Impact case study database

A more personalised approach to clinical management is part of the ‘silent revolution’ unfolding within the NHS and worldwide. The novelty of the research led by Mukhopadhyay is evidenced by Sir Stephen Holgate, an internationally respected expert in asthma, who stated that these results constitute ‘ one of the first demonstrations of the application of personalised medicine to the clinical management of asthma’ [Source 5.1]. The impact of the research on treatment response and genetic variation has affected diverse beneficiaries (patients and carers, clinicians, trainees and regulatory bodies) locally, nationally and internationally. The evidence provided through the body of research has been used to create a notable shift in awareness of alternative treatment options, which is now improving clinical practice, informing GP training (UK), and is formalised within international treatment guidelines (Australia). Life-changing care is now being provided for the patients and families undergoing alternative treatment.

4.1 Developing new personalised clinics for allergy-related disease care management

New paediatric personalised medicine clinics, in operation from 2016, and supported by the NHS and Rockinghorse, a Sussex-based charity, constitute a unique development at the Royal Alexandra Children’s Hospital in Brighton (Royal Alex). These clinics have treated over 60 children with severe, often multi-system disease through repeat visits. The clinics draw on the deeper scientific understanding of the uniqueness of each child with regard to allergy-related diseases, and clinical problems that affect children according to their individual genetic traits and environmental exposures. This is in stark contrast to the way dermatology clinics were run previously, ie on the basis that allergy and eczema were separate entities. Leading paediatric dermatologist, Dr Jess Felton, attributes the shift in clinical practice at the Royal Alex to the research undertaken by Mukhopadhyay’s team [5.2]. This shift directly influences practice by placing greater emphasis on allergy testing and the use of emollients from a very early age in children with eczema and related conditions. As a result, children under the age of 6 months, presenting with eczema are treated more proactively as the research showed that infants with these skin barrier defects develop more severe atopic disease. These clinics focus more on understanding the role of external allergens, performing skin prick testing for allergies in the dermatology outpatient clinic to help with diagnosis of selected type 1 allergies that may be adding to the severity of eczema. This joint clinic where dieticians, dermatologists and asthma specialists devise a care plan in collaboration with the child’s parents has dramatically improved patient experience. NHS consultants and trainees report benefit from this innovative approach [5.2]. The carers interviewed in a 2019 survey (n=30) reported 100% satisfaction following treatment due to their changed care plan, their involvement in treatment decisions and the united approach of their clinicians [5.3]. [text removed for publication] [5.4].

4.2 Increasing awareness of the benefits of a patient-centred approach to the treatment of allergy-related diseases (healthcare professionals and the public)

To extend the clinical impact the research team disseminated their key research findings across a series of events in 2015-2016. This included study days for 43 trainee GPs in Sussex [5.5a], 44 attendees of the National Medical Students Paediatric Conference [5.5b] and presentations to 48 child health professionals in India through links with the Indian Academy of Paediatrics [5.5c]. Feedback from these events indicates that at least 124/135 (92%) of the professional audience had better awareness of how a poor response to asthma medicine could result from genetic variation in patients. All GPs in attendance confirmed they were now more likely to check whether asthma medicines were working in individual patients [5.5a-c]. The team tailored their findings to a health professional audience and disseminated them via presentations and commentary pieces in key UK health channels: Royal College of General Practitioners (RCGP), websites for the journals Pulse and Nursing in Practice. To build on this impact, the RCGP has made this material available through its website and the research into genetic predisposition and its implications for patient care has been incorporated into the RCGP’s online and in person CPD. The research underpins key guidance in the RCGP’s e-learning module on allergy, developed in partnership with Thermo Fisher Scientific [5.6]. This course is designed to educate GPs about the various presentations of allergic disease, how to assess an atopic patient and when to investigate in primary care or refer to secondary care. This course has been completed by 5,489 healthcare practitioners across the UK since its launch [5.6].

In collaboration with the arts group Same Sky, the team organised and presented their work at a public participation event (May 2016) as part of the Brighton Fringe Festival (approximately 250 attendees). The views of the public, captured on video, indicate an increased understanding of a personalised approach to treatment and an interest in participating in the debate around this subject [5.7a]. Similar results were seen at the New Scientist Science Festival, London (2018) where 331 members of the public found the ‘Personalised Medicine’ stand to be important and educational, with 280 reporting a substantial increase in their understanding of how genes affect the way we respond to medicines and how genes affect diseases [5.7b]. The research findings were also presented to two primary schools in rural Portugal (52 children) and three schools in rural and urban West Bengal, India (239 children). As a result of this engagement a change in awareness of the potential of personalised medicine was recorded [5.7c].

4.3 Improving asthma management through genotype-based prescribing

New treatments for severely affected children have proved to be life changing for individual patients. One patient, Ewan Mackintosh, has declared that having faced multiple ineffective courses of treatment, the research-led decision to prescribe montelukast based on his individual genotype, caused his severe breathlessness to disappear virtually overnight [5.8]. Similarly, this has caused other children undergoing the new treatment regime to eradicate problems faced with every day activities including climbing stairs and playing sports [5.8]. The research findings led directly to the first large-scale comparison of genotype-based personalised care with standard care in asthma anywhere in the world. This was the first time that grant funding of this scale (Action Medical Research (AMR), grant GN2203, GBP277,375) was awarded to a precision medicine randomised controlled trial in the field of children’s asthma (2015). Within the trial Mukhopadhyay and colleagues demonstrated the significant benefit of prescribing according to a patient’s genotype. Of the 241 patients recruited from across England and Scotland, the 121 patients randomised to the ‘personalised care’ group, experienced a significant improvement in their quality of life as assessed on a wide range of activities, including physical activities, school work and sleep quality in comparison to the 120 patients randomised to the ‘standard NHS care’ group [reference 3.6]. Completed in 2019, the AMR have noted that the successful findings of this trial, the first of its kind in children and teenagers, are helping ‘t he charity to make a difference’ with children affected by disabling conditions. The AMR selected the project as an Action ‘Steps Forward’ for 2020 and included it in their 2020 Research Review for supporters and trustees due to positive results and its potential to provide a model for other diseases. These publications are used by the charity to demonstrate the value of donors’ giving, and to inspire, motivate and help with communications and fundraising to encourage potential future supporters of the charity [5.9].

4.4 Changes to Australian healthcare guidelines on asthma

In a 2015 review of childhood mortality, doctors in Australia were cautioned that the adverse gene-medicine interaction described in Mukhopadhyay and colleagues’ research may have contributed to multiple asthma-related deaths in children in New South Wales between 2004 and 2013. The review revealed that a large number of children had been prescribed inhaled corticosteroids in combination with regular long-acting beta2 agonist (LABA; eg salmeterol). Citing the team’s findings on the link between β receptor gene polymorphism and LABA adverse effects, the review drew the hypothesis that ‘ LABA use in the children who died from asthma may have, theoretically, put these children at risk of severe exacerbation and […] it might, therefore, explain the increase in asthma deaths seen in recent years’ [5.10].

In the 2015 version of the Asthma Australia Handbook, the national asthma guideline for health professionals in Australia, Mukhopadhyay’s research is one of the key pieces of research evidence cited as part of the recommended stepwise approach to asthma management in children, warning clinicians about the adverse gene-LABA medication interaction [5.11a-b]. As part of this approach, the guideline specifically states that response to treatment partly depends on genetics, referencing the team’s finding that due to the child’s genotype, only a proportion of children will respond to individual asthma treatments [5.11c]. This is to our knowledge the first example of genotype-based advice in any national guideline for asthma.

The body of research led by UoB has offered new critical perspectives on policy, practices, and service delivery that support understandings of the context and lived experience of LGBTI citizens and (health) service-users. A variety of interventions including development of policy tools, frameworks, guidance and training programmes have delivered health policy and healthcare education changes in the UK and Europe that are helping to reduce the structural inequalities affecting the health and wellbeing of the LGBTI community.

