The Medical Futurist | August 10, 2019
Traditional clinical trials are equivalent of billions of dollars and years of hard work with no guarantee for the new drug to be approved by regulatory bodies, not to speak about the dangers of testing medication on animals and/or humans. What if we could take a radical turn? What if we conducted clinical trials on virtual bodies that could perfectly mimic human physiology? With the help of artificial intelligence, enhanced computer simulations, and advances in personalized medicine, in silico trials might be a reality in the coming years.
The magic expression is in silico
As technologies transform every aspect of healthcare, medicine, and the pharma industry, the monstrous clinical trial enterprise cannot be left out either. One way to modernize the drug testing process is applying technologies to the traditional framework, for example through online platformsto seek out participants; while an alternative way is to build a completely new setting. Human organs-on-chips and in silico trials represent the second approach. Researchers of the Wyss Institute have been working on the first strand, human organs-on-chips for years. These microdevices lined by living human cells can mimic the microarchitecture and functions of human organs, and this makes them ideal for replacing clinical testing.
Going one Neil Armstrong-step further, we arrive at in silico trials: no humans, no animals, not even a single cell is required, and yet the impact of any given therapy, treatment option, or drug can be perfectly charted. In silico is the term scientists use to describe the modeling, simulation, and visualization of biological and medical processes in computers. The emergence of in silico medicine is a result of the advance of medical computer science over the last 20 years.
Modeling maps the elements of a biological system, simulation attempts to realistically show how that system evolves over time under given stimuli, and visualization presents the predictions in a graphic form. When looking at an in silico clinical trial specifically, it means an individualized computer simulation used in the development or regulatory evaluation of a medicinal product, device, or intervention. While completely simulated clinical trials are not feasible with current technology and understanding of biology, its development would be expected to have major benefits over current in vivo clinical trials, and the FDA is already planning for a future in which more than half of all clinical trial data will come from computer simulations.
All gain, no pain
The main advantage of in silico trials resides in the context of simulations: the effects of new drugs or treatment options are played out in a virtual setting without real consequences for either animals or humans. They also enhance personalized medicine: these processes allow doctors to try out treatment plans, get to know the behavior of drugs or identify the most appropriate drug dosage.
With the advancement of cognitive computing and bioinformatics, it becomes possible to simulate real biological processes in virtual settings through the use of big data. The computational environment enables researchers to build circulatory, neural, endocrine, metabolic systems – or anything else using these enormous volumes of data sets. As a final objective, these individual layers of the human physiology could be combined to capacitate the examination of the human body as a whole. The ultimate results are faster and more flexible clinical trials and a significant reduction in costs.
Moreover, artificial intelligence can also provide answers to the usually asked question: “why does this work for this patient but not another one?” A.I-building methods, namely machine learning and deep learning have the potential to train a model that will then be able to find patterns and clusters in otherwise unstructured data – and seek out information researchers didn’t expect to be there. In addition, neural networks can be used to predict adverse events or to anticipate the possible risk of patient drop out and compliance to the treatment.
Virtual humans everywhere
While in silico medicine is still in its infancy, there are many promising examples that show the potential for traditional clinical trials to disappear within a couple of years.
HumMod is one of the most advanced simulations to date. It provides a top-down model of human physiology from whole organs to individual molecules. It features more than 1,500 equations and 6,500 variables such as body fluids, circulation, electrolytes, hormones, metabolism, and skin temperature. HumMod aims to simulate how human physiology works, and claims to be the most sophisticated mathematical model of human physiology ever created. Various research projects used HumMod already, for example, to create a heterogeneous population of thousand virtual patients by randomly varying physiological parameters to examine how reduced renal mass could play a role in causing salt-sensitive hypertension.
Another great example of the advancement of the field is the Oncosimulator project. The In Silico Oncology Group is developing an in silico experimental platform, as well as an advanced medical decision support tool called Oncosimulator in collaboration with several research centers in Europe and Japan to optimize cancer treatment. The oncosimulator is an integrated software system simulating in vivo tumor response to therapeutics within a clinical trial environment. It aims to support clinical decision-making for individual patients.
As an excellent cross-industry collaboration, the Virtual Physiological Human Institutehas to be mentioned. It is an international non-profit organization, whose mission is to ensure that the Virtual Physiological Human (VPH) is fully realized, universally adopted, and effectively used both in research and clinical settings. Various medical fields can collaborate through the VPH framework, for example, the CARDIOPROOF initiative brought together more than 170 cardiologists to create new, personalized tools for the management of congenital heart disease through advanced computer models. They claim that the web-based application could reduce hospital expenditures by up to 15 percent per patient. Another similar initiative is the Osteoporotic Virtual Physiological Human Project to predict the risk of fracture in patients with low bone mass. Nevertheless, the list could go on and on.
In silico models for regulators?
Recent developments show that not only pharma companies and medical facilities could make use of in silico medicine. The U.S. Food and Drug Administration also picked up on the potential of in silico trials and it’s actively supporting the development of virtual models – for the testing of new medical devices.
Early August, the FDA issued a request for computational software and services modeling the whole human heart to incorporate in a project that aims to evaluate new medical devices and therapies. In 2014, the FDA initiated its collaboration with French company Dassault Systémes around their simulated 3D heart model, which the duo used to test pacemakers and other cardiovascular devices. Through the new project, researchers will incorporate virtual patients and testing to quicken the pace in which devices are tested and adopted. Ultimately, the agency aims to use digital evidence and computer modeling to tackle the delays and costs that hinder patients from getting their hands on new drugs, treatments, or devices.
We firmly believe that drug development and new therapy experimentation will largely happen through in silico trials in the future since who would want to test new drugs on animals or humans if we have the possibility to accurately measure the consequences of novel medications or treatment paths virtually. Although we have to mention that regulators will face a new, so far unknown challenge here: they will have to let more and more personalized, cheaper, and more efficient drugs be introduced on the market without being tested on actual humans for years.