Delivering Experimental Medicine Research in Critical Care
A report of a workshop held at King’s College London in February 2018 coordinated by the NIHR Network Critical Care Experimental Medicine Group
Introduction
The NIHR is one of the most integrated health research systems in the world. Established by the Department of Health and Social Care, the NIHR aims to improve the health of the nation and to make a significant contribution to the UK economy by making the NHS a strong and effective partner for the Life Sciences industry.
Critical care is a complex and rapidly expanding area for research, requiring clinicians and academics to work across organisational boundaries at multiple sites to deliver studies. A critical care research community involving researchers from across the UK, as well as internationally, has developed as result from over a decade of collegiate working.
Recently the research community recognised an increasing need for a collaborative approach to delivering early phase complex, high intensity and high impact studies to improve critical care. Although, for example in England alone, 96% of the 200 NHS critical care units participate in large scale clinical trials, the increasing complexity of some studies requires focussing of experimental medicine in a few major centres; it is acknowledged that specialist skills, resources and experience are required for the successful delivery of these types of studies.
The Medical Research Council describes experimental medicine as: “Investigation undertaken in humans, relating where appropriate to model systems, to identify mechanisms of pathophysiology or disease, or to demonstrate proof-of-concept evidence of the validity and importance of new discoveries or treatments.”
Studies undertaken in this field are complex and intense. Complexity arises from the selection of patients to participate in studies and the nature of the interventions undertaken. Patients often present as emergencies, are seriously ill and receiving treatment in intensive care units (ICUs) and the acute nature of critical care requires prompt identification of patients who can participate in studies. Careful consideration is devoted to managing consent and ethics. Interventions can be time critical so staff and equipment, including access to imaging facilities, need to be available around the clock.
The NIHR Clinical Research Network (CRN) has helped to establish a Critical Care Experimental Medicine (CCEM) Group to facilitate growth in this area. The Group comprises members drawn from the NIHR CRN National Specialty Group in Critical Care and other experts in critical care experimental medicine, aiming to bring the critical care community from across the UK together to deliver complex, high intensity and high impact studies to improve critical care through research and innovation. These studies are often smaller than Phase III trials but still take place at multiple sites in collaboration. The Group also supports training in critical care experimental medicine for clinicians, scientists and other healthcare professionals.
Important priority areas where there are clear needs for advances in critical care include - but are not limited to - sepsis and Acute Respiratory Distress Syndrome (ARDS). Sepsis has a high occurrence, with 45,000 cases a year in England’s ICUs [Shankar-Hari M et al, British Journal of Anaesthesia, 2017]. Mortality rates have improved in recent years but are still high at around 30%. ARDS accounts for around 10% of ICU admissions [Bellani G et al, JAMA, 2016]. There is no specific drug treatment and mortality is at a similar level to sepsis at around 30%.
The CRN Critical Care Experimental Medicine Group has existed for two years, and the February 2018 workshop brought the community together to explore three topics:
- How to develop a pipeline of experimental medicine critical care studies (including horizon scanning).
- How to ensure that the NHS has the capacity to deliver these studies (including trainee development).
- How to engage industry partners.
The workshop was attended by approximately 80 people including adult and paediatric critical care clinicians, NIHR Biomedical Research Centres, industry, clinical research facilities, academia and contract research organisations. The meeting was informed by clinical teams, NIHR staff and network members, plus large and small companies. It included people in the early stage of their career through to holders of senior clinical academic positions.
Although the remit of the NIHR only covers England, there are strong strategic partnerships with the devolved nations who were represented at the event. The workshop consisted of plenary presentations exploring experiences conducting critical care experimental medicine from the perspectives of both academic and industrial scientists, the developers of training pathways, users of electronic health records and the practice of industrial engagement.
Three discussion groups - one for each of the questions – developed a series of suggested recommendations, and finally debated the outcomes in an open session. This report reviews the learning that emerged from the workshop for each of the questions and concludes with broad recommendations that would advance critical care experimental medicine in the UK.