4.1 Impact on national and international public policy

The outcomes of the Health4LGBTI research were used by the UK Parliament’s Women and Equalities Committee inquiry into health care provisions for LGBT communities in October 2018 [Source 5.1]. The results of this inquiry fed into the LGBT Action Plan 2018 from the Government Office. This plan has over 75 commitments to improving the lives of LGBT people and a further GBP4,500,000 of funding was allocated as part of this work to deliver on the commitments in this plan [5.2]. In November 2020 the European Commission presented its first-ever strategy on LGBTIQ equality in the EU. The Health4LGBTI project is used to underpin guidance in relation to LGBTI health inequalities with recommendations for good practice for Member States to utilize while developing national LGBTI training plans. This is documented as part of the strategy’s overall mission relating to tackling discrimination and combating inequality in education, health, culture and sport [5.3]. In a related initiative Horizon Europe and EU4Health, the European health alliance will dedicate funds to consider the health of LGBTI persons, with a focus on mental health. Based on the comprehensive research underpinning all aspects of the programme, and with the support of the Task Force on Equality, the Commission has committed to integrate the fight against discrimination affecting LGBTI people into all EU policies and major initiatives [5.3].

4.2 Improved training programmes for health professionals

A key structural challenge and primary reason that LGBTI people experience inequalities in health is due to invisibility in health systems including poor/no data. This research advocates for best practice for better data collection by health professionals including how systems can record more appropriate recognition of gender identity. This can help ensure LGBTI people are afforded dignity, respect, and appropriate care. Since participating in the Health4LGBTI training, Brighton and Sussex University Hospitals NHS Trust used the project resources to rapidly upskill staff in the recognition of LGBTQ+ health inequalities, and requirement to collect relevant data to improve their services for patients. These data are instilled into other work within the Trust via inclusion outreach activities and training [5.4]. As part of this the resources have been disseminated to 10 other NHS Trusts for use in their LGBTQ+ Networks and/or Inclusion Teams to help move forward the LGBTQ+ health agenda. Each of these have 20-30 core members, plus wider networks [5.4]. In addition, the Health4LGBTI project was one of the main drivers behind the decision to train all therapists working in psychological (IAPT) services in West Sussex in LGBTQ+ affirmative therapy as part of a project to improve access to the psychological therapies service for the LGBT+ population [5.5]. This project promoted affirmative practice with the LGBT+ population by establishing a baseline of staff experience, confidence, and knowledge. The Health4LGBTI project publications were identified as key research outputs to identify potential needs and to help guide the project deliverables. As a result, 250 staff have now been trained to deliver LGBT+ affirmative therapy to increase access to psychological services across West Sussex [5.5].

The Health4LGBTI project team developed a comprehensive training programme that focuses on knowledge, attitudes and skills of healthcare professionals when providing healthcare to LGBTI people and accounted for the needs of diverse European settings. Training was piloted in the 6 participating countries with a total of 110 participants including doctors, nurses and other medical professions (psychologists, social workers, pharmacists, physiotherapists) or auxiliary medical professions (administrative support, reception workers, medical managers, medical researchers). Using pre and post training questionnaires an increase in knowledge occurred in all pilot countries. Since the completion of the training more than half of the participants (57.4%) were able to apply the knowledge in their role. These findings were mobilised to raise awareness within LGBTI communities, the European Commission, European Parliament (MEPs), and Ministers of Health and their equivalents (134 persons registered from 25 EU countries, and health ministry’s officials from 16 EU countries) [5.6, 5.7]. The evaluation showed that 93% of the 110 healthcare participants agreed that training in LGBTI issues should be a part of general medical education. This finding, supported by evidence from the wider project findings, has led to five European institutions committing to roll out the training as a core part of the medical curriculum. The Ministry of Health in Portugal has launched a new nationwide initiative, including policy and training interventions, based on the learning from this project. In July 2020, the Ministry launched a National Health Strategy for LGBTI people with an inaugural programme dedicated to Health promotion of transgender and intersex people. Following this launch guidelines and recommendations are being prepared for health professionals that are being disseminated nationally. This includes the roll out of the trainers’ manual: Reducing health inequalities experienced by LGBTI people: What is your role as health professional? [5.8].

Dissemination of the training programme developed through the Health4LGBTI project has led to new curricula for student healthcare professionals at the University of Lucerne (Switzerland), Lausanne University (Switzerland), the Medical University of Innsbruck (Austria) and the University of Verona (Italy). In Lithuania, following the pilot, the trainers have established direct contact with the leadership of the national association and are planning the dissemination of the training among general practitioners [5.8]. At the University of Verona, the programme has been used to train medical students and residents with approximately 20 students undergoing the programme in the first year. This is now being extended to nursing students where plans are in place to use the project’s learning with 400 current nursing students to evaluate specific student needs to extend the impact of this training. All organisations are developing these roll-out schemes in the context of a wider need to focus on LGBTI sensitive health care and to fill a known knowledge gap in terms of LGBTI needs and the potential for bias in the healthcare professional community [5.8].

4.3 Influencing wider reform initiatives

The Health4LGBTI project developed a comprehensive set of resources including a bespoke rapid-review template to generate extensive datasets for analysis. Following a conference to disseminate the project results, the European Commission and the WHO committed their institutional support to the reduction of health inequalities experienced by LGBTI people and to promote cooperation among different sectors. DG SANTE, the European Commission’s Directorate-General for Health and Food Safety, has set up a resource centre for best practices and a new ‘Steering Group on Health Promotion and Disease Prevention’. The EC representative confirmed that project materials from Health4LGBTI will be shared with these groups to further the results of this work [5.9]. The Health4LGBTI project is also used in a report from the Organisation for Economic Cooperation and Development (OECD): Over the Rainbow? The Road to LGBTI inclusion. This report follows a Call to Action signed by 12 member countries to support progress with nationwide inclusion agendas. It is the first comprehensive overview of the laws in OECD countries to ensure equal treatment, and of the complementary policies that could help foster LGBTI inclusion. This report references key parts of the Health4LGBTI project including the findings from the focus group studies, the project report and evaluation and the ‘Trainer's Manual’. This report is used to provide evidence that all OECD countries have made progress in their reform agendas across the last two decades, but highlights remaining challenges to help drive forward change.

Patient preference studies such as PrefHER can serve as a powerful tool to engage patients and their communities. Moreover, it can quantify the patient voice across different stages of clinical drug development, drug regulatory approval and care management to support patient-centric, healthcare decision-making. By measuring patient preference for either formulation of trastuzumab, PrefHER revealed an overwhelming preference for its subcutaneous route of administration. This finding contributed to the market approval of trastuzumab subcutaneous by the US Food and Drug Administration (FDA) and its Australian counterpart. In practice, it also provided the research evidence to support the delivery of cancer treatments closer to the patient’s home – a central tenet of the NHS Five Year Forward plan for improvement in outcomes for cancer patients.

4.1 Market approval of subcutaneous trastuzumab by the US Federal Drug Administration and the Australian Department of Health

The submission of patient preference information (PPI) to the US Federal Drug Administration (FDA) is voluntary. However, the FDA recommends applicants to collect and submit such information for certain premarket approval when patient decisions are ‘preference sensitive’ [source 5.1]. Patient decisions regarding treatment options are preference sensitive when multiple treatment options exist and there is no option that is clearly superior for all patients.

In the case of trastuzumab subcutaneous, both HannaH and SafeHER trials had shown the subcutaneous formulation to be of the same efficacy and safety as its intravenous counterpart. PrefHER trial findings were the only research-based evidence revealing an overwhelming preference by patients for the subcutaneous drug delivery. In May 2018, these findings –alongside the efficacy and safety data – were included in Roche’s Biologics Licence Application to the FDA for permission to deliver trastuzumab subcutaneous to the US market [5.2]. As part of its multi-disciplinary review and evaluation of the application, the FDA commented on the robustness of the SHORE-C led interview methods stating:

‘The methods used to conduct the telephone interviews appear to be consistent with best practices of survey research (eg the Applicant [Roche] sought expert opinion [SHORE-C] and patient input for item generation of the interview guide, translated the interview guide using forward and backward translation, and pilot tested the interview guide)’ [5.2]. The FDA concluded its benefit-risk assessment with the following:

‘Results from the patient preference study (PrefHER) suggest patients preferred the SC route due to time. In conclusion, the efficacy and safety of SC trastuzumab was comparable to IV trastuzumab and offers a new route of administration for patients with HER2-positive breast cancer’ [5.2]. In February 2019, the FDA approved trastuzumab for subcutaneous injection for the treatment of eligible patients with HER2+ early breast cancer [5.3]. The FDA approved product labelling refers to the PrefHER trial data to support the Patient Experience subsection in the prescribing information [5.2, 5.4]. In its news announcement, Roche highlighted the importance of this approval, especially concerning the consideration of patient preference in treatment choice. As explained by Roche’s Chief Medical Officer and Head of Global Product Development at the time, Sandra Horning: ‘ The approval of Herceptin Hylecta [ie trastuzumab subcutaneous] gives physicians and patients in the United States a new option to select treatment based on individual needs and preferences’ [5.3].

