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

Lead Research Organisation: University of Liverpool
Department Name: Institute of Translational Medicine

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description 3 year project grant
Amount £217,307 (GBP)
Funding ID CRR1179 
Organisation North West Cancer Research (NWCR) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2019 
End 03/2022
 
Description 3DBioNet: an integrated technological platform for 3D micro-tissues
Amount £626,046 (GBP)
Funding ID MR/R025762/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 02/2022
 
Description A Dragonfly multimodal fast imaging platform with SRRF-stream (Super-Resolution Radial Fluctuation) in the Liverpool Centre for Cell Imaging (CCI)
Amount £450,000 (GBP)
Funding ID BB/R01390X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2018 
End 04/2019
 
Description CRUK Programme Foundation Award
Amount £633,274 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2018 
End 05/2023
 
Description Clinical Scholarship
Amount £116,459 (GBP)
Funding ID G1015 
Organisation Horse Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 08/2018
 
Description Developing an ECODB web-service to store and analyse any type of omics data - awarded to Philipp Antczak
Amount £16,744 (GBP)
Organisation Science and Technologies Facilities Council (STFC) 
Sector Academic/University
Country United Kingdom
Start 09/2016 
End 03/2017
 
Description Development of New Mathematical Sciences for Healthcare Technologies
Amount £6,200,000 (GBP)
Funding ID EP/N014499/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 12/2015 
End 11/2019
 
Description Development of the chick embryo as a replacement for rodent models of tumour metastasis
Amount £240,000 (GBP)
Funding ID NC/R001324/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom
Start 03/2018 
End 02/2021
 
Description DiMEN MRC DTP studentship
Amount £75,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 03/2019
 
Description Evaluation of novel combination drug protocols for neuroblastoma using advanced imaging in a chick embryo model
Amount £117,000 (GBP)
Organisation North West Cancer Research (NWCR) 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2018 
End 01/2020
 
Description International Travel Award Scheme
Amount £3,100 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2017 
End 12/2017
 
Description John Goldman Fellowship Award
Amount £124,798 (GBP)
Organisation Leuka 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 09/2021
 
Description Knowledge Transfer Partnership
Amount £110,000 (GBP)
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 02/2018 
End 01/2020
 
Description NWCR project grant
Amount £195,289 (GBP)
Organisation North West Cancer Research (NWCR) 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2016 
End 08/2019
 
Description NWCRF studentship - Establishment and characterization of a novel pre-clinical animal model to study metastatic recurrence
Amount £85,000 (GBP)
Organisation North West Cancer Research (NWCR) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2018
 
Description North West Cancer Research Development Fund
Amount £8,500 (GBP)
Organisation North West Cancer Research (NWCR) 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 07/2018
 
Description Pfizer Aspire Europe
Amount £43,866 (GBP)
Organisation Pfizer Inc 
Sector Private
Country United States
Start 10/2016 
End 06/2017
 
Description Project Grant
Amount £443,059 (GBP)
Funding ID BB/P001912/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Project grant
Amount £44,000 (GBP)
Organisation The Kay Kendall Leukaemia Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2018 
End 12/2019
 
Description Research Fellowship
Amount £431,861 (GBP)
Organisation Versus Arthritis 
Start 06/2017 
End 05/2022
 
Description TRDF
Amount £43,000 (GBP)
Funding ID BB/M020282/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2015 
End 10/2016
 
Description The North West England MRC Fellowship Scheme in Clinical Pharmacology and Therapeutics - fellowship awarded to Dr Anna Olsson-Brown
Amount £190,885 (GBP)
Funding ID MR/N025989/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2016 
End 10/2019
 
Description clinical-academic fellowship
Amount £50,000 (GBP)
Organisation British Association of Paediatric Surgeons 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 12/2017
 
Title Zegami 
Description A front-end visualisation platform for querying and interrogating imaging datasets. 
Type Of Material Improvements to research infrastructure 
Year Produced 2016 
Provided To Others? Yes  
Impact We have implemented a zegami server to act as a front-end to our public-facing OMERO gallery. This platform allows for the easy visualisation and interrogation of large imaging datasets and so provides an added layer of functionality. Several projects have utilised this system for Open-Data research projects, for an example see: https://doi.org/10.14293/s2199-1006.1.sor-chem.az1mju.v2 and corresponding data available at http://zegami.liv.ac.uk/2016-sf.html 
URL http://zegami.liv.ac.uk
 
Description CyTof procurement 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Professor Rob Beynon negotiated with Fluidigm on behalf of all partners who received funds via the MRC Clinical Research Infrastructure award to purchase mass cytometers. The negotiations resulted in a common discounted pricing structure, elevated service provision, and costs towards user-group network meetings.
Collaborator Contribution Supporting Professor Beynon where necessary and appropriate
Impact Favourable cost reductions for all partners during procurement of seven individual CyTOF machines.
Start Year 2015
 
Description CyTof procurement 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Professor Rob Beynon negotiated with Fluidigm on behalf of all partners who received funds via the MRC Clinical Research Infrastructure award to purchase mass cytometers. The negotiations resulted in a common discounted pricing structure, elevated service provision, and costs towards user-group network meetings.
Collaborator Contribution Supporting Professor Beynon where necessary and appropriate
Impact Favourable cost reductions for all partners during procurement of seven individual CyTOF machines.
Start Year 2015
 
Description CyTof procurement 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Professor Rob Beynon negotiated with Fluidigm on behalf of all partners who received funds via the MRC Clinical Research Infrastructure award to purchase mass cytometers. The negotiations resulted in a common discounted pricing structure, elevated service provision, and costs towards user-group network meetings.
Collaborator Contribution Supporting Professor Beynon where necessary and appropriate
Impact Favourable cost reductions for all partners during procurement of seven individual CyTOF machines.
Start Year 2015
 