Developing a pipeline of Critical Care Experimental Medicine studies
The NHS presents a unique location for critical care experimental medicine studies
The combination of an integrated health system in the UK, the presence of clinical and research staff with ten years’ proven experience of critical care experimental medicine and the use of a unique NHS number for every patient so that they can be followed as they engage with different healthcare providers has created an attractive environment for experimental medicine. The importance of this should not be underestimated and it is contributing to the growth in research studies from all funders, including industry. However, there are still opportunities to further streamline the system.
Growing a pipeline of critical care experimental medicine studies requires a symbiotic relationship between the NHS, industry, academia and funders
In common with many other areas of clinical research, elements that have contributed to the growth in the critical care experimental medicine pipeline include:
- The NHS’s commitment to participate fully in health research;
- Investment by industry to conduct and commission research and also to commercialise the outcomes of the research;
- Academic collaboration on both the science and the training of researchers of all disciplines;
- Long-standing national policies designed to grow the life sciences industry in the UK and to enable patients to benefit from the best treatments supported by sound evidence;
- Funders that provide the physical and organisational infrastructure to support studies;
- A sustained commitment to patient engagement.
The NIHR continues to play a central role in planning and facilitating the integration of these elements to form a single, active and continuously improving research system. Its strategy over the last 10 years has been fundamental to the increase in the number of studies conducted in the NHS. This success stems from its twin objectives of delivering improved healthcare to patients and to stimulating economic activity in the health care and related industries.
Ethics committees and research governance processes can be streamlined
The complex nature of critical care experimental medicine together with the frequent incapacity of seriously ill patients to participate in decisions about their care inevitably requires careful deliberation by research ethics committees. The UK requires applications involving incapacitated adults to be reviewed by specialist ethics committees. However, there can still be variations in decision processes so learning from previous experiences may be useful.
The highest standards of research governance are regarded as a UK strength. The system has recently been re-designed, with the intention of streamlining and reducing bureaucracy. In due course, the contribution of the new arrangements to reducing the time and logistical burden of conducting critical care experimental medicine could be assessed to ascertain how further improvements can be made.
Information science will become even more important in critical care experimental medicine
Increasing numbers of critical care research studies are seeking to apply the principles of stratified and personalised medicine to medical care. For example, investigators are seeking to understand the underlying factors that make some patients more likely to benefit from specific treatments for ARDS while others may not respond. Similarly, genomic reasons are sought as to why some patients are vulnerable to sepsis while others with similar exposure to pathogens are not. These understandings may be pivotal in the development of new therapeutic approaches in critical care, but their investigation depends on experimental medicine research.
Some critical care experimental medicine studies require detailed patient selection to meet complex criteria. These may relate to comorbidities or exposure (or non-exposure) to specific drugs prior to the study. Selection criteria may be complex and may require measurement of novel biomarkers, but decisions need to be made rapidly if patients are to participate in studies whilst in ICU. In practice, this has proven to be a significant hurdle. Advances in information systems will provide tools to overcome this whilst appropriately ensuring patient confidentiality. Interconnectivity between patient record systems, in a framework of appropriate governance, has been demonstrated to provide real time identification of eligible patients for participation in studies. In some studies it has been found that a significant proportion of these eligible patients for critical care studies may be present in settings other than ICU. The patient identification algorithms are capable of raising an alert that appropriately invites clinicians to raise participation in studies with patients. Appropriate use of electronic health records may also transform the cost of investigating the long term impact of critical care interventions, currently a labour intensive process, which is holding back knowledge of the impact of interventions on long term patient outcomes.
Increasingly, studies are using real time information to monitor results as the study is undertaken. Bayesian methods can be used to monitor the likelihood of obtaining meaningful results from a study as it progresses so that the study design can be modified to obtain more informative results. If a study appears likely to be inconclusive it can be terminated early to release resources for other work. This need for real time information is requiring investigators to prepare and submit information in a time critical manner. Form-filling and reporting remain unpopular activities so methods that minimise the burden are increasingly entering research practice. For example, pre-populated electronic forms that only require the essential results to be added are reducing the time burden. Trials will benefit from a reduction in missing data. Efficient infrastructure tools will facilitate the provision of timely information and reduce the bureaucracy experienced by research staff.