[text removed for publication] [5.5, 5.6]. [text removed for publication] [5.5]. With these validated tools, Roche evaluated the patient preference for Perjeta (pertuzumab) and Herceptin (trastuzumab) IV vs PHESGO – Roche’s first example of combining Perjeta and Herceptin for administration via single SC injection [5.6]. As per PrefHER, the PHranceSCa study showed that 85% (136/160) of people showed a strong preference for PHESGO in comparison to IV Perjeta and Herceptin due to less time in the clinic and more comfortable treatment administration [5.6]. In June 2020 PHESGO was approved by the FDA [5.7].

In addition, PrefHER’s main finding relating to patient preference for subcutaneous trastuzumab has been used by its manufacturer, Roche, in its application to the Australian Therapeutic Goods Administration (TGA), part of the Australian Government Department of Health responsible for the regulation of new therapeutic drugs. In its August 2015 evaluation report [5.8], prepared in collaboration with Roche, the TGA cites the PrefHER study and more specifically the overwhelming patient preference for the trastuzumab subcutaneous administration as one of the new formulation benefits. Following this evaluation by the TGA, the Australian Government Department of Health approved the registration of trastuzumab subcutaneous for supply to the Australian market.

4.2 Provided the research-based evidence on patient preference to improve trastuzumab delivery in clinical practices

Several studies have used data from the PrefHER study to determine the timesaving benefits of the subcutaneous compared with the intravenous formulation of trastuzumab. A prospective observational time-and-motion study in 8 countries (n = 488) involved in the PrefHER trial quantified patient time in the infusion chair and active health practitioner’s time [5.9]. Results showed that on average 55 minutes of patient chair time was saved with the subcutaneous formulation. In addition, active health practitioners’ time was reduced on average by 15 minutes per session with the subcutaneous formulation [5.9]. Results from this observational time-and-motion study showed that listening to the patient’s preference for treatment results in substantial reduction in active health practitioners’ time, patient chair and unit time, thus increasing capacity within very limited existing resources. This is particularly significant in the overall context with more than 2,000,000 patients worldwide with breast cancer being treated with trastuzumab (2019); and approximately 80,000 of them via the subcutaneous formulation [5.10].

Results from PrefHER supported practitioners in their recommendations to patients regarding their trastuzumab treatment. [text removed for publication] [5.11]. In practice, this translated into a significant increase in trastuzumab subcutaneous prescription rates from 2014 (one-year following the publication of PrefHER clinical trial results) onwards in England, with the subcutaneous administration route becoming the treatment mode of choice for HER2 positive breast cancer. [text removed for publication] [5.12]. This increased trend in trastuzumab subcutaneous prescription rate was replicated in other Trusts in the England with the subcutaneous formulation of trastuzumab being on average administered 14 times more than its intravenous form [5.13].

[text removed for publication], the significance of PrefHER’s findings was not only limited to trastuzumab, but it helped to evolve the concept of delivering other monoclonal antibodies via the subcutaneous route which was shown to be quicker, easier and lent itself to patients having treatment closer to or at home: [text removed for publication] [5.11].

PrefHER’s findings on patient preference also affected clinical practice outside the UK. In Germany, a project describing the experiences with trastuzumab subcutaneous outside clinical studies at 7 main cancer centres showed that for 2 centres, the results of the PrefHER study were one of the decisive factors motivating them to introduce trastuzumab subcutaneous in clinical practice [5.14].

Since the early 2000s UoB researchers have built expertise and delivered innovations to improve outcomes relating to liver disease and liver cancer. Related strands of research developed strategically and incrementally through large-scale, long-standing industry-focused partnerships to improve drug delivery and toxin removal mechanisms for these conditions. Two examples detailed here evidence UoB’s distinct approach to impact through embedded partnership working linked to commercialisation and clinical care pathways. This includes: i) the DC Bead^® technology, an established cancer treatment product that is now established in the global market, delivering impact for the rapidly growing speciality Interventional Oncology market as well as patients worldwide, and ii) the clinical grade Carbalive^TM product, an emergent technology under clinical evaluation for the treatment of advanced liver disease, commercialised through a UCL spin-out, now generating jobs, GBPmulti-million investments and setting a path towards better health outcomes.

4.1 Advancing embolization technologies to target liver cancer

The research partnership between UoB and Biocompatibles UK, and the development of research into DEB technologies, led to joint patents and commercialisation of the DC Bead^®, a novel combination product for the treatment of liver cancer [Source 5.1]. The commercialisation process, led by BUK but based on the joint underpinning science, underwent intensive clinical evaluation and was the first product of its type brought to the market for launch in 2005. The DC Bead^® has been evaluated in clinical trials worldwide and is now recognised as a gold-standard treatment for intermediate primary liver cancer. The DC Bead^® is proven to offer an improved safety profile over conventional procedures, with chemotherapy drugs only delivered to the site of the tumour and not healthy tissues. Studies using these products have shown less leakage of chemotherapy into the systemic circulation than conventional treatments, resulting in reduced side effects. This is set in a context where patients suffering primary and secondary liver cancer may have limited treatment options, or otherwise poor overall prognosis [5.2]. Product sales have increased globally to 850 hospitals (250 in the period), treating patients across Europe, North and South America and the Asia-Pacific areas. There have been 100,000 reported procedures since 2013 [5.3]. In 2016 BTG announced the DC Bead^® product was upgraded to a classification of Class III based on its ability to administer medicines and the non-clinical and clinical data supporting the safe and effective conditions for use. This classification is awarded following rigorous additional evaluations including by the European Commission [5.4].

The later body of collaborative research into innovative radiopaque drug eluting bead therapy has contributed to the development of new vandetanib-eluting radiopaque beads [5.5], which provided the foundation for the vandetanib-eluting bead, developed by BTG plc in collaboration with Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. Led by UCL’s Cancer Institute, in partnership with Biocompatibles UK, the bead has been used in clinical trials by UK clinicians since 2017. The Chair of Radiation Oncology at UCL has confirmed that the radiopaque bead ‘ offers the advantage of providing visible confirmation of bead location during and after the embolisation procedure, enabling real-time adjustments to optimise patient treatment’, which is ‘ helping to develop a liver-directed treatment as a superior alternative to the rather poorly tolerated drug treatments we currently offer patients with this type of cancer’ [5.5]. Following from the success of the DC Bead^® the newer radiopaque bead (DC Bead LUMI™) was also awarded a Class III CE Mark classification in 2017. This differs from the other products in the range as it provides real time visible confirmation of the bead’s location improving delivery control and analysis post procedure, enabling clinicians to individualize a patient’s treatment and evaluate the completeness of tumour treatment, improving patient outcomes [5.6].

Both the DC Bead^® and DC Bead LUMI™ continued to be sold by BTG until 2019 with sales data showing the firmly established DC Bead^® product as a leader in the market of drug-eluting embolization products, with approximately 70% of the total global market share. Sales of this product provided 15% of BTG’s MedTech revenue and 6% of the company’s total revenue in 2018 [5.3, 5.7]. In 2019 BTG was sold to Boston Scientific in a USD4,200,000,000 acquisition deal. As a legal requirement within the acquisition process, regulated by the US Federal Trade Commission, Boston Scientific sold their own competing bead products to Varian Medical, in favour of the DC Bead Technology [5.8]. The Vice-President for Research and Development at Boston Scientific confirmed that the DC Bead technologies were the main products that made the sale attractive in the first place as the trade names were long established, trusted and respected and based on a strong body of scientific and clinical evidence and rigorous evaluation processes. These products had long been known as best in class technologies [5.9]. As a result of this acquisition Boston Scientific now has the widest portfolio of products in Interventional Oncology [5.7]. The CEO reported that ‘ the addition of the BTG Interventional Medicine portfolio reinforces our category leadership strategy and enables us to offer best-in-class technologies, unparalleled clinical evidence and a strengthened commercial infrastructure to support physicians treating some of the most challenging diseases impacting patient health around the world’ [5.8].

