Impact case study database

Impact on global guidelines

As a combined body of work, MRC LEU research has directly informed patient care through policy and clinical guidelines globally. Studies in older age informed the WHO Report on Ageing and Health 2016 (Cooper is co-chair of the Healthy Ageing Coordinating Committee) [ 5.1]. The early life work informed the WHO Minsk Declaration through the core involvement of Cooper, who gave the keynote speech at the European Health Ministers Conference, Minsk, 2016; European Member States formally adopted the lifecourse approach as the basis for improving population health and wellbeing [ 5.2]. Together these documents demonstrated a commitment to the lifecourse approach to health which Southampton has pioneered and for which MRC LEU has delineated the key clinical assessments necessary to operationalise its evaluation and implementation worldwide.

Secondary fracture prevention

Using state of the art epidemiological techniques and study designs, Southampton work led the field in demonstrating the effectiveness and cost-effectiveness of Fracture Liaison Services (FLS). These studies have informed the global standard of care in FLS, set out by the International Osteoporosis Foundation Capture the Fracture initiative, which provides international quality standards for global benchmarking, key performance indicators and practical support [ 5.3]. Capture the Fracture led to the operationalisation of more than 400 registered FLS across 46 countries over the impact period, directly improving patient care by ensuring patients who experience a fragility fracture get the best assessment and treatment to minimise the risk of a subsequent fracture and associated ill health and death. The operationalisation of this strategy is estimated to have reduced hip fracture incidence by 25% in European countries [ 5.4]. The CEO of the International Osteoporosis Foundation confirmed Southampton research had underpinned its European guidelines and multiple position papers. He said the work ‘ *has established key critical advances in fracture prevention, demonstrating the value of fracture liaison services, indeed instituting the global framework ensuring best practice worldwide (Capture the Fracture), together with the achievement of major advances in fracture risk assessment and screening.*’ [ 5.3]

Capture the Fracture is cited as an example of best practice in the 2019 global Consensus Clinical Recommendations on Secondary Fracture Prevention, published by a multi-stakeholder coalition formed by the American Society for Bone and Mineral Research and including Southampton contributions through leadership positions of Cooper and Harvey at International Osteoporosis Foundation and Royal Osteoporosis Society [ 5.5]. The development of FLS across the UK was directly underpinned by MRC LEU research, through i) the National Osteoporosis Guideline Group (NOGG) recommendations [ 5.6] linked to guidance from the Royal Osteoporosis Society [ 5.7] and ii) the Royal College of Physicians (RCP) FLS Database and associated NHS-wide audit in England and Wales, commissioned by the Healthcare Quality Improvement Partnership as part of the Falls and Fragility Fracture Audit Programme [ 5.7]. This national service development programme has led to dramatic improvements in the reach and quality of FLS provision, with FLS covering 61% of the UK population (100% in Scotland). MRC LEU research was pivotal in the establishment of 73 FLS nationwide between January 2016 and December 2019 and the 230,000 patients subsequently recorded on the RCP FLS national database. The Southampton group’s work to develop Key Performance Indicators, addressing secondary fracture prevention for each acute NHS Trust in the country, was instrumental in achieving increases in risk assessment and in rates of osteoporosis medication prescription rising from 25% to 65% nationally [5.7]. Data from the Royal Osteoporosis Society demonstrate a nationwide saving of £800 million over five years as a result of FLS introduction [ 5.7].

Screening for fracture risk in older age

In order to further reduce the treatment gap in osteoporosis, MRC LEU has undertaken extensive work to develop optimal approaches to primary fracture prevention. Studies into the UK epidemiology of fracture, associated mortality and medication use, funded by the Royal Osteoporosis Society, together with SCOOP trial results, underpinned the assessment of disease burden and risk stratification in the NOGG recommendations (Harvey and Cooper are members of the advisory committee). Published in 2017, they have been cited in 234 publications and downloaded over 24,000 times [ 5.6], and they underpinned the 2019 ESCEO-IOF European guidance for the diagnosis and management of osteoporosis in postmenopausal women [ 5.8], which have been downloaded 17,500 times and cited in 184 articles. The NOGG recommendations have been accredited by NICE and incorporated into the NICE Quality Standards and Osteoporosis Treatment Pathway [ 5.9].

Linked to the NOGG approach and the SCOOP trial, the effectiveness of FRAX contributed to the tool being incorporated in 120 guidelines around the world, 22 of which use age-dependent fracture probability thresholds based on the NOGG methodology, to identify individuals who warrant treatment with osteoporosis medications [ 5.10]. To date, the FRAX website (linked to the NOGG website) has been used to calculate fracture risk in 27 million people worldwide [ 5.11]. In a 2017 assessment of FRAX and NOGG website activity, using Google Analytics, over a one-year period there were a total of 1.77m sessions (a user interaction with the website) on the FRAX website [ 5.11]. More than 250,000 sessions were recorded on the NOGG website, congruent with close to 350,000 visits to the FRAX website from the UK. The findings indicated that users of FRAX in other countries make use of the NOGG guidance, demonstrating impact beyond the UK, and that the vast majority of UK visits to the NOGG website were via FRAX (95.7%), with most from NHS sites (79.9% of locations which were identifiable). MRC LEU has further refined implementation by demonstrating that this FRAX-NOGG approach identifies patients at high risk of fracture and makes most efficient use of DXA scanning, optimising the use of NHS resources and minimising patient exposure to ionising radiation [ 5.12].

“The efforts of the Royal Osteoporosis Society have depended upon the evidence generated through the leadership of Professors Cooper and Harvey, informing our drive to ensure 100% fracture liaison service coverage for the whole of the UK (already achieved in Scotland), and leading the way globally in terms of quality benchmarking. Their work on the epidemiology of fracture, with a large recent project funded by ROS, has established detailed understanding of fractures, medication use and related deaths in the UK and globally; linked to their findings from the seminal SCOOP trial, work from this group has been absolutely central to UK advances in fracture risk assessment, using the FRAX-NOGG approach. Professors Cooper and Harvey have definitively advanced the field in a way that directly improves patient care and health outcomes”. CEO, Royal Osteoporosis Society. [ 5.13]

Maternal vitamin D supplementation in pregnancy and offspring MSK development

The initial work on vitamin D in pregnancy [ 3.6], published in The Lancet and cited 901 times, underpinned part of the 2014 guidelines on pregnancy vitamin D status from the UK Royal College of Obstetricians and Gynaecologists (RCOG) [ 5.14]. The MAVIDOS trial informed the 2016 recommendations for maternal vitamin D supplementation during pregnancy from the UK Scientific Advisory Committee on Nutrition [ 5.15]. These were translated into public health guidance by Public Health England [ 5.16]. Consistent with the winter effect of maternal gestational vitamin D supplementation on offspring bone mass as demonstrated in MAVIDOS, the PHE guidance incorporated seasonal stratification into supplementation advice. MAVIDOS also contributed to the Minsk Declaration on the lifecourse approach [ 5.2]. The 2016 MAVIDOS trial, among the first definitive validations of the Barker hypothesis, [ 3.7] received widespread global media coverage and subsequently informed other guidelines internationally, for example from the Australian Department of Health [ 5.17]. Clinical evidence of the impact of MRC LEU studies on vitamin D in pregnancy comes from the group’s own observations of a 30% rise over the last decade in pregnancy 25(OH)-vitamin D concentrations from the original Princess Anne Cohort Study [ 3.6], through MAVIDOS, to the most recent SPRING trial [ 5.18].

Research at the University of Southampton (UoS) over the past 30 years has led directly to the development of nebulised IFN-β as a new, successful therapy for inflammatory lung conditions such as asthma and COPD. This therapy has had tangible impacts on patient health and wealth creation, culminating in a successful clinical trial during the COVID-19 pandemic.

Formation of Synairgen (covered in REF 2014)

Synairgen was founded in June 2003 by Holgate, Davies and Djukanovic, with investment from IP2IPO Group plc (now IP Group). It was floated on the Alternative Investment Market (AIM) in October 2004, raising GBP10,500,000. [ 5.1]

In March 2004, UoS filed a patent for the use of inhaled IFN-β for treatment of virus-induced exacerbations of asthma and COPD. This allowed the pioneering research to continue through clinical trials testing IFN-β for asthma and COPD. [ 5.1]

From 2008 Synairgen concentrated its effort on the clinical development of inhaled IFN-β for the treatment of exacerbations of asthma and COPD caused by respiratory viruses. In 2009 Synairgen completed Phase I trials in moderately asthmatic subjects and progressed to Phase II proof of concept studies. Underlining significant investor confidence, the company raised GBP6,000,000 in 2009 to fund phase II clinical trials in asthma and GBP2,500,000 in 2011 to accelerate completion of asthma phase II, conduct various in vitro experiments and fund avian flu research. [ 5.1]

Synairgen’s market capitalisation was GBP26,307,751 at the end of 31 July 2013. [ 5.1]

Continued success of Synairgen and nebulised IFN-β for treatment of asthma

Since August 2013, Synairgen has increased the number of staff employed on its drug development from 15 to 19 and aided the career of staff including 9 scientists, 3 nurses and 7 trial managers, either employed directly or indirectly by the company. Its market capitalisation was GBP305,869,035 at when markets closed on 31 December 2020. [ 5.1]

