MRC: IN CONFIDENCE - UK Clinical Research Collaboration

IN CONFIDENCE
UKCRC/13/12
UKCRC Joint Translational Infection Research Initiative
Phase 1 Consortia Progress Reviews - 2013
Background
In 2006 a UKCRC Strategic Planning Group (SPG) on Microbiology and Infectious Diseases
Research (MIDR) was established in response to concerns about the status of clinical
microbiology research capacity and coordination between funders and researchers. The aim of
the group was to take strategic oversight of MIDR in the UK and to identify and implement
appropriate actions that would create the optimum environment to facilitate and fund excellence
in the field. The scope of the MIDR SPG included all research on pathogenic microbes relevant
to human health.
The SPG subsequently carried out a formal review of the area. The sources of input included: a
survey of the infection research activities funded by SPG member organisations; an examination
of recent reports and initiatives; a detailed analysis of the infection research data collected for
the UK Health Research Analysis; and a consultation with key professional organisations in the
area.
The report that followed in April 2008 ‘Developing Microbiology and Infectious Diseases
Research in the UK’ identified four issues specific to MIDR from the consultation and the
examination of reports and reviews in the area, as follows: Clinical and Translational Research;
Medical Intelligence; Communication and Collaborative Working; and Workforce, Training and
Career Structure. The UKCRC SPG agreed to develop a jointly funded initiative to address these
four issues. The resulting UKCRC Translational Infection Research Initiative (TIRI) was
established with the following three specific aims:
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To boost capacity for translational research; and for applied research in the clinical
and public health contexts
To develop research leadership
To encourage collaboration, communication and training; and to facilitate a
strengthening of research activity across this field
The objectives of the Consortium Grants were to add value by increasing infrastructure, building
academic capacity and encouraging multidisciplinary collaborative working in Translational
Infection Research in the UK.
In July 2008 two Consortium Grants were awarded with £9.6 million funding. Two further
Consortium Grants were awarded totaling £7.1 million in July 2010. The four UKCRC TIRI
Consortia are:
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Modernising Medical Microbiology Consortium (PI: Professor Derrick Crook), University of
Oxford
Centre for Infection Prevention and Management (PI: Professor Jonathan Friedland),
Imperial College London
Cambridge Translational Microbiology (PI: Professor Sharon Peacock), University of
Cambridge
eST12 - Electronic Self testing Instruments for Sexually Transmitted Infections (PI: Dr
Tariq Sadiq), St George's, University of London
The seven organisations involved in funding and delivering the UKCRC TIRI initiative are:
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Medical Research Council (MRC)
Department of Health, National Institute for Health Research (NIHR)
Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Health and Social Care Research and Development, Public Health Agency, Northern
Ireland
Chief Scientist Office, Scottish Government Health Directorates
Welsh Assembly Government, National Institute for Social Care and Health Research
TIRI Phase 1 Consortia Mid-term Review Process (2013)
As part of an on-going review process of TIRI by the Initiative Management Board (IMB)
(representatives from the funding organisations), a mid/late-term progress review of the two
consortia awarded in 2008 (Phase 1: Derrick Crook, Jonathan Friedland) was conducted in early
2013. The purpose of this review was to assess progress towards the original aims and
objectives of these programmes, and to help guide and inform future infection research
strategies in the UK. A sub-committee of Scientific Advisory Panel members were recruited to
provide an expert assessment of each consortium’s progress.
In the first stage of this review, grant holders were requested to provide a mid-term progress
report. These reports were distributed to all IMB and SAP members following receipt at MRC.
Following this, progress review meetings lasting approximately half a day were held at the
grant-holders’ institutions (details below). These meetings allowed the PIs and their project
partners to report the key outputs and challenges of their work so far. The SAP had the
opportunity to explore some of the project work in greater detail and to assess overall progress.
Mid-term reviews of remaining Phase II consortia (Peacock and Sadiq) are due to take place in
early 2014.
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Mid-term progress review of the Modernising Medical Microbiology (MMM)
Consortium
Site visit: 14th March 2013, John Radcliffe Hospital, Oxford
PI: Professor Derrick Crook, University of Oxford
Award value: £ 5.1m
Duration: 01/01/09 - 31/12/13
Panel: Prof Brian Duerden CBE (original TIRI Chair), Prof John Coia (University of Glasgow), Dr
Jane Rogers (ex-WT Sanger Institute and TGAC)
Representing funders: James Horswill (MRC), Dermot Maher and Tim Knott (Wellcome Trust)
Summary of translational added value and impact
The Panel agreed that the whole genome sequencing (WGS) approach being applied to
infectious disease surveillance and molecular epidemiology is world-leading. The decision to
alter the original proposal in 2009 from fragment-based sequencing to WGS (quickly
recognising the huge potential of emerging technology) was the correct one. It was a risk worth
taking, and which has paid-off. The results produced so far for the four model organisms
(C.difficile, S.aureus, M.tuberculosis, and Norovirus) represent a paradigm-shift within clinical
microbiology and will have major implications for the prevention and management of
healthcare-associated infections and communicable diseases such as tuberculosis.