4.2 Developing adsorbent technology as a product for oral treatment of liver disease

The second strand of UoB research linking internal, tailored porous structure to the removal of bacterial endotoxins, led to the filing of 2 patents in the period by Mast Carbon International with UoB as co-inventors [5.10]. The first patent Carbon and its use in blood cleansing applications was sold to Immutrix Therapeutic Inc with a US patent 9,278,170 granted in 2016. Immutrix have built a manufacturing facility and subsequently developed a blood cleansing device to target inflammatory and immune molecules for a range of medical applications. The second patent, Shaped nanoporous bodies was sold to Neoteryx in June 2018 for use within a volumetric blood sampling device. Following generation of proof of concept data for use of the adsorbents as an oral treatment for liver disease using UoB Business Investment seed funding, a patent was filed by UCL Business with UoB named as co-inventors [5.10]. This preparatory research using UoB expertise to develop the adsorbent bead technology for biomedical device applications, supported by patented data, led to the award of a successful Horizon 2020 grant (CARBALIVE, UCL lead project partners) and the first EU multi-centre clinical safety study in patients with liver cirrhosis. The trial included 56 patients from 9 hospitals in UK, France, Italy, Portugal, Spain and Switzerland [5.11]. Results from the Phase 2 trial confirmed the safety and efficacy of the product with patients showing a 90% tolerance rate. Preliminary data showed that measures of gut specific health improved, alongside a wide range of biomarkers of systemic inflammation [5.11].

The IP relating to this product was licensed to a UCL spinout company, Yaqrit Ltd, a clinical stage life sciences company established in 2014, focused on clinical solutions for advanced liver disease. As part of the CARBALIVE project Yaqrit Ltd created a manufacturing facility to supply clinical grade product, now under the trademark name Carbalive^TM. This is the world’s only manufacturing facility capable of making Carbalive^TM for oral delivery to humans, resulting in a further planned expansion of the company and a pivotal trial to take the product to the next stage. Yaqrit Ltd is now planning the route to regulatory approvals worldwide [5.12, 5.13]. Yaqrit Ltd employs 15 people and has attracted GBP25,000,000 in investment to develop and supply the product [5.13]. The success of the Carbalive^TM technology, which has utilised UoB’s cumulative research expertise, shows a clear path towards a reduction in the burden of advanced liver disease. Together with the established DC Bead^® brand this shows how teams of UoB researchers apply, position and scale-up their research to meet evolving demands in healthcare worldwide.

Collaborative longitudinal research led by UoB with Physio First (the trade organisation representing chartered physiotherapists in private practice in the UK) and a professional network of the Chartered Society of Physiotherapy (CSP) has led to a significant increase in memberships for the organisation enabling them to provide a standardised and optimal service across the sector. These systematised data collection and guidance tools have affected affiliated clinics, health care providers and individual practitioners, by raising the standard of care across the UK.

4.1 Setting UK standards for professional private practice

The Quality Assured Practitioner award, launched by Physio First in November 2016, and the Quality Assured Clinic award, launched in November 2018, allow Physio First members to demonstrate their quality and patient outcomes to potential patients and health care providers on an annual basis [sources 5.1, 5.2]. These quality awards are based on standards set using the criteria derived from UoB analysis of the DfI national data. Before these awards were introduced, data collection and verification tools were inconsistent with no standardisation to ensure the quality of care. In order to be eligible for the quality assurance awards, Physio First members have to collect DfI and PROM data [5.2]. The Quality Assurance schemes are the only independently analysed MSK data collection schemes in the UK and interest in the schemes continues to grow rapidly. The ‘Quality in private MSK Working Group’, a collective of stakeholders within MSK, including the main private medical insurers (eg Bupa) and the private hospital groups as well as representatives from the Chiropractic and Osteopathic professional bodies, have featured the schemes highly as a key reference point whist agreeing a common sector wide minimum data set [5.3].

Physio First requests that practitioners use the online BmPROM for this data collection exercise. Practitioners submitting a minimum of 50 datasets within a 12-month period via the DfI system and collecting PROM data are automatically assessed for the QAP award by the UoB team. The number of practitioners meeting the eligibility criteria for QAP assessment has increased from 44 in 2016 to 179 in 2020. Practitioners have reported positive feedback on the quality scheme as it provides a professional standard and framework, is used in the recruitment of new staff and applied to market quality assured services, building confidence with potential clients [5.4, 5.8]. Clinics can apply to UoB for a QAC assessment. All MSK practitioners within the clinic are required to collect DfI and PROM data. The minimum number of datasets required per clinic is calculated on a pro-rata basis for each staff member and their working hours over a 12-month period. The number of clinics applying for a QAC assessment has increased from 10 in November 2018 to 55 in September 2020.

In April 2019, BUPA endorsed the Quality Assurance Clinic scheme [5.5]. BUPA, an international healthcare provider and the largest private medical insurer in the UK, contracts physiotherapy practitioners to provide funded treatment for BUPA clients. In order to be part of the physiotherapy network, clinics need to apply for BUPA recognition, which includes the requirement to monitor and evaluate the quality and value of their services. In the contract process with physiotherapy providers in 2019, BUPA identified the Physio First Data for Impact and Quality Assured Clinic scheme as the only quality assurance schemes they would endorse. As part of their application and renewal process BUPA exempted all QACs from their audit of outcome metrics. QAC accreditation can be used as evidence of collection of quality and key performance metrics [5.2, 5.5]. Furthermore, practitioners undergoing an audit by the Health and Care Professions Council can use DfI reports as evidence of continuing professional development [5.2].

4.2 Advancing learning, practice and business management amongst private physiotherapy practitioners

Since its launch in November 2014 there has been a 561% increase in members of Physio First registering to use the DfI system, rising from 158 members registered in 2014 to 1045 in October 2020. The DfI system, which now has in excess of 70,000 patient datasets, provides an evidence base for physiotherapy demand, delivery and patient outcomes, which Physio First use to showcase patient outcomes from private practitioners on a national scale, in the provision of value based private physiotherapy. Physio First has developed a number of evidence-based statements from the DfI data analysis that they and members use to promote physiotherapy in the marketplace [5.3, 5.6]. The DfI findings are also used by Physio First to direct all of their centrally run educational courses for members. The findings are being used with the organisation’s education strand to identify gaps in knowledge, provide webinars on data collection and implementation, and to enable practice principles to target in service training more effectively [5.3, 5.7].

Practitioners have reported that the process of collecting data in a standardised format through the DfI project improves the quality of the data and stimulates reflective practice on patient scores, treatments and outcomes that may not have occurred without the data recording process [5.8, 5.9]. Individual practices have reported that the use of the DfI scheme to measure outcomes gives greater confidence in quality standards. The regular individualised DfI feedback reports are helping practitioners to direct their continuing professional development and training (by identifying their strengths and weaknesses), enabling them to benchmark their practice against the national dataset providing targeted data for business management and marketing [5.8].

In 2017, the BmPROM was made freely available in paper format for any MSK physiotherapist to access before an online version was launched in May 2018 solely for access by Physio First members who are participating in DfI. Consequently, there has been an increase in the number of private practitioners collecting PROM data from their patients both in hard copy and online. By September 2020 more than 150 practitioners were using the online BmPROM with their patients. Practitioners have reported that the two systems have deepened practitioner understanding of the patient needs/expectations which leads to more realistic agreed goal setting [5.9].

4.3 Supporting Physio First growth and strategic development

The DfI project and quality assurance schemes are central to Physio First’s vision to champion evidence-based, cost effective private physiotherapy in a changing healthcare marketplace. Launched in 2018, Physio First’s 3-year business plan aims to replace the term ‘ evidence-based cost effective’ with the term ‘ quality’ by 2020 (Goal 7). This instead became ‘ evidenced value based private physiotherapy’, reflecting its well-documented aim of putting quality at the heart of its work. Goal 4 identifies the critical role of DfI, QAP and QAC schemes in achieving this and creating opportunities and advantages for Physio First and its members in a changing marketplace [5.10].

The programmes are central to Physio First’s offer; participation in the DfI programme and gaining QA awards are promoted to practitioners as two of Physio First’s ‘big 5 benefits’ of membership [5.11]. In 2018, the QAC/QAP ‘ benchmarking’ and ‘ quality’ were keywords emerging from engagement with Physio First members on perceived and actual value of membership [5.2]. Since the launch of the QAC and the endorsement by BUPA, interest in the DfI project and quality schemes has increased exponentially. Physio First reported that between April and May 2019 112 new members joined their organisation, the highest ever number within a similar time period [5.12]. In 2019 Physio First introduced a new membership level allowing part-time employees to access the Quality Assurance schemes. Physio First has also changed their membership structure, offering a reduced fee membership on the condition that part-time practitioners commence data collection via the DfI system and work towards gaining quality assurance status [5.13].