Southampton’s phase II trial of nebulised IFN-β in asthma led to a global license deal between Synairgen and AstraZeneca in 2014, with an upfront payment of USD7,250,000 (06-2014) and potential development, regulatory and commercial milestones of up to USD225,000,000 as well as tiered royalties, a proportion of which goes to the University. [ 5.2]

Nebulised IFN-β for the treatment of chronic obstructive pulmonary disease (COPD)

In December 2017, Synairgen changed its strategic direction to assess IFN-β as a potential therapy for COPD. A phase II Clinical Trial of IFN-β in patients with COPD was launched in February 2018 by Wilkinson and raised GBP4,000,000. The first part of the trial was successful, showing that IFN-β boosts antiviral lung defense mechanisms in the absence of a respiratory virus. This led Synairgen to raise GBP2,900,000 in September 2018 to expand the trial from 80 to 120 patients with a confirmed respiratory viral infection. By February 2020 recruitment was almost completed when the COVID-19 outbreak started to gain momentum in the UK. [ 5.1]

Nebulised IFN-β for the treatment of COVID-19

Synairgen raised GBP5,000,000 for the University’s phase II clinical trial to test IFN-β on patients with COVID-19, which got Medicines and Healthcare products Regulatory Agency (MHRA) and ethics approval within days and was established within four weeks, an unprecedented timeframe for a trial. It involved nine other hospital sites within the UK, recruiting 101 patients, and the first part of the trial was completed within seven weeks. Following the success of the first stage, £3m was raised to expand the trial in May 2020 to include an additional 120 patients in the community setting. [ 5.1]

Results released in July 2020, showed that patients who received IFN-β had a 72% lower risk of developing severe COVID-19 compared to placebo and were more than twice as likely to recover from the disease as those on placebo. It also showed breathlessness was markedly reduced. There were no deaths among the patients who received IFN-β, demonstrating its huge “ potential as an inhaled drug to be able to restore the lung’s immune response, enhancing protection, accelerating recovery and countering the impact of SARS-CoV-2 virus.” [ 5.3]

The phase II trial and subsequent results had a substantial impact on Synairgen’s share price. Within the first 48 hours of the trial launching on 18 March 2020, Synairgen’s share price doubled from GBP0.24 to GBP0.49. Upon release of the positive results in July, the share price soared as much as 552%, taking its year-to-date gain to about 3,194%. [ 5.4].

The launch of each stage of the trial, as well as the announcement of the results, attracted worldwide media attention. Coverage in July 2020 of the first results was across broadcast, radio, print and online platforms including outlets such as The Guardian, New York Times, The Brussels Times, CNN, BBC Radio 4 and Bloomberg [ 5.5].

These positive results led to Synairgen’s inhaled IFN-β being selected for the US Government funded ACTIV-2 trial (estimated value GBP100m) [ 5.6] which evaluates treating patients with mild to moderate COVID-19 symptoms not yet requiring hospitalisation. Additionally, Synairgen has commenced an in-patient global Phase III trial launched in December 2020 [ 5.7], funded through a GBP87,000,000 placement on the London Stock Exchange and led by Wilkinson. This international trial will recruit up to 610 patients and continue to evaluate IFN-β as a treatment of hospitalised COVID-19 patients, aimed at preventing the need for ventilation, and accelerating recovery.

Synairgen’s Investigational New Drug application to the US Food and Drug Administration (FDA) to evaluate IFN-β as a treatment for patients with COVID-19 was approved in December 2020, enabling Synairgen to initiate the Phase III trial in the US [ 5.7]. The FDA awarded it Fast Track status, enhancing the ability of Synairgen to interact with the FDA and shortening review timelines [ 5.8].

Rapid point of care (POC) test for viral infection

The development of the POC test for respiratory infections underpinned the success of the trials for both COPD and COVID-19 by providing quicker patient diagnosis, leading to more effective recruitment. Patients who received a positive POC test for COVID-19 were recruited into the trial two days earlier than patients who were tested by the lab. This successful POC testing strategy has led to further trials, which have had an impact in the clinical setting.

The ResPOC study led to an NIHR post-doctoral fellowship for Clark in 2016 to carry out a randomised control trial to assess the POC test for patients with influenza symptoms. Patients who received the POC test were given antiviral treatment on average 28 hours more quickly than those who did not have the test. Patients who had influenza diagnosed by the POC test were also isolated more appropriately and rapidly [ 5.9].

Southampton’s POC test research underpinned and was cited in Public Health England guidance, published in November 2018 and updated in October 2019, describing the benefits of implementing POC testing in hospital settings. Southampton was described as an Early Adopter (EA) site where “successful outcomes reported by EA groups include improved patient triage, better cohorting and use of isolation rooms during periods of winter pressure.” [ 5.10]

During Synairgen’s COVID-19 trial, the POC test had positive impacts on waiting times for COVID-19 results and patient flow through Southampton General Hospital. A clinical impact assessment trial of POC testing during the first wave of the pandemic showed that instead of taking a day to receive results, clinical staff received results in just 1.7 hours on average. Patients who received the test were transferred to the appropriate ward within eight hours, compared to 28 hours for those who did not. Additionally, patients in the emergency department who received the POC test were not transferred to an assessment area unnecessarily. This resulted in fewer bed moves, reducing the need for deep cleaning and staff exposure to COVID-19 in contaminated areas. [ 5.11]

Due to Southampton’s ground-breaking work with the POC test, Clark was asked to contribute to the Academy of Medical Sciences’ Preparing for Winter report, which gave a ‘reasonable worst case scenario’ of between 24,500 and 251,000 virus related deaths in hospital, peaking in January and February 2021. This report and the successful results of the POC test in Southampton led to Clark being seconded to the Department of Health & Social Care to assist in the national roll out of POC tests to all acute trusts. [ 5.12]

Gastrointestinal clinical cancer research designed, led and delivered by University of Southampton researchers has, since 2014, directly included over 14,000 people and changed practice in multiple domains, resulting in better patient outcomes and estimated world-wide cost savings of approximately GBP2,000,000,000 per year.

Colorectal cancer

In colorectal cancer, a disease that affects 1.4 million people a year globally, Southampton researchers have performed the definitive studies in treatment and follow-up after surgery. The FACS trial has set the standard on the follow up of patients with resected colorectal cancer and has informed all guidance on colorectal cancer follow up globally since the results were published in 2014, including NICE Guidance NG151 [ 5.1]. This recommends the follow-up protocol tested in the FACS trial: “For people who have had potentially curative surgical treatment for non-metastatic colorectal cancer, offer follow-up for detection of local recurrence and distant metastases for the first 3 years. Follow-up should include serum CEA and CT scan of the chest, abdomen and pelvis”. In a 2018 analysis of 21 national guidelines from countries represented in the European Society of Coloproctology [ 5.2], the guidelines committee recognised the singular importance of the FACS trial findings as underpinning follow up protocols including CEA testing and CT scans. Adherence to these protocols has been subject to published nation-level audits in countries including the Netherlands, where guidance is based specifically on FACS, and Norway which is proposing reducing intensity of guideline. The lower intensities of follow up have equal efficacy in detecting recurrence and have identical overall survival. A 2017 economic analysis [ 5.3] suggests a saving of around GBP2,000 per patient suitable for reduced surveillance (20,000 annually) resulting in around GBP40,000,000 per year saving in the UK alone, mainly by reducing the number of CTs. Globally around a million patients will suffer colorectal cancer requiring follow-up, and hence very substantial global savings could be expected depending on local practices.

Chemotherapy following potentially curative surgery has been shown to improve survival in many cases of colorectal cancer, but at the cost of significant toxicity. The toxicity relates to duration of chemotherapy but until now the duration to achieve efficacy was unknown. In combination the MRC SCOT and the IDEA Collaboration studies included over 13,000 people with stage III colorectal cancer from around the world. Results were immediately incorporated into national and international guidelines 2018-2019 [ 5.4, 5.5]. NICE Guidance NG151 (2020) [ 5.1], makes recommendations based directly on the SCOT study findings: “Halving the standard care from six months to three months (for people who can have CAPOX) will reduce treatment time and costs, meaning people have chemotherapy side effects for a shorter time, and will lower the incidence of long-term toxicity (neuropathy) and its consequences”. Analysis undertaken in 2020 of these findings [ 5.6] concluded that the survival difference between three and six months was minimal, especially if CAPOX is used, but the toxicity markedly reduced with three months treatment. An economic analysis of SCOT [ 5.7] suggests a saving of GBP4,881 which, applied globally to 700,000 stage 3 patients annually (based on a conservative estimate of 50% of patients receiving post-operative chemotherapy) results in a saving of approximately GBP1,700,000,000 per year.