Another aspect of information management involves the sharing of non-proprietary information and samples obtained from critical care experimental medicine studies. At present, there is no mechanism to do this. Data obtained from many studies, such as those that are inconclusive or terminated early, may not be published. There is a clear opportunity to make more use of the data obtained during trials than is the case at the moment, without undermining commercial or intellectual property interests.
Small studies are as time consuming and expensive to establish as larger ones
Small scale patient studies are attractive to researchers seeking to rapidly test or validate a scientific insight in humans. In principle they require less funding and can be conducted quickly and are cost-effective. However, critical care experimental medicine researchers report that it is as difficult and time consuming to establish a small study as it is a larger one. This is because the same steps are required to design and obtain approval for the study, to obtain funding, to identify and recruit potential centres to participate and also to find and train staff in the study protocols at each of the centres. It is also important to monitor the early results to verify that the study is proceeding as planned and to intervene if necessary.
Ensuring the NHS has the capacity to deliver studies
Embedding research in clinical care
Embedding research as core business for the NHS remains a key aim for the NIHR and much progress has been made in the last decade. However, the perceived tension between the provision of clinical services in an NHS environment and the desire to deliver research outcomes can still be a real barrier to experimental medicine in critical care. The imperative of delivering care to seriously unwell patients takes priority over research studies when resources are scarce. In some cases, structural, organisational and cultural barriers to research delivery are encountered by staff of all disciplines involved in patient care and can impact on their delivery of research studies. One established approach to overcoming these barriers is to hire dedicated research staff, including research nurses, to work on studies. The nature of critical care and the complex intensive interventions that are studied requires research nurse provision 24/7, which is a more demanding and expensive requirement to satisfy than the more usual provision of research nurses during the normal working day. There are no easy solutions to this, but progress would be made if contributions to research were perceived to be fully embedded into job descriptions and performance metrics and were recognised for career progression. There is a perception that this is not yet widely the case and this perception is sufficient to inhibit research activity. Recent developments in NIHR training and new NIHR CRN workforce development strategies address these issues.
A key factor for successful delivery of critical care experimental medicine studies is a keen interest in early phase research. Potential sites need to be engaged early at the study design stage to ensure study protocols are deliverable in the ICU. This is particularly important for industry studies who might have limited experience of clinical operations in an ICU context. Other issues for industry include lack of continuity of staff in ICUs leading to loss of expertise and the risk of inconsistent or missing data being generated in trials.
On occasion, industry directly approaches clinicians with a known interest in a particular technology / field to seek their assistance with the design of studies to validate the clinical effectiveness of their healthcare technology. These can be challenging requests for clinicians. Although many clinicians, and allied health professionals, are eager to participate in research studies, the time requirements to provide assistance are difficult to satisfy alongside the principal purpose of their role as deliverers of healthcare in a stretched NHS.
Research training and career recognition
The NIHR has made significant progress over that last 10 years in developing a portfolio of high quality training schemes for health researchers, managed by the NIHR Academy. A recent review of these schemes undertaken by the NIHR Academy recognised a number of areas where change was now appropriate, including the formation of the over-arching NIHR Academy, and consolidation of the current range of schemes. This will introduce consistent terminology to describe research skills and research posts into a common nationwide structure and provide a framework to engage deaneries and professional associations in a structured way to recognise skills and coordinate career development for clinicians, scientists and allied health professionals. Building on the success of the existing schemes, the revised arrangements will address the research training needs of healthcare professionals at all stages of their careers from the pre-doctoral stage through to postdoctoral lecturerships and newly appointed professors, and for clinicians, scientists and allied health professionals. Research training funding schemes will include existing responsive mode for personal awards and pre-doctoral, doctoral and post-doctoral placements, and a new strategic mode, intended to direct funding to areas where skills are scarce (including, for example, data science) and where the needs of the health system are a particular priority (for example, in public health, mental health and acute care). Flexibility is being introduced to the system to potentially allow clinical lectureships, which normally last four years, to span formal completion of clinical training. Joint funding with industry as part of research training are also planned as part of the revised schemes.