Rabe’s Cochrane Review on the optimal timing of the umbilical cord clamping has been instrumental in changing UK and international policy (EU, Canada and USA) on the use of delayed cord clamping in preterm births. In doing so, it has led to a shift in the understanding and acceptance on the importance and benefit of DCC, with these results filtering through to a reactive shift in practice to realise these benefits.

4.1 Informed national and international healthcare policies and guidelines on optimal cord management

Since its original publication in 2012, Rabe’s Cochrane Review on DCC has been adopted in 17 national and international guidelines [Source 5.1a; as recorded on the Cochrane Review website on 20 Oct 2020] including the WHO 2014 Guideline on Delayed Umbilical Cord Clamping [5.2], the European Consensus Guidelines on the Management of Respiratory Distress Syndrome 2016 Update [5.3], and the National Institute for Health and Care Excellence Preterm Labour and Birth Guideline [5.4a and b; 2015 updated 2019].

4.1.1 WHO Maternal and Infants’ Health: The WHO 2014 guideline on DCC [5.2] was developed following a request from Member States for the WHO to provide guidance on the effects of DCC to improve maternal and infant nutrition and health as a public health strategy. The Guideline Development Group (GDG) evaluated updated evidence from two existing WHO guidelines (both published in 2012) on optimal timing of the umbilical cord clamping. Rabe’s 2012 Cochrane Review was one of three Cochrane Reviews assessed by the WHO 2014 DCC GDG and the only one that considered optimal timing of cord clamping in preterm babies. The GDG considered the benefits of DCC for preterm to be critical and concluded with a strong recommendation that DCC should form part of the essential neonatal care provision and be applied equally to preterm and term births [5.2]. Adherence to this recommendation is a reasonable measure of good-quality care. For policymakers, it means that it can be adapted as an instruction for most clinical situations. The 2014 WHO guideline on DCC in preterm births has since been used as a key reference in the WHO 2018 recommendation on Intrapartum care for a positive childbirth experience [5.5], as well as the WHO recommendation on ‘Optimal timing of cord clamping for the prevention of iron deficiency anaemia in infants’ [5.6].

4.1.2 American College of Obstetricians and Gynecologists/American Academy of Paediatrics Guideline: Rabe’s 2012 Cochrane Review informed the latest American College of Obstetricians and Gynecologists (ACOG) Committee opinion on cord management which now ‘ recommends a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30-60 seconds after birth […] given the benefits to most newborns’ [5.7a]. Professor Tonse Raju, Medical Officer of the National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health USA (NIH) contacted Rabe requesting a draft of her 2012 Cochrane Review to support the development of neonatal care policies with the Committee on Foetus and Newborn of the American Academy of Pediatrics (AAP):

*‘Thanks to the cumulative research data from Prof. Rabe and her colleagues and the strong message from their systematic review, the committee’s approval accepting my draft was unanimous. The ACOG/AAP members were particularly impressed by the strength of the evidence related to lower rates of anemia, improved blood pressure, and reduced rates for all grade of intraventricular hemorrhage – the last one being the most important, prevention of which could improve long-term outcomes of preterm infants. Interestingly, the above paragraph is still retained in the ACOG Committee Opinion #684 published in January 2017 [*5.7c] along with the citation for Prof. Rabe’s 2012 publication’ [5.7b].

4.1.3 The European Consensus Guidelines on the Management of Respiratory Distress Syndrome (RDS): The 2016 update [5.3] provides a set of recommendations for the optimal management of preterm babies with, or at risk of, RDS to achieve the best outcomes for neonates in Europe. Developed by European neonatologists, this guideline is endorsed by the European Association of Perinatal Medicine. Rabe’s 2012 Cochrane Review has informed the 2016 updated recommendation on optimal cord clamping which states, citing Rabe’s Review: ‘ if possible, [to] delay clamping the umbilical cord for at least 60 s to promote placentofetal transfusion.’ [5.3]. The European Consensus Guidelines provide a strong recommendation to use the intervention listing its benefits as reported in Rabe’s 2012 Review (higher haematocrit, transiently higher blood pressure with less need for inotropic support and fewer intraventricular haemorrhages).

4.1.4 NICE Guidance on Preterm Labour and Birth: Both the original 2015 and the updated 2019 versions of the NICE Guidance on Preterm Labour and Birth [5.4a and b] recommends waiting for at least 30 seconds, but no longer than 3 minutes, before clamping the cord of preterm babies if the mother and baby are stable. Among the 3 evidence sources cited for these recommendations, Rabe’s 2012 Cochrane Review is the only one noted as presenting no major limitations and providing research-based evidence on the timing of cord clamping ranging from 30 to 180 seconds.

4.1.5 British Association of Perinatal Medicine Optimal Cord Management Toolkit: The national rollout of the DCC practice to all maternity and neonatal units in England is supported by several interventions and organisations such as the British Association of Perinatal Medicine (BAPM) Perinatal Optimisation Care Pathway. Rabe was part of a four-nation team of obstetricians, midwives and neonatologists with parent representation leading on the BAPM Optimal Cord Management Toolkit development [5.8]. This toolkit, which draws significantly on Rabe’s research-based evidence review, is one of four produced by the BAPM for their Perinatal Optimisation Care Pathway. Its implementation in maternity and neonatal units across NHS England will be supported throughout England by the Maternity and Neonatal Safety Improvement Programme (MatNeoSIP). One of the MatNeoSIP key drivers to improve the optimisation and stabilisation of the very preterm infant mandates the recording of the proportion of babies less than 34 weeks who received DCC at the time of delivery [5.9]. To justify this mandate, MatNeoSIP refers to the NICE 2015 Preterm Labour and Birth [5.4] which based their DCC recommendations on Rabe’s 2012 Cochrane Review.

4.2 Produced change in health practitioners’ attitudes towards DCC resulting in its increased adoption in clinical practice in the UK and the USA

The ACOG/AAC policy endorsement of Rabe’s Cochrane Review recommendations has had a significant effect on the practice of cord clamping in the USA:

‘A 2012 survey (published in 2014) showed that 88% of respondents of ACOG member-hospitals did not have a policy on cord clamping. But, a small 2014 survey showed that the policy implementation is improving—between 50% to 80% of preterm infants are getting the benefits from delayed cord clamping by adapting the ACOG/AAP policy’ [5.7b].

This uptake of the DCC practice, following its endorsement by the ACOG, is reflected in a 2017 survey of the American College of Nurse-Midwives concerning their umbilical cord clamping practices [5.10]. The survey (1,050 responses analysed) revealed that DCC was performed in 65% of preterm births and that the existence of guidelines on the timing of cord clamping was associated with two-fold increased odds of practicing DCC for preterm newborns. A survey conducted in the same year on USA Obstetricians (n=137) following the recommendation of the ACOG showed that 73% waited at least 30 seconds before clamping the cord for preterm births and showed that employing strategies to implement the full uptake of this practice could prove vital [5.11].

In the UK, Rabe’s 2012 Cochrane Review formed the basis of DCC practice guidelines developed and implemented by regional maternity and neonatal units as part of their contribution to the MatNeoSIP. Delivered through a network of 15 regionally based Patient Safety Collaboratives (PSC), one of the MatNeoSIP primary drivers for change to the maternal and neonatal care is the optimisation and stabilisation of the very preterm infant. In the West and South West England PSC, the delivery model developed and implemented for this primary driver is PERIPrem, a perinatal care bundle to improve the outcomes for premature babies across the 12 maternity units in the region. Launched in May 2020, PERIPrem is formed of ten interventions designed to improve preterm health, one of them being DCC [5.12]. The Operational Clinical Lead for PERIPrem, Dr Sarah Bates [5.13] explained the importance of Rabe’s Cochrane Reviews in driving change in maternity units as part of PERIPrem:

‘Including the clear findings of Prof Rabe’s work on DCC and in particular, its mortality statistics (reduction by a third of preterm death following DCC), in the PERIPrem message has been one of the key drivers for change in the units.’

The maternity units were performing well in nine of the ten PERIPrem interventions (eg steroid and magnesium administrations); however, all of them needed support to improve their rates of DCC for their preterm population. For the majority, their baseline rates in DCC were about 30-40% of babies born at less than 34 weeks. Six months after its launch, the latest data received from Nov 2020, showed that 85% of all babies born before 34 weeks across the region now have their cord clamped following a delay of at least a minute [5.13].