There are around 3,200 patients annually in the UK with operable colorectal liver metastases. These patients were commonly treated with neoadjuvant chemotherapy to treat micro-metastatic disease, and increasingly with an anti-epidermal growth factor receptor antibody, cetuximab. The New EPOC study demonstrated the harm in the use of cetuximab in patients with operable colorectal liver metastases, resulting in a two-year reduction in median overall survival and a 15% reduction in survival at five years. As this schedule was commonly used, changing practice has had major impact on the survival of patients in this cohort globally. The 2016 guidelines of the European Society of Medical Oncology (ESMO) [ 5.8] makes the change in practice clear, stating: “EGFR-targeting monoclonal antibodies (cetuximab and panitumumab) are not to be used in this setting, based on the data from the New EPOC trial”. This is further supported by a 2020 Lancet editorial [ 5.9]. Based on UK rates of operable colorectal liver metastases, 240 lives are saved every year by not using cetuximab. This increases into the thousands when applied globally.

Biliary Tract cancer

The BILCAP trial showed that adjuvant capecitabine following surgery for biliary tract cancer improved median overall survival by 16% with no measurable reduction in quality of life. Treatment was well tolerated. The result of the study was published in 2019 [ 5.10] and immediately incorporated into standard of care in EUROPE and the USA; American Society of Clinical Oncology (ASCO) guidelines were also produced as a result of the trial outcome [ 5.11]. Based on a conservative estimate of 500,000 annual biliary tract cancer cases globally, implementation of this process around the world could result in a saving more than 4,000 lives every year in a disease with large unmet need and no major Pharma interest. A heath economic assessment suggested treatment was also highly cost effective at GBP2,725 per Quality Adjusted Life Year (QALY) [ 5.10].

Minimally invasive surgery

Minimally invasive surgery (MIS) is developing rapidly in surgery of the liver and pancreas but this is technology-driven with little evidence of patient benefit. Primrose and colleagues have led efforts in the UK to develop an evidence base and standards of training and care in this area. The group have led three randomised trials, one completed (ORANGE 2), and two ongoing (ORANGE SEGMENTS and DIPLOMA). The University of Southampton (Primrose, Cook and colleagues) organised two global consensus conferences in MIS in liver (Southampton) and pancreas (Miami), which were attended by approximately 100 leading cancer experts. Guidelines have been developed from the events and set global standards for safe practice and training in these areas [ 5.12, 5.13]. The recommendation for more research in MIS is included in the 2018 NICE guidance NG85 on pancreas cancer, which was chaired by Primrose [ 5.14].

Biologics are large biomolecular drugs, now ubiquitous in the treatment of human disease ranging from cancer to autoimmune disorders, comprising half of the top-ten blockbuster pharmaceuticals and grossing around USD30billion/year worldwide. Eighty per cent of these biologics are mAb. Researchers at Southampton have played a leading role in bringing two types of anti-CD20 mAb from lab to clinic to treat B cell disorders and inspiring the development of a new class of immunostimulatory mAb to treat cancer.

Clinical and commercial impact of ofatumumab (Arzerra)

Ofatumumab, marketed under the name Arzerra, was developed and patented by Glennie and colleagues in 2004 and licensed from Genmab to GSK in 2006. It was approved by the FDA in 2009 and the EU in 2011 for the most prevalent form of leukaemia, CLL, after Southampton researchers proved it was able to kill target cells resistant to similar drugs (covered in REF2014).

Globally, leukaemia accounts for some 300,000 new cases each year with 222,000 deaths, giving Ofatumumab a wide reach in its first approved indication. In 2016 it was approved by the FDA as a treatment for recurrent or progressive CLL [ 5.1] and for relapsed CLL in combination with Fludarabine and Cyclophosphamide [ 5.2]. Since August 2013 it has been assessed in 99 clinical trials [ 5.3], including in autoimmune conditions such as rheumatoid arthritis, which affects more than 400,000,000 patients worldwide, and multiple sclerosis (MS), which affects 2,100,000 patients worldwide. In MS, exciting phase 3 data (involving 1,882 patients), published in August 2019, was observed (ASCLEPIOS I and II trials), showing that ofatumumab reduced the annualised relapse rate over current treatment (teriflunomide) in patients with relapsing forms of MS [ 5.4].

Ofatumumab’s commercial impact since August 2013 has been highly significant, achieving sales revenues of more than GBP200,000,000, translating to GBP41,000,000 in royalties for Genmab [ 5.5]. GSK’s rights to its use in cancer were acquired by Novartis in August 2015 in a deal worth up to USD1billion (GBP6,500,000,000) [ 5.6].

Clinical and commercial impact of obinutuzumab (Gazyva)

The same programme of Southampton research was instrumental in the selection of a second anti-CD20 mAb, obinutuzumab (GA101, trade name Gazyva). The Head of Oncology at Roche Pharmaceutical Research and Early Development said: “The characterisation of type I and II CD20 mAb by the Southampton Lab and their clear demonstration of increased potency by type II reagents was an important factor in our decision to select GA101 for clinical development. Their pre-clinical work has now been validated in several phase 3 trials and has supported our expansion to new diseases such as lupus” [ 5.7].

Gazyva was the first type II anti-CD20 mAb to be humanised for clinical work. Capable of killing a significantly higher number of cancerous cells than its type I counterpart, and being less subject to internalisation, it was assessed in several multicentre phase III trials involving Southampton lead investigators (e.g. Professor Andrew Davies), head-to-head against rituximab in FL and CLL. Gazyva was shown to provide significantly better responses than rituximab in combination with chlorambucil in CLL and in previously untreated advanced FL patients. As a consequence of this phase III study, the drug was FDA-approved for CLL in November 2013 [ 5.8] and FL in November 2017 [ 5.9], changing frontline clinical treatment of these diseases. It was also approved as the first Non-Chemotherapy Combination Regimen for Treatment-Naïve Patients with CLL, alongside ibrutinib in 2019 [ 5.10].

Since August 2013 there have been 68 clinical trials assessing Gazyva [ 5.11] in multiple settings, from post-transplant lymphoproliferative disorder and renal disease, to lupus where the FDA granted Breakthrough Therapy Designation for adults with lupus nephritis based on data from the phase II Nobility study [ 5.12]. In adult patients with proliferative lupus nephritis, Gazyva, in combination with standard of care, demonstrated enhanced efficacy compared to placebo plus standard of care alone in achieving complete renal response at one year.

The commercial impact has again been highly significant. Sales of Gazyva have grown considerably year-on-year since its FDA approval in November 2013, reaching CHF632m (GBP515,000,000) in 2020 and giving a total of CHF2.2bn (GBP1,700,000,000) over the period. [ 5.13]

Clinical and commercial impact of work involving FcγRIIB mAbs

The added insight from the Southampton team also revealed a novel and unexpected mechanism of resistance for CD20 (and other) mAb through the inhibitory FcγRIIB. The pre-clinical work and partnership with BioInvent International led to the development and characterisation of new fully human FcγRIIB mAb and a first-in-human trial [ 5.14] assessing its safety and utility in B cell malignancies with promising safety and therapeutic profiles in patients.

Patents around this biology have been granted and licensed to BioInvent [ 5.15]. These approaches are also being explored in mantle cell lymphoma and in solid tumours in combination with checkpoint inhibitors such as anti-PD-1 including with a new FcγRIIB reagent (BI-1607) following pre-clinical evidence and mechanistic insight from Southampton. This work led to a deepened association with BioInvent, leading to GBP3,140,000 in funding since 2014. An example of the significant commercial impact arising from this clinical trial programme came in October 2020 when BioInvent and US-based CASI Pharmaceuticals announced an exclusive licensing agreement worth up to USD95m (GBP73,000,000) for the development and commercialisation of novel anti-FcγRIIB antibody, BI-1206, in mainland China, Taiwan, Hong Kong and Macau. [ 5.15]

Promising results from the phase 1/2a clinical trial of BI-1206, in combination with rituximab, for relapsed NHL were published in Blood in November 2020 [ 5.16]. In total 15 NHL patients were recruited to the Phase I trial, all of whom were late stage and had failed conventional treatments, including several lines of rituximab-containing therapies. Notably, of the 9 patients who completed the induction cycle, 6 patients showed either complete or partial responses several of which are still ongoing. Remarkably, two patients achieved a complete response, which continues to be sustained 12 and 24 months later. [ 5.14]

Clinical and commercial impact of the Southampton immunomodulatory antibody programme

Under its immunomodulatory antibody programme, Southampton has developed a range of novel immunostimulatory mAb (CD40, CD27, OX40, 4-1BB) and protein engineering approaches to boost their activity. This led to the discovery and patenting of several of these reagents, including a novel target CD27, immunostimulatory mAb which can promote anti-cancer immunity [ 5.17]. This intellectual property is licensed exclusively to Celldex Therapeutics, USA, who have undertaken several trials with a fully human mAb, varlilumab in combination with nivolumab/atezolizumab/ipililumab etc. in haematological and solid malignancies [ 5.18].

Impact on patients and families

Temple and Mackay’s research has made early diagnosis of IDs a standard practice. As an example, the Wessex Regional Genetics Laboratory has increased its reporting of ID tests from 378 in 2012/13 to 535 in 2018/19, an increase of 42% [ 5.1]. Early diagnosis enables access to the stratified treatment that patients require for optimal outcomes.