NIHR Incubators are a new concept that will support the development of a critical mass of researchers in priority areas through engagement with academia, charities and the life sciences industry.
These changes are intended to ensure sustainable development of the research skills that are needed to deliver experimental medicine. For example, early career professionals repeatedly spoke about their desire to undertake research and research training, but also of their concerns that this would be regarded as peripheral or even a diversion from their principal clinical training for career progression purposes. This perception that time spent on research or research training is at the expense of professional advancement is a genuine barrier to early stage clinical researchers. This is important as early career health professionals would value opportunities to participate in research and acquire research skills.
These concerns have been recognised and some new training pathways have been developed for clinicians. For example, the University of Cambridge offers training for clinicians and scientists in experimental medicine skills to develop future study leaders. The Experimental Medicine Initiative offers PhD studentships and Clinical Lecturer posts funded jointly by the Cambridge NIHR BRC and industry partners. Clinical Research Training Fellowships offer opportunities for clinicians to undertake out-of-programme research leading to a PhD. These provide clinicians with dedicated research time. These awards can be granted to clinicians and allied health professionals. The development of trainee research networks - for those at various stages of their medical training but not engaged in formal NIHR academic training – and pioneered in anaesthesia and surgery, are already showing much promise as a vehicle for clinical engagement with research at scale.
Early career scientists and clinicians who are attracted by research-oriented careers in clinical settings are reported to be more attracted to the major research centres. It is proving to be difficult to fill research lectureships at other centres despite the paucity of such posts.
The training review also recognises the need to encourage more nurses and allied health professionals to undertake research training and new schemes are starting to be established, in partnership with Health Education England and other national organisations. In some cases, they provide a pathway for established health professionals, such as nurses, to further their career without taking management posts, and this can be attractive.
Engaging industry partners
NIHR places a high priority on engaging with industry. This directly contributes to its key objectives of improving healthcare through research and innovation, and also realising economic benefits for the country by attracting and supporting growing businesses in the Life Sciences sector.
NIHR recognises that it is difficult for industry, particularly from overseas, to easily identify how to engage the NHS to conduct experimental medicine research. This complexity arises from the presence of multiple bodies such as the Academic Health Science Networks (AHSNs), Medicines and Healthcare Products Agency (MHRA) and the National Institute for Health and Care Excellence (NICE). Even within NIHR there are multiple points of engagement. For this reason, NIHR offers a single point of contact and a wide range of services to UK and overseas enterprises of all sizes to assist them to engage with the systems in England. These services are free to industry and have a two week target to actively support industrial partners to identify and engage with appropriate partners to conduct their work.
The industry engagement mechanisms are attracting increasing amounts of industry investment in studies in England. The number of commercial studies in the NIHR CRN portfolio has increased from 325 in 2010/11 to 697 in 2017/18. However, feedback from industry and CROs is that they still find it difficult to fully appreciate the capability of the UK as a location for conducting studies, and also some find it challenging to understand the ways of working. CROs in particular experience a mismatch between the expectations of their industrial clients and the reality of engaging with the healthcare system to conduct research.
Industry reports that experimental medicine research studies usually need to be conducted at multiple sites. They value networks of experienced and equipped centres to expedite their engagement, simplify the involvement of staff at an early stage and conduct feasibility assessments. Industry partners therefore welcome the creation of the NIHR CRN Experimental Medicine Group for Critical Care.
Three important messages arose from these discussions.
- It is vitally important for industry to engage with NIHR’s industry teams at a very early stage of formulating a research study. This will help to design and frame the study in a way that achieves its scientific objectives and that is readily deliverable by healthcare systems in the UK. The CRN will support the early identification of appropriate centres and expertise, and facilitate the design of deliverable studies. Early engagement fosters a strong sense of partnership between those undertaking the research and those commissioning it, which is more personally rewarding for those involved and will increase interest in research participation by those working in the NHS.
- NIHR needs to continue to explain and promote the broad and comprehensive services that it provides to industry to increase their understanding of the services that NIHR offers and the benefit that industry can obtain through engaging with them. For example, they can assist companies to make the best use of research funding, guide them on how to present high quality critical care experimental medicine proposals to funders, and inform the selection of participating centres.