Dr Bates credits this most significant growth area for PERIPrem to Rabe’s research-based evidence on the effects of DCC on preterm mortality rates, which was used by Bates and colleagues to influence clinicians’ attitude to change [5.13]:

‘Prof Rabe’s Cochrane Reviews provided the research-based evidence used in DCC training materials to educate teams to be able to overcome barriers to implementation of this practice.’

Rabe’s research on DCC was also a pivotal source to Dr Donna Winderbank-Scott, Quality Improvement Lead for the Neonatal Department at the University Hospitals Southampton. The consultant neonatologist used Rabe’s work to develop a new clinical guideline for DCC, and educate colleagues about the benefits of DCC on preterm babies [5.14]:

‘Southampton has a busy maternity unit (>5,500 births/year) with the Neonatal Unit admitting 15-20 inborn preterm babies per month. […] in 2016, the Trust had a significant variability in the implementation of DCC in term babies and very little implementation in preterm babies. […] I developed a new guideline for DCC […], I used Prof Rabe’s 2012 Cochrane Review and her 2016 publication on neurodevelopmental outcomes to convince the local team of the benefits of DCC to preterm babies, and thus the need for a change to the current working practices. […] This proved to be invaluable in overcoming resistance to implementation from some clinicians who had not seen the latest research on the topic and who held beliefs or concerns which had been proven to be unsubstantiated.’

Following formal approval of the new clinical guideline on DCC in May 2018, the Unit has seen a steady increase in DCC rates in preterm babies, measured via correct adherence to the guideline raising from 50% in Oct 2018 to 100% in Oct 2019 [5.14]. Since the implementation of the new clinical guideline, informed by Rabe’s research-based evidence on the topic, the overall DCC rate in the Unit for preterm babies (<32 weeks) has increased from 35% in 2016 to 48% in 2020 – a relatively high rate for a tertiary centre with a significant proportion of complicated births [5.14]. DCC teaching sessions are now included during induction and on mandatory study days to reach the entire midwifery team and to train junior medical staff within the Trust [5.14].

The HYVET Trial provided the research-based evidence needed to establish a blood pressure target within national and international healthcare guidelines. This measure is specifically for the treatment of hypertension in the over 80s. Prior to this study, this patient group had been neglected with no appropriate measure available to guide clinical practice in relation to these patients. As a result General Practitioners in England now have a set blood pressure threshold to refer to when considering hypertensive treatment in this age group.

4.1 Providing clinical guidance on hypertension in the UK (NICE) and internationally (USA, Canada, Europe and China)

Research within the HYVET programme provided guidance to physicians and policy-makers to improve standards, assist in the knowledge and training of health care professionals and to help patients make informed decisions about their care. These national guidelines undergo regular reviews to ensure that recommendations provided are based on the most recent and robust research findings.

In the UK, the findings of the HYVET trial were incorporated originally into NICE guidelines as recommendations for the treatment of hypertension in 2011. Following a review of these guidelines in 2019, it was confirmed that these findings remain the critical reference point for guideline committees to base their recommendation for the treatment of hypertension in the very elderly [source 5.1]. Professor Terry McCormack, member of the NICE 2011 Guideline Development Group and the NICE 2019 Guideline Committee on Hypertension confirmed that this study was ‘ pivotal in setting the standard for the treatment of hypertension in the very elderly’. Professor McCormack further clarifies that:

‘In both instances when considering the optimum blood pressure in the very elderly, the HYVET study provided the most robust and highest quality evidence compared to all the other studies reviewed. Based on the trial results, the 2011 Guideline Development Group recommended that people aged 80 years old and over […] should be treated to a clinic blood pressure target of under 150/90mmHg, as defined by the HYVET Trial. This recommendation was sustained in the updated version of the guideline published in August 2019 […] Based on their experience the [NICE 2019] committee members agreed to retain the recommendation from the 2011 guideline, which was based on the HYVET Trial - the only large, outcome-based randomised controlled trial in this age group’ [5.2, 5.3].

HYVET is the key evidence cited in international guidelines to treat high blood pressure in people aged 80 years and over [5.4], and by providing this guidance to healthcare professionals worldwide, the HYVET study has contributed to ‘ an improved quality of care’ [5.2]. The international guidelines that utilise the HYVET results to evidence their recommendations include the American College of Cardiology and American Heart Association guidelines, the Hypertension Canada Guidelines, the European Society of Cardiology/European Society of Hypertension guidelines, and the Chinese guideline for the management of hypertension in the elderly. Each set of guidelines adopts a rigorous, evidence-based approach to recommend treatment thresholds, goals and medications in the management of hypertension in adults and grade the quality of evidence. Recommendations are made based on their effect on prioritised outcomes. Adopting this stringent evidence-driven process, the authors of these guidelines, drawn from a significant pool of international experts in the field, cited the HYVET Trial as one of the critical studies for clinical effectiveness of the treatment of hypertension in the very elderly.

One of the most influential guideline updates is the eighth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC8) published by the American Medical Association in 2014 that replaces the previous guidelines published in 2003. Panel members appointed to this review developed evidence statements and recommendations for blood pressure treatment based on a systematic review of the literature to meet user needs and the needs of the primary care clinician. Randomised controlled trials, including the HYVET study, formed the basis of these new guidelines, as they represent the gold standard for determining efficacy and effectiveness. In this guideline the recommendation to initiate pharmacologic treatment to lower BP to 150/90 to treat patients over the age of 60 (including the very elderly) was given a Grade A recommendation, the strongest grade given to recommendations where ‘ there is high certainty based on evidence that the net benefit is substantial’ [5.5].

4.2 Changing clinical practice and the treatment of hypertension in the very elderly in England

Due to the introduction of a new blood pressure target for the very elderly, based on the HYVET findings, monitoring of clinical practice data is now available. In March 2015 a review of the adoption and implementation of NICE Guidance CG127 (2011), showed that 85.6% of patients in England with peripheral arterial disease had their last blood pressure reading (measured in the preceding 12 months) set at 150/90mmHg or less [5.6]. This is directly in line with NICE Guidance for Recommendation 1.5.6 based on the HYVET Trial. NICE generate Quality Standard (QS) for GPs and other care providers to use to evaluate their current practice and understand how to improve care. The uptake of the NICE QS is measured via various national records such as the Quality Outcome Framework (QOF). QOF is a voluntary annual reward and incentive programme for all GP practices in England. It consists of a set of achievement measures, based on the NICE indicators, against which GP practices are scored and rewarded financially. The QS28 'Hypertension in Adults' Statement 4 is based on the HYVET Trial findings that recommends ' people with treated hypertension have a clinic blood pressure target set to below 140/90 mmHg if aged under 80 years, or below 150/90 mmHg if aged 80 years and over.' As part of its uptake assessment, QOF recorded the percentage of patients with hypertension in whom the last blood pressure reading (measured in the preceding 12 months) was 150/90 mmHg or less. Data collected from GP practices across England, in March 2016, March 2017 and March 2019 showed that 79.6%, 80% and 79.7% of patients reached this blood pressure target, respectively [5.7]. These data confirm that the blood pressure targets in the very elderly, informed by the HYVET trial, have been met in up to 80% of patients treated for hypertension at GP practices in England.

There are currently 400,000 patients with T1D in the UK. A typical T1D patient suffers an average of two symptomatic hypoglycaemic episodes a week, hence thousands of episodes across a lifetime. They will suffer at least one episode of severe, disabling hypoglycaemia (often with seizure or coma) every year. This number rises dramatically in patients with poorly controlled diabetes, leading to frequent hospitalisation and life-threatening consequences. Prior to islet transplantation therapy, the gold standard for treatment of T1D was a complex regime of manual, sub-cutaneous insulin injections, in combination with frequent finger prick blood glucose monitoring and carbohydrate counting. Optimising this regime for an individual is extremely challenging and requires immense commitment from patients. UoB’s sustained developmental research programme, working collaboratively with clinicians, charities and industry, has produced innovative solutions that have transformed the treatment of T1D. This is partnered with embedded public engagement strategies that have resulted in the reversal of pre-diabetes and greater awareness of life-changing therapies amongst those at greater risk of developing T2D.

