing cost.

Almost every day regulators worldwide are authorizing in Silico technologies that are directly used in the therapeutic pathway as decision-support systems, through the “software as a medical device” regulatory pathway. If computer models can guide the diagnostic, prognostic, or therapeutic decision for individual patients, why should they not be able to advise on the safety and efficacy of new medical products?

We are convinced that regulators such as EMA must play a key role as In Silico Trials are introduced. Like every disruptive technology it brings promises of drastic reduction in the cost of innovation and the time to market, but also new, and substantially different, risks. Thus, the safe adoption of In Silico Trials should be at the core of the EMA strategy, and not only in connection with the reduction of animal experimentation.

There are a number of challenges for EMA associated with adoption of in Silico Trials, but a major one is that this “technologization” of the regulatory process requires different skills within EMA and among the advisory panels. As EU universities are starting only now to train specialists in In Silico Trials, it is reasonable to foresee a shortage of skilled workforce in this area in the next few years, which requires a strategic reflection.

Another challenge is that the FDA is clearly leading the way in relation to the use of In Silico Trials for the regulatory evaluation of medical devices, but, if we move quickly enough, there is an opportunity for the European Union to lead this revolution for the medicinal products and for Advanced therapy medicinal products. On the other hand, in the spirit of “collaborative competition” there is an urgent need for a harmonization effort between EMA, FDA, and other regulators around In Silico Trials.

Yet another challenge is that while there is a massive experience on the credibility assessment of predictive models in other industrial domains, In Silico Trials pose specific issues in terms of regulatory science. Dedicated research within the Horizon Europe program may be required, and EMA must play a central role in it.

In conclusion, we believe that it is important to recognize the huge potential that In Silico Trials have, not only in relation to animal alternatives, but also on the need to reduce the cost of innovation in healthcare. The adoption of In Silico evidences in the regulatory process poses a number of challenges, which need to be addressed at the strategic level. Thus, we recommend EMA to consider the inclusion in their strategic plan of a specific goal associated to the adoption of In Silico Trials.

Prof Marco Viceconti – Alma Mater Studiorum, University of Bologna

Prof Liesbet Geris – Executive Director, VPH Institute

Dr Thierry Marchal – Secretary General, Avicenna Alliance

Prof Claudia Mazzà – Executive Director, Insigneo Institute for in silico Medicine

[1] International Avicenna Alliance Report, avicenna-alliance.com/conference-2018/conference-report-and-video/