- There is an opportunity for the industry-facing elements of NIHR, which works with the devolved nations, to provide a single point-of-contact portal for the whole of the UK, to also engage with Critical Care Experimental Medicine Group so that there is two-way proactive engagement between critical care experimental medicine centres and industry. The personnel in these centres are sources of study proposals and are keen to showcase their capability to industry partners. NIHR desires to learn more about the motives and ambitions of centres to undertake research and engage with industry – at present only some provide feedback on these points to the NIHR.
The benefits for industry
The rewards for industry of participation in critical care experimental medicine are multifaceted. The most obvious benefit is the outcome of the study which fulfils its primary objectives relating to efficacy or effectiveness of an intervention and so informs decision making about commercialisation of research outputs. Industry reaps other ancillary benefits too. For example, it is well known that the costs of developing a new therapy are high and that an increasing proportion of candidate therapies are failing in the late stages of clinical trials after very considerable cost has been incurred. Pharmaceutical companies are increasingly looking to how they can transfer the risk of failure onto early phase trials.
While this increases the risk of failure in early phase trials, it is preferable that a candidate therapy fails at an early stage rather than a late stage. Accordingly, they are looking at how early phase trials, such as introduction of a compound to man for the first time, can provide deeper and more extensive scientific information that can be used to assess its potential as a therapy. Stratified studies, precision medicine and fundamental understanding of disease are all motivating industry to participate in experimental medicine. Small molecules are a current focus.
It is attractive to use safe molecules in rigorous human experiments that examine drug exposure at target sites, assess whether drugs are binding at the expected target and to confirm pharmacological activity and exposure levels – these three factors provide strong evidence that increases the likelihood of beneficial results from later clinical trials. Good quality science is also a source of ideas for new interventions. All of this is increasing the complexity and intensity of studies. Another ancillary benefit is that such studies serve to increase the skills and experience of the people working on them. This helps increase career attractiveness in industry, and upskills the industrial workforce. It also provides a recruiting mechanism to recruit able research-active employees into industry.
Recommendations to further Critical Care Experimental Medicine
Critical care experimental medicine is a success story in the UK. The NIHR and partners have increased the number of critical care studies by more than 150% in the last 7 years and attracted industry partners and investors. Challenges arise from the desire of all stakeholders to conduct more research faster and more cost-effectively than ever. This is essential if the NIHR is to fulfil its twin aims of contributing to the health and wealth of the nation.
There is a strong desire among all parts of the critical care community to jointly increase further the quantity and velocity of critical care experimental medicine research in the NHS without compromising the quality of the work undertaken. The NHS was regarded as already providing an internationally attractive location for experimental medicine. It is not a question of persuading stakeholders of the benefits of collaboration, but of further developing the research infrastructure in England and the devolved nations so that stakeholders can direct an ever-increasing proportion of their endeavours to the delivery of high quality studies.
Recommendations for increasing experimental medicine in critical care fall into five broad but mutually supporting areas. Responsibility for progressing these recommendations rests on all those who participate in the healthcare system. The NIHR CRN Experimental Medicine Group in Critical Care will play a coordinating role, recognising that UK system-wide responses are needed. A series of specific steps which are linked to these five broad recommendations and which will be led by the NIHR CRN Experimental Medicine Group in Critical Care, are set out in Section 6, with supporting resources for each of the 5 areas set out in Section 7.
Develop capacity for experimental medicine research in the ICU
ICUs are designed, operated and assessed as providers of critical care to seriously unwell patients. To also be effective places of research their organisation and culture, and sometimes their facilities, should be further developed to be more aligned with that of clinical research but without compromising the provision of care. There is no doubt this can be done – some ICUs have extensive successful experience in the delivery of experimental medicine research studies. Best practice can be shared and existing staff, including management, supported to acquire relevant experience. The benefits to staff and patients of participating in the research process should be explained and promoted. Successes can be recognised and celebrated to showcase what can be achieved to leaders throughout the healthcare system.