Description CyTof procurement 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Professor Rob Beynon negotiated with Fluidigm on behalf of all partners who received funds via the MRC Clinical Research Infrastructure award to purchase mass cytometers. The negotiations resulted in a common discounted pricing structure, elevated service provision, and costs towards user-group network meetings.
Collaborator Contribution Supporting Professor Beynon where necessary and appropriate
Impact Favourable cost reductions for all partners during procurement of seven individual CyTOF machines.
Start Year 2015
 
Description CyTof procurement 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Professor Rob Beynon negotiated with Fluidigm on behalf of all partners who received funds via the MRC Clinical Research Infrastructure award to purchase mass cytometers. The negotiations resulted in a common discounted pricing structure, elevated service provision, and costs towards user-group network meetings.
Collaborator Contribution Supporting Professor Beynon where necessary and appropriate
Impact Favourable cost reductions for all partners during procurement of seven individual CyTOF machines.
Start Year 2015
 
Description CyTof procurement 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Professor Rob Beynon negotiated with Fluidigm on behalf of all partners who received funds via the MRC Clinical Research Infrastructure award to purchase mass cytometers. The negotiations resulted in a common discounted pricing structure, elevated service provision, and costs towards user-group network meetings.
Collaborator Contribution Supporting Professor Beynon where necessary and appropriate
Impact Favourable cost reductions for all partners during procurement of seven individual CyTOF machines.
Start Year 2015
 
Description Partnership with Illumina for provision of the NextBio Clinical tool 
Organisation Illumina Inc.
Department Illumina
Country United Kingdom 
Sector Private 
PI Contribution We have provided complex data-sets (genomic, transcriptomic, proteomic) to Illumina and asked for specific functionality in the NextBio Clinical system.
Collaborator Contribution Illumina have provided training in NextBio Clinical and hae been working to try to integrate different deata types (transcriptomic, proteomic) into the software tool.
Impact None yet
Start Year 2016
 
Description workshop focused on cell imaging and image analysis 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The Centre for Cell Imaging organised a 2 day workshop focused on light microscopy techniques and image analysis. 90 researchers and students attended the event mainly from Liverpool and Manchester but also from other Universities in the UK. Industrial partners were invited and the director of the Advanced Imaging Centre at the HHMI Janelia Research Campus, Teng-Leong Chew gave a keynote lecture and a comprehensive hands-on training session on Image Analysis.
Year(s) Of Engagement Activity 2017
URL https://cci.liv.ac.uk/2017_workshop.html
 
Description "Meet The Scientist" exhbit at the World Museum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Our exhibit was entitled: "Seeing inside cells". More than 300 visitors stopped at our exhibit and learned about cells, and how we can use microscopy to understand how they function. Children have visualised cells using a fluorescent microscope.
Year(s) Of Engagement Activity 2015
URL https://www.liverpool.ac.uk/health-and-life-sciences/meet-the-scientists/21-november/
 
Description Health is Wealth conference Liverpool Jan 2015 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact The purpose to highlight the development, progress and outputs of academic-industrial partnerships in early clinical translation.



The purpose of the workshop is to highlight the development, progress and outputs of academic-industrial partnerships in early clinical translation.
Year(s) Of Engagement Activity 2015
 
Description Hosting Lower 6th form summer students via the Nuffield scheme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The Centre for Cell imaging has hosted 2 6th form students for 4 weeks as part of the Nuffield Foundation scheme
Year(s) Of Engagement Activity 2017
 
Description Image Analysis Blog 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact A blog, outreach and teaching resource based around the work done by Dave Mason, the CCI BioImage Analyst. The tutorials and educational material largely focuses on Open Source and Open Access tools such that others can apply the methods and techniques to their own quantification.

This platform also provides a route to engage with the wider community through comments and interactions on-site and via other social media platforms (IE twitter).
Year(s) Of Engagement Activity 2015,2016,2017
URL http://postaquisition.wordpress.com
 
Description Imaging workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact More than 50 attendees participate to the yearly workshop organised by the Centre for Cell imaging. it provides training and awareness of new imaging technologies to group leaders, members of staff and students from the University of Liverpool, other Universities and local companies.
Year(s) Of Engagement Activity 2012,2013,2014,2015
URL http://pcwww.liv.ac.uk/~cci/2015imagingday.html
 
Description Imaging workshop September 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Annual imaging workshop, focused on fundamentals in imaging and specific seminars on microscopy techniques such as super-resolution microscopy, intravital imaging, Life-time imaging. The main purpose is training and increasing awareness of the imaging capabilities in Liverpool
Year(s) Of Engagement Activity 2016
URL http://cci.liv.ac.uk/2016imagingday.html
 
Description Liverpool Cell Imaging annual workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The Centre for Cell Imaging organised a 2 day workshop focused on light microscopy techniques, imaging probes and image analysis. 90 researchers and students attended the event mainly from Liverpool and Manchester but also from other Universities in the UK. Industrial partners were invited and attended.The second day was a focused hands-on training on image analysis.
Year(s) Of Engagement Activity 2018
URL https://cci.liv.ac.uk/2018_workshop.html
 
Description Primary school visit for the Science week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The activity consisted in 2x2h sessions with 2 year 6 classes in a primary school in Liverpool (Mosspits Lane primary school) for the Science week 2017. The children were offered activities focusing on scales in biology, use of microscopy and building their own magnifier.
Year(s) Of Engagement Activity 2017
 
Description School visit to the CCI 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 50 A-level students visited the Institute of Integrative Biology, and were given a talk about imaging in the 5 dimensions.
Year(s) Of Engagement Activity 2018