4.1 Improving transplant technologies and outcomes

UoB research provided much of the basic science underpinning both the initial establishment and the ongoing activity (2013-onwards) of the UK Islet Transplant Consortium (UKITC). An islet transplant is a low-impact, but life changing therapy as it controls hypoglycaemic events for those patients most severely affected and is offered only when all other treatment options have failed. The clinical translation of beta-cell replacement therapy was used to establish the UKITC. Transplants provided through the consortium have, on average, reduced hypoglycaemic events from 23 per person per year to less than 1 per person per year. These islet transplants lead to improved awareness of hypoglycaemia, less variability in blood glucose levels, improved average blood glucose, improved quality of life and reduced fear of hypoglycaemic events [Sources 5.1, 5.2, 5.3].

Seven designated centres within the consortium, based in Bristol, Edinburgh, North and South London, Manchester, Newcastle and Oxford, provide a cost-effective national programme for islet transplantation, which helps to reduce the GBP1,170,000,000 per year that is spent on hospitalisation of poorly controlled T1D patients. Diabetes UK have invested over GBP2,300,000 into the research and development of this treatment option including the ongoing work of the UKITC [5.2]. Since August 2013, the number of successful islet transplants delivered through the consortium has risen from 65 to 202 across the UK. These numbers are limited by the availability of donor tissue and because donor pancreases are shared equitably between islet and solid organ recipients. There are approximately 40 people on the islet transplantation waiting list each year. All patients who have undergone a transplant experience a long-term reduction in severe hypoglycaemic events [5.1, 5.2, 5.3]. Since 2013 the improved avoidance of hypoglycaemic episodes in these patients has increased from ≥95% to >98% and the longevity of transplant function has improved, with many patients now entering their second decade of clinical benefit. Results are continuing to improve all the time with clear effects on quality of life as a result of these transplants [5.1, 5.3]. Patient stories, reported as part of Diabetes UK’s highlight notices, tell of sustained reduction in HbA1c, or glycated haemoglobin, a key measure in the reduction of risk of severe complications with eyes and feet [5.3]. For those suffering with T1D an ideal HbA1c level is 48mmol/mol. Figures in the islet transplant annual report 2018-2019 show that median HbA1c dropped from 62mmol/mol prior to transplant to 48mmol/mol at one-year post-transplant [5.3, 5.4]. The success of this transplant programme has ‘provided a sustainable platform for ongoing service provision and further innovation’ [5.5]. The UoB has also played a key role in improving patient acceptance of the technology behind islet transplantation. Local and national coverage of this research led to a BBC Inside Out documentary (2017), helping patients and the public understand both the science and the benefits of the islet transplant technology. Patient testimonials included within this documentary evidence the profound impact of this life-changing therapy. In particular this documentary covers the story of one patient severely affected by unpredictable blackouts who is now able to engage with everyday activities post-transplant: ‘ I can now live and do whatever I want to do whenever I want to do it without having any worries’ [5.6].

4.2 Building healthcare and industrial strategies to fight Type 1 diabetes

Collaborative research with industrial partners has helped build capacity for technological development and to ensure success of the experimental technologies. Challenges in the expansion of islet transplantation therapy are based on the difficulty in transporting living cells to transplant centres. A partnership with Cellon International (Luxembourg) used UoB research into clinically-reflective cellular model systems to develop a novel microgravity-based cell clustering technology. This technology helps overcome the damaging effects of tissue hypoxia (very low oxygen) in the crucial first 48 hours post-transplant. This led to the creation of the first portable microgravity cell enhancement system for the transportation of islets to transplant centres and the first culture system allowing real time testing of islet function. This is the first direct clinical application of Cellon microgravity technology, helping to drive forward the company’s work in this sector by opening technology routes. This is the first step forward in the strategy around the engineering of islet cells for different clinical applications to improve the efficacy of transplant technologies in the long-term fight against the condition [5.2, 5.7]. As confirmed by the Cell Therapy Advanced Specialist to the Northern Alliance Advanced Therapy Treatment Centre ‘ 3D microgravity culture had previously only been used on solid organs, but is now widely utilised in both islet and stem cell biology practice. Pioneering work from the Brighton team in the original development of 3D polymer scaffolds for the growth and differentiation of stem cells also resonates now across a massive expansion in scaffold technologies in this field’ [5.2].

UoB helped to drive the establishment of the Islet Research European Network (IREN), which led to the creation of INNODIA (2015-2022), a global partnership between 31 academic institutions, 6 industrial partners, 1 SME and 2 patient organisations [5.1]. The establishment of this private-public partnership has built capacity by uniting a broad range of knowledge and experience in a unique network now delivering work supporting the long-term strategy to slow down or prevent the onset of T1D. INNODIA is purposefully closely guided by the patients themselves through its Patient Advisory Committee which informs the concept and work of INNODIA, including the development of protocols and the dissemination of this work to the wider public. This ensures that INNODIA helps retain focus on the central voice of those living with T1D and how it affects every day life [5.8]. In September 2020, INNODIA received approval from the regulatory authorities to start MELD-ATG, a study for newly diagnosed T1D patients between the ages of 5 and 25 to slow down the onset of T1D. This is building towards the overarching goal of INNODIA to predict more effectively the risk of developing T1D and the development of novel treatment strategies to delay and ultimately prevent T1D development [5.1, 5.8].

4.3 Delivering effective public engagement programmes that increase patient awareness and acceptance of new technologies

Promoting patient understanding and acceptance of new technologies is a fundamental part of UoB work with the UKITC, Diabetes UK and the Juvenile Diabetes Research Foundation International. UoB have a long and established track record in increasing public awareness through events run for patients and the parents of those with diabetes [5.1, 5.2, 5.9]. This is becoming increasingly important as the NHS now faces a dual challenge of rising numbers of obese and diabetic patients. Treatment costs for complications relating to the disease account for 10% of the NHS budget and in the South East 1% of the regional budget is spent on amputations due to uncontrolled diabetes [5.10]. This is the driver behind a sustained programme of patient and public engagement to deliver early interventions with at-risk groups. Since August 2013, focused engagement with voluntary support groups has expanded to engage with a further eight new diabetes support groups nationally, three new obesity support groups for young patients nationally (<18 years old); eleven new schools and community colleges locally; and three new local hospitals (Royal Sussex County Hospital, the Royal Alexandra Children’s Hospital and the Princess Royal Hospital in Haywards Heath). The focus of this programme is on individual patients and personal management of the condition. Events have increased patient knowledge and understanding of how best to manage the disease, and how to understand the emerging treatment options now available. Evaluation data shows that out of 168 diabetes patients participating in these events 78% felt more positive and confident about managing their diabetes and 83% strongly agreed that they had more knowledge of all the possible treatment options available to them after attending these events [5.9, 5.10]. UoB work with at-risk teenagers has seen the research on glycaemic variability translated into tailored diet and exercise programmes, specific to each patient’s own metabolism. A new research-based motivational tool based on stabilising glycaemic profiles, developed as part of this programme, has also had an impact through the reversal of T2D in older patients [5.9, 5.10, 5.11]. The research-led engagement programme allows young patients to understand the effects of food, beverages and exercise on their blood glucose and has helped them to reverse their pre-diabetes and restore a normal balanced metabolism. Since 2013, over 80 young adults have graduated from the Redhill support group and no longer have pre-diabetes or T2D [5.10]. A specialist nurse working closely with the UoB team has confirmed that these successful interventions continue to be ‘ transformative’ and have built ‘ a platform for ongoing work in this area’ [5.10].

Verma and team, via the ITTREAT and VALID projects, provided the research-based evidence essential to the development and implementation of an innovative community-based HCV model of care for high-risk populations. This led to a substantial increase in access to and treatment of HCV in the Brighton and Hove area, improving the care experience for vulnerable members of the community. It also provided a robust good practice care model that is now leading the way for further replication of improved care services in England.

4.1 Increased access to and treatment for HCV

As of June 2018, ITTREAT and VALID studies have linked 700 homeless individuals and PWUD to care services in Brighton and Hove. The number of PWUDs and homeless individuals referred from the community to receive treatment increased from 0 in 2011 to 153 between 2014 – 2018 [3.3, 3.5]. The then local lead commissioner (Alcohol and Substance Misuse), Ms Kathy Caley, linked the increased number of individuals accessing HCV treatment services to the successful delivery of the BSMS innovative model: ‘ *The intensive support provided by the [ITTREAT] HCV nurse means that service users are more open to being tested, and are more informed about treatment options. The integrated nature of the HCV nurse with substance misuse treatment services has been very important in driving forward the success of this project [ITTREAT]. The outcomes of the service have been very positive with a significant increase in the number of individuals that are now accessing HCV treatment services (October 2015)*’ [5.1]. This view is seconded by Dr Tim Worthley, GP at the only homeless surgery in Brighton (Arch Healthcare), one of the VALID study sites, who notes: ‘ The significant impact that BSMS VALID study had is that it immediately removed all major blocks for our patients to access HCV care: patients did not need to go to hospital to receive treatment, they did not have to stop using drugs or alcohol, and the treatment was not based on interferons thus rendering the treatment protocol more acceptable for adherence. In a short space of time, our GP surgery went from 5% to approximately a third of our patients [total registered patients 1400] accessing treatment for HCV’ [5.2].