Developing and recognising research skills in the healthcare community
Critical care experimental medicine requires multi-disciplinary teams of clinicians, scientists and allied healthcare professionals to participate in research. The increasing number of studies requires more people to be engaged. This has been recognised, and initiatives such as the NIHR Academy and creation of research skill pathways are welcome and are starting to align the strategies of different participants in England’s healthcare system. However, not all early career clinical professionals perceive experimental medicine research experience as contributing to career development. The work which has started to integrate the system of career pathways should be accelerated, driven by conversations throughout all organisations involved in UK healthcare about skill acquisition and recognition, including deaneries and other providers of professional qualifications, universities and the NHS itself.
Promote information management to accelerate and deepen studies
Critical care experimental medicine is being transformed by information technology. New science insights arising from genomic and biomarker technology are leading the introduction of stratified and personalised medicine approaches to care; the use of big data and electronic health records are facilitating alternative study design as well as patient recruitment and real time data provision is enabling the use of Bayesian methods to improve study efficiency.
There are new opportunities to gather and share non-proprietary information. The development of systems, protocols and tools, together with training skilled people in health information science will contribute markedly to the UK as a leading location to conduct critical care experimental medicine research.
Improved processes to support critical care experimental medicine
The UK is already an internationally attractive location to conduct critical care experimental medicine studies, but there are opportunities to improve further. Opportunities have been identified to facilitate centre recruitment, guide study investigators through ethics committees and other regulatory approvals, provide tools for rapid data provision and reduce the costs and time to establish trials. Building on such opportunities requires a holistic system-wide approach that engages and responds to all those who are engaged with critical care experimental medicine. NIHR could use its nationwide coordinating role to streamline processes, put in place tools and building upon best practice to further ease the burden to establish and run studies without compromising research governance, ethics or patient safety.
Strengthening engagement with industry
NIHR successfully provides a portfolio of services to industry and industrial support is deeply embedded into its culture. This is a strength to build upon. Feedback from industry, including those overseas, is that they do not fully understand how experimental medicine is organised and delivered in the UK. Early engagement also strongly supports study design and delivery, and recruitment of capable centres and guidance through the experimental medicine process. The universal message is to approach NIHR at the earliest possible stage and it will provide support through its extensive and comprehensive portfolio of services. This could be communicated even more prominently than it is already. There is also an opportunity to promote unmet needs and/or opportunities for innovation in critical care to industry by using the engagement process to recruit industrial partners to work on opportunities identified in the critical care system itself.
Actions led by NIHR CRN CCEM
(target completion date)
- Add centres with Phase 1 accreditation to the NIHR CRN CCEM Group (12/2018)
- Working with other specialties and organisations, explore the development of an NIHR Incubator (06/2019)
- Support the development of applications from multiple institutions to the new NIHR fellowship scheme, funded jointly with industry (06/2020)
- Working with the UKCCRG, NIHR CC NSG and other stakeholders, publish an article on best practice in CC research workforce development (06/2020)
- Working with the NIHR Health Informatics Collaborative (HIC) and Health Data Research UK, expand participation in the HIC beyond the five existing centres and maximise value of the data-rich environment in ICU by streamlining / automating data collection and exploring applications of artificial intelligence (06/2020)
- Work with NIHR infrastructure and equivalent in the devolved nations, including Biomedical Research Centres, Clinical Research Facilities and Bioresource to use existing samples and data to back translate for new discoveries (review in 06/2020)
- Work with pharma to take new drugs or “stored compounds” forward into early phase clinical testing (review in 06/2021)
- Publish an article on novel methods to expedite CCEM research (09/2020)
- Refresh NIHR CRN CCEM marketing material (06/2019)
- Using the NIHR marketing material, double the number of EM studies in critical care (06/2022)
- Hold follow-up workshop (02/2021)
Resources
Bringing research into the ICU
Developing and recognising research skills in the healthcare community
Promote information management to accelerate and deepen studies
- NIHR Health Informatics Collaborative (HIC)
- Health Data Research UK (HDRUK)
- Research Advisory Group (RAG)
- HRA guidance on GDPR
Improved processes to support critical care experimental medicine
Strengthening engagement with industry
Contact us
Get in touch with the NIHR Critical Care Specialty Experimental Medicine subgroup.