Key achievements and outputs to date
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WGS of TB demonstrates greater resolution than current typing methods and indicates
direction of spread in the community and the presence of super spreaders. This will
clearly assist cluster investigation and add to understanding the epidemiology of TB.
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WGS of C.difficile is a higher resolution typing method than any of the currently used
methodologies. Using this combined with conventional epidemiological information it has
been demonstrated that no more than 20% of C.difficile infections occurring in
Oxfordshire are acquired from another hospital case. A very small number (<2% of
cases) arise from contamination in a hospital after a patient is discharged. A very large
reservoir of C.difficile causing infection independent of hospital in-patient care has been
demonstrated. This indicates a significant change in the epidemiology of C.difficile
infection since the mid-2000s when hospital outbreaks were driving a nationwide
epidemic.
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WGS of S.aureus shows excellent resolution, greater than other available typing
methods. This is helping to develop the knowledge base to investigate why the numbers
of MSSA cases remain unchanged whereas MRSA numbers have reduced markedly.
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Sufficiently high specificity and sensitivity has been achieved for genotype prediction of
S.aureus antibiotic resistance and susceptibility; however, this will need a formal
evaluation in parallel with currently used processes.
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WGS of Norovirus is now possible because of a new innovative method for achieving
whole genome sequencing based on Illumina RNASeq protocols. This has also been
facilitated by the introduction of the Mi-Seq instrument with improved sample handling
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and data analysis capabilities. In the large number of outbreaks investigated it has been
demonstrated that within an outbreak, between outbreaks in a hospital, and between
hospitals strains are highly heterogeneous, suggesting the presence of a wide diversity
of strains circulating in the community and in hospitals. Limited transmissions within
closed spaces occur for brief periods of time. Data also suggest that hospitals are
involved in large community outbreaks rather than being the source of major outbreaks
and show the impact of the emergence of new strains (e.g. Sydney). The methodology
can also be applied to Hepatitis C.
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A prototype informatics pipeline for processing, assembling, storing, analysing and
depicting whole genomic sequence data linked to epidemiological data has been
designed and is being developed. This needs to be converted into automated application
software that can be integrated, in full or in part, with data solutions under development
elsewhere in the NHS.
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14 papers published or in press. 8 submitted and under review.
Progress towards meeting clinical academic training needs
The Panel recognised that the Consortium has provided training opportunities for scientists and
clinicians at various stages in their careers and has produced several academically orientated
clinical microbiologists and research leaders (an original TIRI goal); for example, Dr Danny
Wilson has become a Group Head. It was pointed out by the Panel that these developments
were not made evident enough in the mid-term report and any future reports should place
greater emphasis on these achievements.
Challenges
Development of informatics solutions to manage the data generation and analysis pipeline
(based on the use of whole genome sequencing) has proved to be a huge technical challenge
for the Consortium and the milestones associated with this aim have slipped. The Panel
recognised that this slippage was mostly unavoidable due to the decision to switch to WGS, the
complexity of the methodology employed, and the enormity of the task. A major challenge
would be to develop an informatics system that would have application beyond the scope of this
project and for which adequate and on-going support could be identified. It was acknowledged
that the MMM group are making substantial efforts to tackle this aim and that it will be a major
focus during the remaining lifetime of the grant.
Weaknesses
The Panel noted an apparent lack of collaboration and communication with the other TIRI
programmes – even though the original awarding Panel had suggested and expected that this
would happen. Such collaborations would have been beneficial and will be strongly encouraged
by WT and DH during the lifetime of the Health Innovation Challenge Fund (HICF) grants
(awarded to both the Oxford and Cambridge groups).
Future developments
Two of the original aims of the TIRI programme were to establish a research base of sufficient
substance to attract further significant funding and to develop on-going collaborations between
academic institutions, NHS and public health bodies (e.g. HPA). Both have been achieved. The
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Oxford MMM Group has secured significant funding to build upon this work through the HICF
grant and other sources; it will be important to ensure that there is no break in continuity
between these programmes. The collaborations with Leeds, Birmingham, Brighton and Colindale
have had a crucial role in the success of this programme and the HPA has had an important role
in delivering this partnership.