Diagnosis of Temple Syndrome (TS)

TS was described as a clinical entity by Temple in 2014 [ 3.7], and has been recognised as a key differential diagnosis for Silver-Russell Syndrome (SRS) [ 5.2], notably in the 2017 international clinical consensus guidelines for SRS [ 5.3]. Children diagnosed with TS benefit from early intervention to mitigate complications such as early puberty and resistant central obesity, with critical benefits for growth and wellbeing. The positive impact was observed by a Director at the MAGIC Foundation in the USA – the global leader in endocrine health, advocacy, education, and support – who stated in 2020: “The chromosome 14 patients I know that were diagnosed at one to three years old and have been following the SRS Consensus Statement recommendations… are far leaner, their parents are educated and, in many cases, the whole family exercises together.” [ 5.4].

Genetic testing for TS was developed by Temple and Mackay and made available to the NHS in 2008. From 2008 to 2013, only 1% of SRS referrals received TS testing on chr14; but since its description in 2014 it has grown in recognition, and in 2019 TS testing was performed in 62% of SRS referrals [ 5.1] . Thus, a diagnosis before 2014 is now widely available. This has been welcomed by patient support groups, with the Membership & Parent Support Manager of the Child Growth Foundation commenting: “Receiving a diagnosis of Temple Syndrome … can be very important to families. Without a diagnosis, many families constantly question ‘why’ and can be concerned for the future for their child, due to the unknown. A diagnosis can help with management and treatment of the condition, as well as peace of mind for all concerned.” [ 5.5]

In 2017 Temple established a multidisciplinary clinic in Southampton treating UK patients with TS, SRS and other IDs. This clinic, which enrols five to 10 new cases per year and sees over 50 cases regularly, is part of the prestigious European Reference Network for Endocrine Disease, and provides integrated precision management of nutrition, growth, body composition, puberty timing, orthopaedics and additional specialist referrals [ 5.6].

Diagnosis of Transient Neonatal Diabetes Mellitus (TNDM)

TNDM, defined by the Wessex Imprinting Group led at Southampton by Temple, is now clinically well-recognised through online resources including GeneReviews, which consistently receives over 2,000 views per year by clinicians, scientists and families globally (2,921 views in 2019 [ 5.7]). The Group remains in periodic contact with patients and families worldwide through their International TNDM Register, which is supported by families [ 5.8].

The Register provided patients for the landmark study, Lango et al 2015 [ 5.9], which showed that 38% of all neonatal diabetics have the imprinting disorder TNDM. As a direct result of this research, all patients with neonatal diabetes receive early testing (including TNDM testing) as standard, with 2,298 patients referred from 103 countries as of July 2019 [ 5.10]. Accurate diagnosis enables appropriate management, including the cessation of insulin treatment in early childhood when it is no longer required, and screening to prevent complications of diabetes when it recurs in later life

Multi-locus imprinting disorder (MLID), described by Temple and Mackay, is recognised as a component of TNDM among other imprinting disorders. Zinc finger protein 57 homolog ZFP57 sequencing is now included in genetic testing for neonatal diabetes in the UK, France, Germany, Italy , Spain and Switzerland, as well as in Chicago, USA [ 5.11].

Patient advocacy groups

As medical advisers to the UK Child Growth Foundation and the Global Alliance on SRS, Temple and Mackay receive more than 100 enquiries a year from clinicians and families for advice on IDs. Temple actively supports the MAGIC Foundation USA. At panel clinics in 2018 and 2019 she gave clinical support to more than 100 families and in 2019 she spoke to the MAGIC Congress on how a TS diagnosis alters management . There is now a TS subgroup of the MAGIC Foundation; parents have reported how a diagnosis has changed their child’s treatment and meant that doctors took their concerns seriously, seeking help from experts [ 5.12].

Impact on international clinical practice

In 2012 Temple and Mackay were founders of the EU Consortium on Imprinting Disorders (EUCID) and continue to be working group leaders. EUCID is an EU network dedicated to implementation, harmonisation and education in diagnosis and management for IDs. EUCID developed clinical consensus guidelines for SRS (incorporating Temple syndrome) in 2017 and Beckwith Wiedemann Syndrome (BWS) in 2018; Temple and Mackay were senior authors on both. These guidelines have been accessed more than 55,000 times and used by health professionals around the world to guide testing and treatment for patients [ 5.3, 5.13].

Mackay co-wrote European guidelines for diagnosis of SRS and BWS and implemented a European quality management scheme for SRS and BWS testing, active since 2015, with 40 participating labs annually from 14 nations on three continents. Ongoing annual reports from EMQN demonstrate that both diagnosis and interpretation have rapidly increased in quality [ 5.14].

Our research, as outlined in Section 2, demonstrated the clinical need for ID testing that drove development of multiplex ligation-dependent probe amplification diagnostic kits by MRC-Holland. The kit contains sufficient reagents to perform 100 tests. Two decades ago, TNDM, TS and MLID were undefined disorders; one decade ago, testing was limited to a handful of specialist research centres; now, commercial tests are available for all known IDs, making diagnosis available to patients internationally. Over 2016-2019 MRC-Holland sold 4,000 tests for TNDM, 31,000 for TS and 8,200 for MLID, with an estimated value of GBP378,000.  Notably the sale of the MLID test has increased 40-fold since its introduction in 2017 [ 5.15].

University of Southampton research has shown that the environment experienced in the womb, and at conception, can have profound consequences on the long-term health of a person including the risk of obesity and NCDs. This has had a direct impact on intergovernmental, government and NGO health policy, clinical practice and health literacy in the UK and around the world.

Impact on intergovernmental, government and NGO health policy

According to WHO [ 5.1], the research of Hanson, Godfrey, Cooper and colleagues ‘ has led to recommendations by WHO in relation to the prevention of childhood obesity, through the ECHO (End ChildHood Obesity) Commission and also the Nurturing Care Framework, both of which have been adopted by the World Health Assembly and are now having an effect on government nutritional policy in many countries’. Specifically, this policy impact at WHO and UN level involved:

• Influencing the WHO Guideline on Improving Early Child Development (March 2020) [ 5.1].

• Informing the UN’s Global Strategy for Women’s, Children’s and Adolescents’ Health 2016-2030 (published 2015); DOHaD research by Hanson and Cooper cited on page 103 [ 5.1].

• ‘Catalysing’ the WHO-coordinated, 10-year, multi-country Healthy Life Trajectories Initiative, which is examining the effect of preconception health on markers of metabolic health. [ 5.1].

• Co-chairing (Hanson), of the Working Group on Science and Evidence for WHO’s ECHO Commission. The resulting implementation plan was adopted at the World Health Assembly in 2017, which mandated 194 member states to adopt the plan [ 5.1].

• Introducing the concept of ‘nurturing care’ to promote healthy development across the first 1000 days of life through a co-authored (Hanson) paper in The Lancet (2017). The paper underpinned WHO’s Nurturing Care Framework, which was adopted at the World Health Assembly in 2018, again mandating 194 member states to adopt the framework [ 5.2].

• Authoring (Cooper and Hanson) the WHO Health Evidence Network report (2019): What quantitative and qualitative methods have been developed to measure the implementation of a life-course approach in public health policies at the national level? [ 5.3]

• Chairing (Hanson) international expert meetings at WHO on the effects of environmental toxicants on development in June 2016 and Nov 2017, which led to the new initiative Don’t Pollute My Future! The impact of the environment on children’s health [ 5.4].

• Informing the WHO-UNICEF-The Lancet Commission A Future for the World’s Children March 2020 (paper by Cooper and Hanson cited on page 651) [ 5.5].

DOHaD research also influenced policy development and debates in the UK. Due to Southampton’s ground-breaking findings on the effect of maternal diet and lifestyle on offspring health, Hanson was invited by the UK’s Chief Medical Officer to author a chapter on preconception health for her 2014 Annual Report [ 5.6]. For the first time, this report focused on the importance of the preconception environment, making recommendations for greater continuity of health care to reduce transmission of NCD risk across generations and focussing on the most vulnerable sections of the population. In 2018, Hanson made a significant contribution to the Parliamentary Office of Science and Technology POSTnote The Ageing Process and Health (No. 571, Feb. 2018), which emphasises DOHaD (papers by Hanson and Godfrey both cited) [ 5.7]. Godfrey’s work on preconception health was cited in a House of Lords debate in April 2018 that was called in order to challenge the Government on the steps it was taking to address childhood obesity [ 5.8].

Their research and involvement in policy formulation at an international level led Hanson and Godfrey, in 2019, to establish the first Preconception Partnership, a group of leading epidemiologists, scientists and clinical academics. It proposed an annual ‘report card’ to measure progress in improving a set of preconception health markers. The report card uses metrics from data sources such as the Maternity Services Dataset and the Sexual and Reproductive Health Activity Dataset, and is designed to hold governments to account. As a result, Public Health England (PHE) updated their policies on preconception care to identify opportunities for intervention, and issued resources to primary and secondary care trusts detailing the available interventions [ 5.9]. PHE also made an unprecedented move to release national maternity and newborn data to Southampton researchers to assess against the report card.