In Brighton and Hove, the percentage of PWUDs tested for HCV has increased from 87.6% in 2012 – 2013 (prior to ITTREAT project) to 96.4% in 2017/18 (5 years into the ITTREAT project). This represents the highest rate in South East England [5.3a]. Mortality from advanced HCV-related liver disease/ liver cancer, has reduced by 48% from 2012 – 2014 to 2016 – 2018, compared to a 9% reduction in mortality nationally over the same period [5.3b]. ITTREAT and VALID studies were the only clinical research conducted in the area during this period, specifically targeted at improving HCV testing and treatment of these high-risk populations. Dr Worthley acknowledged the impact of BSMS research on their approach to provide HCV care, noting that ‘[they] were able to emphasise with other healthcare services the importance of getting this population tested for HCV because for the first time there was the possibility of treatment’ [5.2]. The BSMS HCV care model has since been adapted to other services in the area, and in the last 5 years Dr Worthley has run specialist community clinics in diabetes and respiratory diseases.

4.2 Improved patients’ HCV care experience, understanding of HCV, and other health-related outcomes

The community-based HCV cure was associated with significant improvements in HRQoL, including improved mental and physical health, decreased distress and, most importantly, a reduction in the stigma associated with HCV [3.3]. This innovative model of care also contributed to an improved treatment experience in this group with the trusting client-provider relationship being instrumental in the individual’s recovery pathway and their own health awareness [3.4]. This is illustrated by patient testimonials: ‘ I thought it was a little less, err, impersonal. You just feel like you’re a cow being forced through, like a sheep dip kind of system in hospitals. But here you know they know your name and they’re a little bit more personal with you. I think a little bit more caring cos they have a little bit more time’ [3.4]. By providing a simplified HCV care pathway, patients experienced benefits over and above that related to the liver. According to Dr Worthley: ‘ patients […] immediately became more engaged with their healthcare, knowing they no longer had to face the numerous hurdles for them to access care. It thus provided them with the opportunity to regain control of their health. It also had a significant impact on their understanding of the disease and their ability to access treatment. As a result, once treated for HCV, they were able to address other issues in their lives such as their drug or alcohol use’ [5.2].

4.3 Developed a good practice care model for replication by HCV healthcare professionals

The BSMS holistic model of care for HCV has been commended by NHSE following its review of the Sussex ODN in 2018: ‘ the ‘one-stop shop’ model of community service provision provided easy access for clients and provided a great model to replicate around the country’ [5.4]. This view was seconded by Professor Graham Foster (ODNs National Clinical Lead) and Peter Huskinson (NHSE Commercial Director of Specialised Commissioning) who stated that ‘ Brighton’s initiative to treat people who are homeless [...] indicate the ingenuity and determination of colleagues who are pushing the boundaries of treatment access’ [5.5]. Consequently, Sussex ODN treats the highest number of people with HCV in addiction centres nationally, representing >20% of all its total treatments [5.6]. Public Health England’s HCV in England 2020 Report states: ‘ The majority of patients (78.5%) were treated in secondary care, with the remainder receiving treatment in either drug services, prisons or elsewhere […] with Nottingham and Sussex, [each] treating around a fifth of [their] patients in drug services’ [5.6]. The research by Verma and colleagues has been credited by the Sussex ODN manager as being key to the Brighton and Sussex University Hospital Trust ‘ achieving the NHS targets because it allowed the Trust to address the long patients’ waiting list’ [5.7]. It provided the evidence-base to convince Trust executives across the 3 Trusts in the Sussex ODN to support business cases for 3 community nurses, thereby ensuring roll out of the HCV care model across East and West Sussex. In 2016 – 2017, 11% of the Sussex ODN patients were treated in the community, with the majority of them in Brighton, but as of 2019 – 2020, approximately half of the ODN patients are treated via the community-based HCV services. This has become the principal HCV service delivery within the Sussex ODN.

The BSMS HCV care model has been endorsed as a good practice model by the British Viral Hepatitis Group and the largest national charity (HCV Trust/HCV Action) as evidenced by the HCV Action website hosting the ITTREAT case study and related business case template for other ODNs to consult. Since April 2018, the case study has had 585 views and the template 748 [5.8]. Birmingham ODN and Nottingham ODN – two of the largest ODNs in England – credited BSMS work as ‘ leading the way of HCV care in the community’ [5.9a] and providing ‘ an innovative set of solutions to a very difficult clinical problem’ [5.9b] to find, test and treat high-risk groups with HCV. Professor Stephen Ryder, Clinical Lead at the Nottingham ODN added that ‘ *Verma’s HCV care model was innovative […] it triggered a complete overhaul of the way we provide HCV care to this high-risk population (ie homeless and PWUDs)*’ [5.9b]. Both ODNs adopted elements of the BSMS HCV care model, adapting to their patients’ needs and local settings. This resulted in the Birmingham ODN being able to cure >200 patients whom they would have struggled to reach before [5.9a]. Similarly, Nottingham ODN used the BSMS model to expand their services and in particular their HCV care delivery to the homeless [5.9a]. As Chair of the HCV Coalition (a group of stakeholders working together to influence HCV policy and ensuring that HCV elimination target in England is met), Ryder and colleagues have used BSMS research data to advocate for HCV treatment for hard-to-reach groups, specifically the homeless. They used the BSMS model as an effective and successful clinical intervention for HCV care targeting this high-risk group [5.9b]. Both ODNs agreed that the work conducted by Verma and colleagues was one of the significant drivers for England to reach the target set to eliminate HCV by 2025, and that without this research-based evidence it will be difficult if not impossible to achieve it [5.9a, 5,9b]. [text removed for publication] [5.10].

Internationally, data from the ITTREAT study are contributing to the 2021 revised guidelines on Recommendations for the management of hepatitis C virus infection among people who inject drugs published by the International Network for Hepatitis in Substance Users [5.11].

4.4 Contributed to Gilead Sciences new patient access to care pathway initiatives leading to their successful NHSE tender in 2019

Gilead Sciences, an international pharmaceutical company (total revenue of USD22,400,000,000, 2019), has pioneered DAA development. Dr Murad Ruf, Director of Public Health Strategy and Implementation Science for Gilead Sciences, acknowledged the key role BSMS research played in their company’s understanding of HCV care in England [5.12a]: ‘ Professor Verma and her team were key in Gilead’s successful care implementation initiatives around HCV as they not only provided the research-based evidence that inform the new model of care, they also actively contributed to Gilead’s understanding of the integrated care pathway and the importance of the patient centric approach.’ This understanding in turn informed Gilead’s own patients’ access to care initiatives that were a key element of the company’s successful bid in response to the 2019 NHSE tender. Peter Smethurst, Director of the Patient Access to Care, Gilead Sciences, explained [5.12b]: ‘BSMS *ITTREAT study provided robust scientific evidence that co-location of care was a more effective way to deliver HCV care to this population, providing a measurable impact. The supporting principles of ITTREAT (co-location and patient-centric provision of care) have informed Gilead’s strategy for this patient group to be more effectively diagnosed and treated in addiction settings.*’ In partnership with Change Grow Live (CGL) – the largest provider of drug treatment services in England – the company demonstrated that this model of care could be successfully scaled up to more than 50 different drug services in England. This evidence formed part of Gilead Sciences elimination initiatives submitted in response to the NHSE tender, and for which the company was awarded Gold status (ie winning the greatest share of patients treated with the company’s drugs). Gilead Sciences have since expanded the partnership with CGL to 4 other providers, thus covering most of the third sector and NHSE Addictions Providers. Approximately 90% of the clients in drug treatment services are being cared for by one of Gilead Sciences elimination partners who are moving towards greater co-location and integration of care, as per the ITTREAT work [5.12b].