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Mid-term progress review of the Centre for Infection Prevention and
Management (CIPM)
Site visit: 16th April 2013, Imperial College London (Hammersmith Campus)
PI: Professor Jonathan Friedland, Imperial College London
Award value: £4.5m
Duration: 01/01/09 - 30/07/14 (including 6 month extension)
Panel: Prof Deenan Pillay (UCL), Prof Alistair Leonard (University of Glasgow)
Representing funders: James Horswill (MRC), Ursula Wells and Carole Fry (Department of
Health), Dermot Maher (Wellcome Trust)
Summary of translational added value and impact
The Panel noted that the approaches to innovation adoption taken by CIPM, such as the mHealth mobile phone app, are innovative and have been expertly designed. Such technologies
have the potential to make significant impacts in the healthcare environment, although it is not
yet apparent what impacts they are currently having. Additionally, the work on group A
streptococcus diagnosis and typing has added substantial value and represents an exemplary
translational element of the Centre’s work. These achievements have been reflected by the
substantial number of publications coming from the consortium. The CIPM work has also been
successful in leveraging further funding for Imperial College. The Panel acknowledged that the
MSc and other training courses have been very successful in providing necessary skills to
healthcare workers.
Key achievements and outputs to date
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CIPM has developed the Imperial College Healthcare NHS Trust’s first smartphone
application for use by medical staff at the point of care. The HPA and other local and
national NHS Trusts have expressed interest in developing something similar with CIPM.
CIPM Research into nosocomial transmission of group A streptococcus underpinned new
national HPA guidance, “Guidelines for prevention and control of group A streptococcal
infection in acute healthcare and maternity settings in the UK”. This is in addition to
influence on national policy through participation in consultation on the UK five year
Antimicrobial Resistance Strategy and Action Plan, other DoH evidence calls and work
with the Royal College of Physicians on the setting of the MRCP exam and the Healthcare
and Associated Infections Top Ten Tips series.
The CIPM lecturer, Dr Drumright, was successful in her application for an NIHR Career
Development fellowship, marking her out as an emerging leader in applied research in
her field and funding the recruitment of another research assistant to the Centre
Obtained a further 26 grant awards. CIPM has also supported two large applications
which led to the successful awards of the MRC Centre for Molecular Bacteriology and
Infection (CMBI) and the £7.2M NIHR Patient Safety Translational Research Centre
(PSTRC). The latter is of particular relevance to the CIPM.
CIPM is increasingly developing international collaborations in Europe, Africa, the Far
East and the USA which are raising the profile of CIPM and bringing expertise and work
to bear in a more global context.
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CIPM has been instrumental in spearheading a major expansion of the Trust Data
Warehouse, bringing together complex information currently held in a number of
disparate databases for the very first time.
Published 42 papers.
CIPM awarded its first doctorate to Carina King. All other CIPM PhD students have
successfully upgraded.
The Centre has developed novel e-learning packages for Trust staff to improve the
clinical management of C.difficile and promote Trust IPC policy and guidance.
The Centre has recruited to its Postgraduate Certificates and Diplomas alongside its
MScs.
CIPM held its first joint research meeting with the Centre for Medication Safety and
Service Quality to explore potential opportunities for collaboration, in particular
combining research on junior doctor prescribing and the nurses’ role in antimicrobial
stewardship.
The Centre hosted the first joint UKCRC TIRI Centres’ meeting in March. CIPM,
Cambridge and St Georges came together to hear about each other’s research and,
where appropriate, identify synergies and opportunities for collaboration.
Progress towards meeting clinical academic training needs
The Panel agreed that CIPM has made vital contributions to improving translational microbiology
by designing and implementing excellent training schemes such as the MSc courses and short
courses. It was also recognised by the Panel that CIPM has produced a number of strong and
highly capable research leaders in the translational microbiology field.
Challenges
The consortium has struggled to establish meaningful collaborations outside the Imperial
College Hammersmith Trust. For example, developing the m-Health technology with other NHS
trusts has been problematic as they tend to be developing their own apps in isolation. The
interdisciplinarity of the consortium has not really been evident.
Weaknesses
Although considerable efforts have been made in the development of innovation adoption
technologies, CIPM has not yet demonstrated the effectiveness and impact of these approaches;
an example being the m-Health app, the impacts of which on antimicrobial prescribing bestpractice have not yet been shown. Whilst “improvement science” approaches are central to the
CIPM, it was felt that the outputs were more conceptual, rather than actually leading to impact.
The Panel also raised concerns about the interdisciplinary nature of the consortium, with the
interlinking of social science and clinical microbiology often not being evident.
Furthermore, the Panel agreed that too much of the CIPM work was embedded in the
Hammersmith Trust and not enough effort had been made to collaborate or exchange
information with other UK trusts, and thus not meeting a central TIRI aim. Examples include ehealth, where there are currently a number of cross Trust initiatives.
The panel noted the sources of leveraged funding - a significant degree is from the Imperial
BRC, which perhaps enhances the inward feel of the Centre.
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Future developments
CIPM have had their grant extended until end July 2014 so there is at least one year of funds
remaining (at the time of writing). To maximise the outputs of the various research work
streams, it could be beneficial to request that CIPM focus more attention on establishing the
impacts of their research. The CIPM could also be asked to provide evidence that its various
scientific disciplines are working in an interdisciplinary way as was desired by the TIRI initiative.
It is probably too late to encourage building collaborations with other UK institutions and NHS
trusts, but CIPM could be urged to communicate their activities more broadly.
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