Today we meet Andrew Worth, Senior Scientific Officer and Group Leader at the European Commission’s Joint Research Centre in Ispra (IT), and Alicia Paini, researcher in the same group who specialises in physiologically based kinetics model to evaluate the toxicity of chemicals.
Q: Can you tell us something about you, your background, and your role in your organisation?
Alicia Paini: We work at the Joint Research Centre (JRC), which is the European Commission's science and knowledge service. The role of the JRC is to support EU policy makers with independent scientific evidence throughout the whole policy cycle. As scientific officers within the JRC, we work at the science-policy interface, in particular in relation to policies on chemical safety, consumer protection, the environment, and on the protection of the animals used for experimental purposes. This is in line with the mandate of the European Union Reference Laboratory for alternatives to animal testing (EURL ECVAM), which recently published a relevant report. My own background is in food science, technology and food safety; PhD in Toxicology. I gained know-how in the generation of data to develop physiologically based kinetic (PBK) models for genotoxic chemicals and developed these models for risk assessment. Now I am working on implementing, promoting and gaining acceptance of in silico models for application in regulatory decision making.
Andrew Worth: I have a background in biochemistry, physiological sciences, linguistics, and computational modelling of chemical toxicity. I’m currently responsible for overseeing various projects in the area of predictive toxicology and chemical safety assessment, all with a view to supporting EU policies.
Q: What are, in your opinion, the grand challenges associated with the use of predictive models in the regulatory evaluation of new medical products?
Alicia Paini: The grand challenges are related to the acceptance and use of new technologies, including experimental techniques and modelling and simulation (M&S) approaches, some of which are difficult to explain to the non-specialist. This has been discussed in various papers, such as the recent commentary by Worth.
Andrew Worth: This challenge is partly scientific, relating to the availability and quality of relevant data, but also social and psychological (trust in the model validation process; new and unfamiliar ways of assessing and managing risks). In relation to the evaluation of new medical products, the regulatory framework needs to allow for the use of modelling and simulation (M&S), and this needs to be accompanied by adequate guidance and tools. We also need specific provisions for the data protection of information concerning individual patients, to ensure that these data cannot be misused.
Q: What do you believe could accelerate the adoption of In Silico Trials technologies?
Andrew Worth: A political will to develop a harmonised regulatory framework in the major economic regions, particularly in the EU and US. It is necessary to develop standards and guidelines that are accepted at an international level (hence the importance of international collaboration). We also collaborate with the Avicenna Alliance, who are doing a lot to promote this vision.
Alicia Paini: The DG CNECT e-health callSC1-PM-16-2017 - In-silico trials for developing and assessing biomedical products, is already a step forward in realising such in silico trials/technologies. As an output, the projects should produce libraries of virtual patients, which we believe are crucial to improve clinical trials. This will be a second step toward application of these data. Good communication with relevant parties will be essential, too, as well as training those who will need to use these data in a healthcare context.
Q: Some IST experts believe that the creation of a community of practice where specialist of in silico technologies, clinical and industrial users, and regulators can openly discuss the pros and cons of this new approach could accelerate the adoption. What is your opinion?
Andrew Worth: This is necessary, but not sufficient, in the absence of clear and harmonised regulatory guidelines. Also, sustainability of project outputs is important, for example in the case of digital databases and modelling tools. There is also a need to incentivise academic groups to carry out research that is not necessarily novel and cutting edge, but which provides essential information to carry out M&S in support of healthcare. For example, the development of standards for measuring the properties of healthy and diseased tissues, and building transparent and accessible databases of such properties. This is important work that does not typically interest academic groups.
Alicia Paini: It is also important to bear in mind the innovative potential and needs of SMEs, who can make a large contribution to this emerging field. As mentioned previously, good communication with relevant parties is key to accelerating adoption; the Avicenna Alliance is doing a laudable effort in this.
Q: What is the greatest benefit you expect IST can offer in the future? Some suggest lower development cost, less animal and humans involved with experimentation, faster time to market, etc.
Andrew Worth: We agree that these are all expected benefits of IST; in addition, to address ethical issues (with animal and human testing), IST can help in reducing costs and risks (both clinical and financial) involved in trials, and ultimately increase the rate of innovation in healthcare. IST can be seen as an enabling technology for the more efficient and effective design of clinical trials. This will be particularly evident in cases where clinical data are scarce or associated with ethical considerations. For example, it is difficult to establish the population characteristics of individuals suffering from rare diseases, and there are ethical considerations in recruiting children in the clinical assessment of paediatric therapies.
Alicia Paini: Importantly, some challenges can only be addressed by M&S. For example, it would be unethical to test the safety of new medical devices in diseased individuals. Fortunately, there are examples where this has been circumvented, such as in the development of new heart implants. Another challenge, which may be tackled by IST modelling, is the problem of co-morbidities (multiple related diseases) in the ageing population. This needs to be understood before it can be treated or prevented. Healthcare in low- and middle-income countries could also benefit hugely from IST, for example in cases where infectious diseases are having a significant burden on public health, and where resources for tacking such diseases are limited. This is where projects such as StriTuVaD have an important role to play.
Q: Where do you expect are the “low hanging fruits” for IST?
Andrew Worth: The acceptance of new technologies depends not only the state of the science, but also on whether alternative strategies are available and feasible. Thus, the use of IST for special cases, as mentioned above - rare diseases and paediatric illnesses, might be an opportunity. Also, the use of IST for the repurposing of established and authorised drugs, with known safety profiles, could be a means of gaining experience and confidence.
Andrew Worth, MA, MSt. PhD
Alicia Paini, PhD, ERT