Impact on clinical awareness and practice

University of Southampton research demonstrating the importance of nutrition before conception and during the first 1000 days of life led Godfrey and colleagues to initiate eLearning platforms to educate the healthcare workforce, in both low-middle and high income settings. The aim was to impact real-world healthcare practice in early nutrition at scale. The eLearning programmes in Early Life Nutrition have been developed and distributed to healthcare professionals and young couples in areas such as Africa, Europe, the Middle East and South East Asia. Collectively the platforms have more than 89,000 registered users. [ 5.10]

With DFID funding, the team developed an eLearning programme for management of malnutrition. Their evaluation in Ghana, Guatemala and El Salvador for 2015-2017 showed it cut mortality rates from severe acute malnutrition from 5.8% to 1.9% (difference -4.0% (95% CI -6.7 to -1.8), p<0.001). The malnutrition eLearning course improved knowledge, understanding and skills of health professionals in the diagnosis and management of children with severe acute malnutrition, and changes in clinical practice and confidence were reported following the completion of the course [ 5.10]. Based on WHO guidelines, the course has been taken by 17,000 health professionals, trainees and educators in 120 countries [ 5.10]. It has improved clinical practices in hospitals and community settings in Ghana which has seen an improvement in mortality rate as demonstrated by a director of the district health directorate, who said: “rehabilitation rate has increased from about 80% to about 95%. And the mortality rate … has decreased to about 50% of what we used to see before the training.” [ 5.11]

Southampton research on nutrition in the adolescent, preconception and maternal periods and on transgenerational passage of NCD risk led directly to mutliple guidelines [ 5.12] developed by the International Federation of Gynecology and Obstetrics (FIGO), which represents national professional organisations in 130 countries. The Think Nutrition First guideline was chaired by Hanson and launched in 2016 at FIGO World Congress in Vancouver, attended by 5,000 delegates. The FIGO Global Declaration on Hyperglycemia in Pregnancy, co-chaired by Hanson, was launched at the Congress in Rio de Janiero in 2018, attended by 11,500 delegates. The guidelines were disseminated to 132 Obs and Gynae professional societies globally and translated into several languages. In 2020, Hanson led the development of the Pregnancy Obesity and Nutrition Initiative under the Pregnancy and NCDs Committee at FIGO, which published guidelines on obesity management before, during and after pregnancy. This led to a clinical nutrition checklist being developed for healthcare professionals to assess pregnant women’s diets and identify any nutritional risk in early pregnancy. Early analysis of its use in Hong Kong showed that among the 156 women who used the checklist, 95% had nutritional issues identified. [ 5.12]

Increasing health literacy and inspiring positive lifestyle changes among teenagers

The research on nutrition in adolescence and the importance of the preconception environment to the transmission of NCD risk to the next generation led Hanson, Godfrey and colleagues to develop a purpose-built teaching laboratory, LifeLab, at Southampton General Hospital to educate school students about how their current health and life choices affect the health of their future children. LifeLab is a structured education programme over a two-week period. It comprises: a professional development day for science teachers; pre-visit lessons at school; an immersive, hands-on visit to the LifeLab facility; follow-up lessons at school; and a celebration event for all LifeLab students, parents, local health professionals and public officials.

The facility was formally launched in 2014. Since then, 11,591school pupils and 342 teachers from 66 schools have participated in the programme [ 5.13]. Schools embed the programme into their science curriculum for Years 8 and 9; it is designed to be linked into several work strands and referred back to over the year. Southampton’s RCT of LifeLab [ 5.14] demonstrated that, prior to participation, 50% of teenagers had an above average score, whereas 12 months after participation the proportion increased to 61% (adjusted difference between groups = 0.27 SDs (95%CI=0.12, 0.42)). Students also judged their own lifestyles more critically, with fewer reporting their behaviours as healthy (53.4%) compared to the control group (59.5%) (adjusted PRR=0.94 [0.87, 1.01]). Additionally, they had greater understanding than control students of the influences of health behaviours on their long-term health and that of their children; for example, they knew that our nutrition starts to affect our future health before we are born (p <0.001) and the food a father eats before having a baby will affect the health of his children (p<0.001).

Qualitative data [ 5.15] also demonstrated the profound impact that LifeLab has had on the health literacy of students. Representative feedback included: “ If we change our lifestyle, we can more than halve our chance of getting an illness later on in life”; “Eating unhealthy is not only bad for your health but your child's also”; “How unhealthy my lifestyle actually is and the small changes that need to be made just to make sure I'm at less of a risk”; “I’ve eaten less fatty foods and seen how it could actually affect it [my health], before I thought I could just change it and it would all be better, but it can actually affect it long-term as well”. There is evidence of the programme inspiring students to consider future careers relating to science and health, and changing perceptions of science as an academic discipline. Representative feedback included: “ I found them (the scientists) really inspirational and am now considering going into nursing or medical care”; “They (the scientists) made me change my mind about what I went to be when I am older”.

According to the CEO of University Hospital Southampton NHS Foundation Trust, LifeLab has contributed directly to meeting this aspect of the Trust’s vision: ‘ We will play our part in the fight to improve population health working with the University of Southampton on their world-renowned research demonstrating how lifestyle and behaviour not only impacts on an individual’s health but that of future generations [ 5.16].’ LifeLab resources form part of the Royal Society for Public Health (RSPH)-accredited Level 2 Young Health Champions qualification. LifeLab was awarded RSPH centre status in 2017 and in 2019 won the RSPH national Centre for Excellence Hygeia Award [ 5.17]. It was a key part of BBC Horizon episode Why are we getting so fat? (2016) [ 5.18] which was watched by 1.82m people and was the 11th highest-rated BBC2 programme that week.

The University of Southampton’s respiratory research has had an instrumental impact on public policy debates around air quality, underpinning evidence-based advocacy by professional organisations for urgent action, leading to significant changes to government policy and legislation and providing crucial evidence for a High Court ruling on the death of a child with asthma.

In October 2013, the RCP President invited Holgate to chair a two-year systematic review of evidence of the health effects of air pollution and make recommendations for action. Holgate’s appointment was made ‘ on the basis of his published research over the previous decade evidencing the health effects across the lifecourse of nitrogen dioxide from diesel exhaust emissions, and the acute impact of air pollution on adults and children with asthma and other chronic respiratory conditions’ [ 5.1]. Alongside this role, Holgate was appointed as the RCP’s Special Adviser on air quality in September 2016 ‘ as a result of his published studies that demonstrated the negative health consequences of exposure to nitrogen dioxide, ozone and particulate matter even at ambient levels’ [ 5.1]. In February 2016, Holgate led the publication of the landmark report Every breath we take (EBWT) : the lifelong impact of air pollution [ 5.2], authoring the preface and the resulting peer-reviewed journal article [ 3.8]. University of Southampton research made ‘ a fundamental contribution’ [ 5.1] to the evidence base that underpinned Chapter 3: In the beginning: protecting our future generations, Chapter 4: Health effects of air pollution over our lifetime and Chapter 5: Our vulnerable groups. Holgate’s co-authored COMEAP reports and WHO 2013 technical report were also cited throughout. EBWT was the first review to conclude that ~40,000 UK deaths each year are attributable to outdoor air pollution with an annual cost to the UK economy of >GBP20 billion. It identified 14 calls to action.

The EBWT report was covered by all national media outlets and websites of professional bodies (e.g. nhs.uk), reaching an audience of more than 100 million people in its first month [ 5.3]. An accompanying editorial in The Lancet called the report ‘ one of the clearest calls to action to advance the UK’s environment health’ [ 5.4]. On 16 March 2016, Leader of the Opposition Jeremy Corbyn cited the report’s findings in Prime Minister’s Questions to challenge the Government’s record on air pollution [ 5.5]. The report has continued to be cited in national media reports on air quality through to the end of the impact period and has had a transformational effect in increasing awareness and raising the policy profile of air pollution as a cause of adverse health. The report page on the RCP website has had more than 81,000 views [ 5.1]. The RCP President said: ‘ His (Holgate’s) 2016 report proved to be magisterial and as important in the battle against pollution and climate change as the College report Smoking and Health in 1962, and a worthy successor to it [ 5.1].’

Impact on parliamentary debates, advocacy campaigns and legal challenges

In 2017 four House of Commons Select Committees held a joint inquiry into ‘Improving Air Quality’. Based on his research and chairing of EBWT, Holgate was invited to provide oral evidence in November 2017. The joint committee’s final report, published in March 2018, said there was an ‘ urgent need’ to ‘ bring about a step change in how the problem of air quality is tackled’ and that the Government ‘ cannot continue to put public health at risk’ [ 5.6]. Holgate’s evidence and findings were extensively cited throughout the lead ‘Health impacts’ chapter (17 citations). The report called for a new clean air act (to enshrine in law the right to breathe clean air), a clean air fund and a national air pollution monitoring programme – all of which reflected the key recommendations of the EBWT report. Shortly afterwards, Holgate chaired a RCP roundtable with ministers for the environment and public health and primary care and published a RCP ‘Progress Report’ to maintain the momentum for action and reemphasise the EBWT recommendations made two years earlier [ 5.7].

