MICA: Applying innovative technologies to improve benefit-risk ratio of drugs: developing a national resource underpinned by the MRC Centre for CDSS

The use of drugs as medicines has made an enormous contribution to human health with the drug discovery process being directed to most aspects of human disease. However, all drugs are associated with variability in response: that is some patients do not respond to drugs, while others develop side effects or adverse drug reactions (ADRs). This may be related to patient factors (genetic or environmental) or differences in their disease. The overall burden caused by differences in the way patients respond to drugs is large to both the NHS and Industry. For example, with ADRs, we have shown that at least 6.5% of all adult admissions to hospitals are due to ADRs and that approximately 15% of inpatients suffer an ADR during hospitalisation. Extrapolated nationally, ADRs are thought to cost the NHS in England in excess of £637 million annually, or approximately £5000 per hospital bed per year. This is a conservative estimate and is likely to be much higher. Our findings in the UK have been replicated in many countries showing that ADRs are a global health issue.

Our application focuses on the MRC Centre for Drug Safety Science (CDSS) which has an international reputation. The patient is at the centre of the work we undertake. We have developed an infrastructure that allows pre-clinical and clinical scientists to work side-by-side using cutting-edge technologies to analyse well-defined clinical samples. In this application, we request state-of-the-art technologies to build upon this infrastructure and produce a step-change in the area of stratified medicine - that is, to identify the best treatments for patients based on profiling their disease, genetic and environmental factors. Our aim is to develop a comprehensive resource, based on our existing expertise and experience and the technology platforms, to allow for assessment of how individuals vary in drug responses, how diseases differ between individuals, and how this relates to variation in clinical outcomes. We will do this through investigation of different "experimental" systems ranging from single cells in test-tubes to experimental studies in man, to careful clinical observation of patients in clinical settings. This will facilitate translation of findings in the laboratory to clinical care (bench to bedside), but importantly lessons learnt in clinical settings will also be investigated further in the laboratories (bedside to bench), so that we can learn more about disease processes.

Our research vision aims to identify clinically relevant problems (using a variety of patient recruitment strategies including electronic health record databases such as CPRD and the infrastructure being developed through the Farr Institutes), and use the requested state-of-the-art technologies (single cell genomics, metabolomics, proteomics, mass cytometry, and computing infrastructure) to identify mechanism-based disease strata to improve the benefit-risk ratio of current and new medicines, for the benefit of patients, industry and regulators. The application builds on the existing infrastructure of the MRC Centre for Drug Safety Science (CDSS) at the University of Liverpool (UoL).

The overarching aim is to optimize 'systems pharmacology' approaches applying scientific innovation that will produce physiologically and mechanistically-based biomarkers, which will tailor drug treatments, prevent the development of more serious ADRs, identify new treatment strategies, and define novel disease mechanisms and pathways. By using drugs as tools, we will not only uncover the mechanisms by which drugs act in the body (in terms of efficacy and toxicity), but also uncover novel pathways of the disease mechanisms (both for diseases for which the drugs are used, but also for unrelated diseases where an ADR acts as a mimic for a disease). The combination of the two provides a powerful platform to catalyse short-, medium- and long-term innovation in stratified medicine, and will ultimately improve clinical outcomes of disease, reduce iatrogenic morbidities, reduce hospital admissions from drug- and non-drug induced disease, and improve cost-effectiveness of therapy.

The beneficiaries from our research and the requested technologies will be:
1. Academia
Publishing our research in high-impact journals will ensure that the science-base grows in the mechanism-based understanding of why drug response varies between individuals.
The technologies will further our aim to bring together diverse groups of experts (those with and without experience in drug safety science and stratified medicine).in order to enhance our specific research programmes.
The new technologies will enhance the standing of CDSS as a national and international resource, with collaborators benefitting from access to our clinical samples, access to our cross-cutting technologies, and/or access to our intellectual expertise.
The technologies will further enhance the strong training element of the Centre and Faculty ensuring that non-clinical and clinical academic capacity in drug safety science, stratified medicine, 'omics technologies and systems pharmacology is enhanced. Such comprehensive training will produce 'rounded' scientists with sought-after skill-sets who will make a valuable and practical contribution to the continued growth of this cross-disciplinary medical research activity in the UK.
2. Health Service providers
The information gained from electronic health records will be used to enhance our understanding of variability in drug response
Knowledge gained from our research will lead to changes to drug labels, and clinical guidelines, and thereby more effective prescribing.
Our research will inform prognostic and diagnostic testing strategies that will lead to safer and more cost-effective personalisation of therapies
Scientific outputs will ultimately reduce variability in drug response and their associated financial burden, and improve the benefit-risk ratio of medicines
Continued training will increase the capacity in Clinical Pharmacology and Therapeutics and Translational Medicine in the UK.
3. Pharmaceutical Industry
Scientists from the pharmaceutical industry will continue to use our resources as a focal point for non-competitive research. The technology platforms will further enhance Industry collaborations with the Centre.
Workshops run by the CDSS will incorporate the applications of these technologies which will enhance collaborative links (not necessarily with Centre scientists) that drive novel scientific plans.
Scientific outputs from the CDSS, the Faculty in Liverpool and its collaborators will be used to develop drugs with better benefit:risk profiles
4. Diagnostics Sector
Advances in mechanistic understanding of ADRs and variability in drug response more generally will open up new opportunities for the development of diagnostic and prognostic testing strategies that can be commercialised by the diagnostics sector leading to an improvement in the benefit:risk of drugs
The availability of the technologies will enhance interactions with SMEs especially within the diagnostics sector
5. Regulatory Authorities
Regulatory scientists will input into and gain benefit from the activities of the CDSS and its associated technologies
CDSS scientists will continue to provide expertise to various advisory committees of the MHRA and EMA.
Scientific outputs from the Centre and Faculty enhance the ability of drug regulators to include the relevant information in drug labels. This will thereby contribute towards better evidence-based policy making at a global level.
6. Patients and the General Public
By feeding knowledge and scientific advances through to other stakeholder groups, we will ultimately improve the benefit-risk ratio of drugs. These advances will have a major impact on enhancement of the clinical care of patients thereby leading to an improvement in quality of life.
The general public retains a great deal of interest in all matters relating to drugs and healthcare, and our work will educate the public in their perception of risks and benefits associated with medicines.