The EBWT report, alongside Holgate’s expertise and previous research, was used to support three successful legal challenges (2016-2018) by environmental law charity ClientEarth in response to the UK Government breaching EU-level statutory NO₂ limit values. ClientEarth confirmed the report ‘ provided invaluable evidence to help us hold the UK government and local authorities to account on their legal and moral duty to tackle illegal and harmful levels of air pollution’ and that ‘ this research-based report helps us … to ensure policy and decision makers respond to this crisis’ [ 5.8]. In 2019 the Times launched its Clean Air for All Campaign with a manifesto that reflected Holgate’s EBWT recommendations. Its Environment Editor wrote: ‘ The RCP report proved to be a very valuable source of authoritative information for The Times’s Clean Air for All Campaign. We are very grateful for the work done by you and your colleagues as getting information we can trust has been vital to running this campaign and trying to make a difference on air quality [ 5.9].’

Holgate also applied his research expertise to the chairing of a further systematic review for the Royal College of Paediatrics and Child Health and RCP: The inside story: Health effects of indoor air quality on children and young people, published in January 2020 [ 5.10]. Citing BMJ paper 3.9, the report highlighted that the cumulative health effects of children’s indoor exposures to pollution sources can be wide-ranging, a considerable source of inequality, and in many cases such effects could be reduced with coordinated actions by key stakeholders. It was widely covered in the media, reaching an audience of more than 18 million, and prompted the Local Government Association to call on developers, manufacturers and businesses to do more to tackle indoor air quality. [ 5.3]

Impact on government legislation and national and regional policy decisions

In 2017, Holgate’s research expertise was requested for an evaluation of Public Health England (PHE), carried out by The International Association of National Public Health Institutes. Holgate’s expertise led to Recommendation 4: PHE should discuss with partners ways to increase research funding for PHE in critical areas of concern such as air pollution, including expanding PHE’s ability to lead research projects and a potential new pool of funds at PHE [ 5.11]. Holgate has also been an official advisor on PHE steering groups for initiatives such as a study to quantify the potential costs to the NHS and social care system from the health impacts of PM_2.5 and NO₂, and development of a tool for local authorities that quantifies the number of expected disease cases and costs in their local area.

ClientEarth’s three successful legal challenges, supported by EBWT evidence, compelled the Government to publish a more ambitious air pollution plan, which it did in January 2019 through its Clean Air Strategy 2019. It named London, Southampton, Birmingham, Leeds and Derby as cities where air quality was the worst in the country and mandated the introduction of local air quality improvement plans. The five cities published new clean air strategies, with each one citing EBWT as evidence to support their actions [ 5.12]. The EBWT evidence that identified the scale of the health impacts from petrol and diesel cars was used by the Mayor of London and other city mayors for the scientific justification of new Low Emission Zones. Holgate advised on the Mayor of London’s Clean Air Strategy; City Hall regularly cites EBWT findings and direct insights from Holgate in its statements on improving air quality [ 5.13], including the launch of the world’s first Ultra Low Emission Zone in April 2019, which has reduced NO₂ by 44%.

Impact on a landmark legal case on the link between air pollution and the death of a child

Based upon his clinical research in asthma and air pollution, in 2018 Holgate was asked to prepare a report to support the reopening of an inquest into the death of nine-year-old girl Ella Kissi-Debrah from catastrophic asthma in 2013. Lawyers for Ella’s family argued that illegal levels of pollution from traffic on London’s South Circular Road caused the acute asthma attack that resulted in Ella’s death; the first inquest in 2014 did not mention air pollution. Holgate examined Ella’s health records, autopsy report and correlations between neighbourhood air pollutant levels and her admissions to hospital. Citing Southampton research on NO₂, PM and diesel emissions, Holgate was able to incriminate exposure to unlawful levels of air pollution as a major contributory factor to her asthma and cause of death. The new evidence was presented to the Attorney General and the High Court in July 2018 and a new inquest was granted and began in November 2020. Holgate gave oral and written scientific evidence to the new inquest. In December 2020 the coroner made legal history by ruling that air pollution was a cause of Ella’s death. Other causes also listed were acute respiratory failure and severe asthma. The ruling was the first of its kind in the UK and received widespread global media attention, the majority of which cited Holgate’s evidence to the inquest [ 5.14].

The lawyer for Ella’s family confirmed that Holgate’s evidence was ‘ absolutely central to persuading the Attorney General to approve an application to the High Court for the first inquest into Ella’s death to be quashed,’ and that his evidence to the new inquest was relied on by the Coroner in reaching his decision. ‘ The subsequent evidence he gave during the proceedings, meant we were able to demonstrate the fatal role air pollution had in Ella’s death. Not only did his research and expertise underpin our argument, but Professor Holgate’s presence was of much support to our legal team and the family. The evidence he gave in the inquest was persuasive and relied upon in the Coroner’s conclusions.’ [ 5.15] In a letter to Holgate following the ruling, Sadiq Khan, Mayor of London, confirmed Holgate’s key role in the proceedings, saying: ‘ *I hope this landmark ruling, which would not have been possible without your report, will provide some comfort and closure to Ella’s family.*’ [ 5.16]

The Stem Cell Group’s research on biomaterials, stem cells and regenerative medicine led to ground-breaking, cost-saving approaches to clinical practice that have significantly enhanced patients’ quality of life. It has had an economic impact through the formation of a spinout company to commercialise the next generation of biomaterial treatments. Through creative public engagement initiatives, it has increased the public’s understanding of stem cells and enjoyment of science, inspired a series of collaborations between the University and Winchester Science Centre, and stimulated interest among GSCE students in STEM study and careers.

Improving quality of life for hard-to-treat patients through pioneering, cost-saving changes to clinical practice

The underpinning research led to the first patient in the UK being treated with a stem-cell augmented 3D-printed hip replacement in 2014. This was reported widely in the national and international media, including reports on the BBC, Sky News, Research Councils and industrial organisations [ 5.1]. The patient, 71-year-old Meryl Richards from Hampshire, had undergone six hip operations since a traffic accident in 1977. In December 2020, seven years after the surgery, Mrs Richards remains pain free and mobile.

Subsequently, 20 patients have been treated in Southampton using this technique, some of whom contacted the Southampton team directly after reading the 2014 media reports. Follow-up studies, including an 11-patient case series published in 2018, demonstrated the impact of this treatment. New bone was formed in challenging clinical cases, important as these large custom-made 3D printed implants are usually an operation of last resort in patients with reduced biological potential, caused by previous implant effects and increasing patient age [ 5.2].

A review of all 20 patients presented at the Wessex Gauvain Society Annual Meeting in 2020 showed no one needed to have their implant replaced or suffered any dislocations or fractures. Pre-operation, many of these patients were immobile, with some reliant on a wheelchair. Post operation, there was significant improvement in the patients’ Oxford Hip Score, a patient reported outcome measuring hip function and pain with return to much improved mobility level. [ 5.3] To date no implants have been revised. As orthopaedic revision burden increases, the frequency of the most challenging cases has increased with nearly 33% of revisions being re revisions. These re revisions are three times more likely to fail. Given there are 3,150 revisions a year, albeit not generally as complex as the Southampton group’s series, a 6% revision rate after 12 months would save the NHS GBP1.6m if we used our stem cell 3D implant approach. Assuming a best case scenario, application across all 3,150 patients, at 50% implant survival enhancement, would save the NHS GBP34.8m. The UoS series resulted in 100% survival which equates to GBP3.2m saving for the NHS. If applied only to complex revisions such as Southampton’s, then assuming 10% were of similar complexity, this would still save the NHS a total of GBP3.5m. The intervention has therefore transformed patient lives and demonstrated significant cost savings, through fewer revisions, as well as improved patient quality of life.

Delivering economic impact through clinical innovations and commercialisation of underpinning research

Oreffo and Dunlop’s 3D-printed hip research was responsible for significant commercial revenue growth for Materialise NV, the Nasdaq-listed company which produced the hip implant. Brigitte de Vet-Veithen, Vice President of Materialise Medical, wrote: ‘ *The research from Prof. Dunlop and the University of Southampton Bone Research Group has contributed to create strong clinical outcomes of our personalized aMace implant. Their work has helped us to better position this solution in the market and as such expand the treatment to more patients in need to break the revision cycle. The resulting growth of our aMace implant has over proportionally contributed to the 17.6% revenue growth of Materialise’s medical devices and services in 2019.*’ [ 5.4]

Oreffo and Dawson co-founded spin out Renovos Biologics Limited, a regenerative medicine company, in 2017; the underpinning science outlined in [ 3.6] was protected in a patent family [ 5.5, 5.6]. Renovos is pioneering its nanoclay gel technology platform Renovite®, which addresses an unmet clinical need for long-term tissue regeneration for patients with debilitating bone and joint conditions ; it acts as injectable scaffold that attracts cells and localises and retains delivered biologics at ultra-low doses for safer and more efficient regenerative medicine applications. Market research with key opinion leaders affirmed the commercial and clinical potential of the technology. For example, Prof Ashraf Ayoub, Oral and Maxillofacial Surgery, Glasgow, recognised the USP of the nanoclay gels, stressing the ‘ huge need for an injectable and easy to apply delivery material for bone morphogenetic protein’. Steve Charlesbois, Director of Orthobiologics, Cook Regentec, stated: ‘ This biomaterial has big potential in orthobiologics delivery’ and Ian Dunkley, Senior R&D Engineer at Medtronic, emphasised ‘ the need for a safe delivery carrier that stays where it’s delivered’ and endorsed the minimally invasive delivery technology as an approach that ‘aligns with [their] strategy’.

This demonstrable unmet clinical need has resulted in Renovos raising GBP870,000 from public (e.g. Innovate UK) and private sector funding to the end of the impact period. This included a GBP140,000 investment in February 2020 by charity Orthopaedic Research UK and healthcare accelerator HS [ 5.7]. Dr James Somauroo, HS Founding Partner, said: ‘ *It quickly became apparent that Renovos has the potential to fundamentally change the way extremely powerful and sometimes harmful drugs are given around bone. During the interview phase we were impressed by the immense knowledge and expertise of the team and we’re now excited to join the journey and to use our networks to help take them to the next level.*’ [ 5.7].

Renevos’ other commercial propositions include the supply of primary mesenchymal stem cells for research and the delivery of contract research to those carrying out R&D in biomaterials and orthopaedic compounds [ 5.6]. Renovos has generated initial sales of skeletal stem cells worth GBP24,500 via a licensing agreement with European distributor Caltag Medsystems [ 5.6]. This commercial activity enabled the company to create 3.5 FTE employment positions (two scientists, a development manager, Executive Chairman and an administrative role).

Increasing public understanding of stem cell biology and stimulating interest in STEM study and employment

A series of workshops and lab visits for teenagers, based on the Southampton group’s published work and research interests in clay biomaterials and stem cells, took place between 2014 and 2019. Led by Dr Nick Evans, in partnership with educational charity The Smallpeice Trust, 142 students aged 15 to 16 completed workshops; 91.6% of males and 85.3% of females agreed with the statement: ‘ This course has increased your interest in engineering generally’, and 48.3% of males and 54.9% of females agreed with the statement: ‘ This course has persuaded you to follow a career in this field of engineering.’ Of those students who selected science or engineering degrees at university and participated in the Southampton course during the REF period, 84.8% (28/33) said the course had ‘ increased interest in the subject’ and 26.8% (9/34) said the course directly ‘ influenced (their) degree choice’ [ 5.8].

The research on stem cell differentiation to bone led to the conception and creation of a large exhibit to communicate stem cell potential and differentiation. The ‘Stem Cell Mountain’ was designed by Dawson and Dr Ben Ward, CEO at the Winchester Science Centre (WSC), in the University’s first formal collaborative partnership with WSC in 2014. It has since been taken to around 30 festivals including Glastonbury, Cheltenham Science Festival and Countryfile Live. During an impact assessment across six events in 2015, the exhibit was seen by 21,100 people and facilitated in-depth engagement with 7,450 people on the subject of stem cells and regenerative medicine [ 5.9].

Due to its popularity, additional funding from Dawson’s fellowship and WSC workshop funds were allocated to build a permanent replica, which continues to be resident at the Winchester Science Centre (WSC) . During an assessment period undertaken by WSC between 30 April 2015 and 29 November 2018, it reached 613,219 people (133,960 school children, year R-year 9, and 450,709 members of the public). The Stem Cell Mountain consistently receives positive user feedback. Representative examples include: ‘The stem cell mountain – thank you for having this idea. It’s such a clever way to explain the concept’; ‘Such a simple way to represent a very complicated thing’; ‘We need science like this in school. It’s so much more interesting’; ‘I was considering doing a PhD at one point – I didn’t think I’d reconsider it here’ [ 5.9].

As the first successful partnership between the University and WSC, the Stem Cell Mountain led to 11 more joint projects amounting to a value of GBP500,000 and a formal memorandum of understanding between the two organisations in a public engagement partnership inaugurated by the Vice-Chancellor in September 2017. Dr Ben Ward sums up its success: ‘ It has been instrumental in trail blazing an ongoing and fruitful collaborative relationship between our two organisations’ and ‘The Stem Cell Mountain is now one of our most popular exhibits with our visitors, and we see it as a perfect example of how we blend education with fun at the Centre - engaging children and adults alike with science.’ [ 5.10]

Research at Southampton has developed new understanding around the molecular classification and pathogenetic processes of lymphoid malignancies. This led to the development of new prognostic tools to inform the timing of early-stage treatment, regulatory approval of ‘blockbuster’ targeted therapies and changes to standards of care via large-scale, international clinical trials.

New prognostic tools and approaches to optimise early-stage CLL/lymphoma treatment

Patients with U-CLL have a worse prognosis than those with M-CLL in all studies investigating the significance of IGHV mutational status, and this classification, first described and elucidated by Southampton [ 3.1, 3.2], is the dominant prognostic factor out of all those studied. This was confirmed in a 2016 meta-analysis of data from 4,933 patients with early-stage CLL, leading to the publication of an international prognostic index for CLL patients: CLL-IPI [ 5.1]. This tool stratifies CLL patients into four risk categories (ensuring high-risk patients are identified early) and provides a score to estimate prognosis and time to first treatment. It was published on MDCalc [ 5.2], the most broadly used medical reference for clinical decision tools (including by 65% of US physicians). The National Comprehensive Cancer Network (NCCN) updated its clinical practice guidelines in 2020 [ 5.2]; it recommended IGHV mutational status analysis for CLL prior to treatment if not done at diagnosis, and repetition of the test when considering treatment with chemoimmunotherapy instead of novel BCR inhibitors. In 2018 IGHV analysis was listed as a standard in NHS England’s Genomic Test Directory for cancer [ 5.2].

Evidence from the UoS-led, phase 3 REMoDL-B trial [ 3.6, G5] identified a subgroup of diffuse large B-cell lymphoma (DLBL), molecular high-grade (MHG) lymphoma, determined by gene expression profiling, with a clearly inferior prognosis (progression-free survival of 37% compared to 72% from a study of 928 patients) [ 5.3]. Published in 2019, the results identified a new patient group that can benefit from intensified chemotherapy or novel targeted therapies [ 5.3].

Development and approval of novel therapies targeting BCR signalling pathways

A significant translational impact arising from Southampton’s insights into the centrality of BCR signalling as a prognostic marker [ 3.1, 3.2] is the development and regulatory approval of new targeted therapies for CLL. The first-in-class ibrutinib, marketed as Imbruvica (AbbVie and Janssen), and the second generation acalabrutinib, marketed as Calquence (Astrazeneca and Acerta), specifically target BCR signalling pathways. Ibrutinib was first approved for CLL by the US FDA in 2014 and by NICE in 2017 for use on the NHS. Acalabrutinib received FDA approval in 2017 and EU approval in 2020. The clinical/patient benefits and economic impact of these BCR-inhibitor therapies, initially derived from Southampton’s observations, has been vast, transforming CLL treatment by challenging the prior dominance of chemoimmunotherapy regimens. Annual sales revenues of ibrutinib alone reached USD7.24bn (GBP5,460,000,000) in 2019, with CLL the most profitable indication, while sales of acalabrutinib were USD522m (GBP382,000,000) in 2020 [ 5.4].

Clinical trials have demonstrated the significant clinical benefit of targeting BCR signalling using ibrutinib-based regimens over immunochemotherapy, particularly for the U-CLL group. In a phase 3 trial of previously untreated CLL receiving either ibrutinib-based therapy or standard chemoimmunotherapy, ibrutinib-based therapy resulted in much better progression-free survival: 90.7% vs. 62.5% at 3 years; hazard ratio for progression or death at 3 years, 0.26; 95% CI, 0.14-0.50 [ 5.5]. Southampton was the leading centre in the phase 2 CLARITY trial, reporting the remarkable efficacy and low toxicity of ibrutinib in combination with BH3-mimetic venetoclax in patients with recurrent CLL. This combination has shown unprecedented efficacy, with eradication of the disease in more than 60% of patients. The study marked the first demonstration that combining BCR targeting with BH3 mimetics can result in molecular eradication of CLL [ 5.6]. In Diffuse Large B Cell Lymphoma, Acerta invested GBP800,000 for Southampton to carry out the phase 1/2 ACCEPT trial of acalabrutinib in combination with standard chemoimmunotherapy (2018) and Astrazeneca invested GBP3,200,000 in Southampton-led phase 2 trial REMoDL-A to to establish whether this combined approach may become the new standard of care [ 5.7].

Changing standards of care and validating new treatments through large-scale trials

Southampton has led practice-changing trials that have demonstrated the value of FDG-PET imaging in lymphoma therapy. The phase 3 RATHL trial [ 3.5, G2] showed that negative PET imaging after the first 2 months of treatment in advanced Hodgkin lymphoma could predict 5-year progression-free survival of 82%. For this group, the RATHL findings demonstrated that incidence of lung toxicity could be reduced without compromising cure rates by omitting the drug bleomycin, a treatment that had been used in chemotherapy for 30 years but which can cause long-term lung damage. This finding translated into changes to clinical practice, as recommended in NHS guidelines, the 2018 European Society for Medical Oncology (ESMO) Guidelines and the US National Comprehensive Cancer Network (NCCN) guidelines [ 5.8]. The overall RATHL results showed 5 year survival of 95%, leading to adoption of treatment modulated according to PET results in the UK, wider Europe and US [ 5.8].

In primary mediastinal lymphoma, the international IELSG 26 trial of PET imaging led by Southampton showed 95% 5 year survival. This defined the response criteria to be used in this illness (cited in 2016 ESMO guidelines [ 5.9]). In follicular lymphoma, the GALLIUM study [ 3.7], for which Southampton led the correlative laboratory studies, demonstrated that progression-free survival for patients treated with the novel anti-CD20 antibody obinutuzumab (80%) was superior to that seen with the previous standard rituximab (73%) when given with chemotherapy. This changed practice internationally. Citing the Gallium results, the US FDA and the EU approved obinutuzumab (tradename: Gazyva in US; Gazyvaro in Europe; Roche) as a treatment, in combination with chemotherapy, for follicular lymphoma in 2017. In March 2018 NICE recommended obinutuzumab ‘ as an option for untreated advanced follicular lymphoma in patients at higher risk’ [ 5.10]. This led to significant commercial impact too. As an indication, when obinutuzumab was approved with bendamustine for follicular lymphoma in 2016, the media reported a likely sales uplift for Roche of USD500m to USD1bn [ 5.11]. In phase 3 UoS-led trial SABRINA, the maintenance antibody therapy for follicular lymphoma – rituximab (marketed by Roche as MabThera in Europe and Rituxan in US) – was shown to be equally effective and safe when given subcutaneously as intravenously (published in Lancet Haematology, 2017 [ 5.12]). This was shown to increase convenience for patients and reduce healthcare costs by 25%, from EUR1,956 per cycle to EUR1,460, or a total of EUR6,000 for the full course of treatment [ 5.13]. As a direct result of SABRINA, the subcutaneous version of rituximab received approval for common forms of NHL from the EU in 2014 and the US in 2017. In 2014 NICE cited SABRINA as providing key evidence for its use [ 5.14]. The commercial impact was significant; as an indication, rituximab has been one of Roche’s best-selling drugs, with USD7.39bn (GBP5,010,000,000) in global sales in 2015 [ 5.15] and in 2016 Roche said the subcutaneous version of MabThera had secured an average 35% market share [ 5.16].

Southampton’s distinguished research in Age-related Macular Degeneration (AMD), led by Lotery, has supported the use of a more cost-effective treatment, bevacizumab, which has changed clinical practice in the UK and abroad, helping thousands of patients. It also led to the discovery that the same drug could be used to treat a previously untreatable disease, Sorsby Fundus Dystrophy.

4.1 Bevacizumab for the treatment of AMD

4.1.1 Influence on WHO guidelines

Based on major clinical trials including the IVAN study, in October 2013 the World Health Organisation included bevacizumab in its essential medicine list for the treatment of AMD and continued to include it in its revised lists in 2015, 2017 and 2019 [ 5.1].

4.1.2 Influence on policy and guidelines of the General Medical Council (GMC) and NICE

The regulatory hurdles to adopting bevacizumab for treatment of AMD in the NHS were discussed in a 2014 British Medical Journal editorial written by Lotery and the President of the Royal College of Ophthalmologists Professor Carrie MacEwen [ 5.2]. Drawing on the IVAN study, they argued that ranibizumab and bevacizumab have the same efficacy in the treatment of AMD, but since they were both manufactured by Roche, then the company had little incentive to request NICE appraisal for the cheaper, unlicensed drug. They noted that ranibizumab was marketed by Novartis in the UK.

Further, given bevacizumab wasn’t licensed by the MHRA for treatment of AMD, its use would go against guidance from the General Medical Council (GMC) that doctors should prescribe unlicensed drugs only if “there is no suitably licensed medicine that will meet the patient’s need”, with no consideration of cost effectiveness. Without unequivocal GMC and NICE support, Lotery and MacEwen argued that ophthalmologists were “understandably concerned that they may be assuming unacceptable personal liability by using an unlicensed drug when a licensed alternative exists.”

This editorial and the IVAN study were prominently cited by a group of 120 NHS Clinical Commissioning Groups (CCGs representing almost 60% of the UK) in February 2015 when they wrote to the Secretary of State for Health, the Chair of NICE, the GMC and the chief of NHS England [ 5.3] in order to:

• Ask the GMC to provide a specific exception to their standard guidance to support practitioners who wish to prescribe bevacizumab 'off-licence' for use in the eye on the basis of clinical and cost effectiveness;

• Ask the Secretary of State for Health to ask NICE to consider the status of the current Technology Appraisal guidance and authorise NICE to undertake an multiple treatment appraisal looking the comparative cost effectiveness of bevacizumab with ranibizumab and aflibercept;

• Ask the chief of NHS England to support the case for change and to support clinical commissioners who wish to make local commissioning decisions to prescribe bevacizumab 'off-licence' on the grounds that it is safe and a cost effective treatment.

The response from the Department of Health was that “it would not only be unlawful but against the wider public interest if ministers were to attempt to set aside [the EU medicines licensing legislation] in order purely to cut costs.” [ 5.4].

The increasing challenge of delivering healthcare equitably continued to concern health commissioners. To estimate the potential savings, a group of ophthalmologists from University Hospital Southampton used freedom of information requests to identify how much bevacizumab, ranibizumab and aflibercept were prescribed in the NHS during January 2015. Their calculations, published in Eye in August 2016, showed a potential saving to the NHS of GBP449m (GBP539m with VAT) per year if all injections used bevacizumab [ 5.5].

In his role as Chair of the Scientific Committee of the Royal College of Ophthalmologists, Lotery participated in meetings held at the College with CCGs and the General Medical Council (GMC) to determine if the GMC could permit ophthalmologists to use bevacizumab outside its licensed indication and not risk disciplinary procedures by the GMC. Following these discussions, in which the impact of the GMC advice on ophthalmologists was conveyed to the GMC, on 23 January 2018 the GMC changed their position on the use of bevacizumab in the treatment of AMD, ostensibly in response to NICE guideline NG82 that was published the same day.

The GMC Chief Executive stated: “We expect doctors to make good use of the resources available to them and sympathise with the concerns of ophthalmologists making decisions between using a cheaper product outside the terms of its license or a more expensive licensed alternative. We cannot of course give specific clinical or legal advice. But we can say that where doctors are working in partnership with patients, following clinical guidance and making prescribing decisions in good faith on the basis of evidence and experience, the use of Avastin [bevacizumab] would not cause us any concerns.” [ 5.6]

In NICE guideline NG82 Age-related macular degeneration published the same day, the committee for the guideline recognised the results of the IVAN trial, stating that “no clinically significant differences in effectiveness and safety between the different anti-VEGF treatments have been seen in the trials.” In a footnote they cautioned that bevacizumab didn’t have UK marketing authorisation for AMD, but added: “Given the guideline committee's view that there is equivalent clinical effectiveness and safety of different anti-VEGF agents (aflibercept, bevacizumab and ranibizumab), comparable regimens will be more cost effective if the agent has lower net acquisition, administration and monitoring costs.” [ 5.7]

4.1.3 Influence on NHS policy and defence of subsequent legal challenge

In late 2017 the North East and North Cumbria CCG Forum, made up of 12 NHS CCGs in the region, agreed on a policy to offer patients diagnosed with wet age-related macular degeneration the choice of bevacizumab as preferred treatment. Citing a BMJ article in which the IVAN trial and Lotery featured prominently [ 5.8], the Chair of the Forum stated: “We intend to share information with patients through accessible media (including leaflets and audiovisual material) about the treatment options available, the evidence base, and the comparative costs—and allow them to make their own choice. The policy could save the region’s NHS up to GBP13.5m a year over the next five years. That could pay for an extra 270 nurses or 266 heart transplants every year. In a financially stretched NHS, the alternative for CCGs is that we may have to make less evidence based savings, including rationing other treatments such as in vitro fertilisation.” [ 5.9]

The policy was immediately met with a threat of legal action from Bayer PLC and Novartis Pharmaceuticals UK Ltd, who held UK marketing authorisations for ophthalmic use of aflibercept and ranibizumab respectively. In 2018 they applied for a judicial review, arguing that the CCGs’ use of bevacizumab, manufactured by Roche, to treat wet AMD was unlawful under EU law because Roche holds no marketing authorisation for ophthalmic use [ 5.10].

The review was dismissed, with Mrs Justice Whipple, who heard the case, calling the argument an “absurd proposition.” She said: “It would give unbounded power to the pharmaceutical companies to decide which medicines to make available for which purposes.” She added: “That would be seriously detrimental to the wider public interest in maintaining a cost effective public health system.” [ 5.11].

Lotery was the single expert witness for the CCGs and his evidence is listed in the judgement. As well as evidence to demonstrate its cost effectiveness, Lotery described the extensive peer reviewed clinical trial data that bevacizumab was a clinically efficacious treatment for macular degeneration and summarised the bevacizumab safety data from multiple clinical trials.

The judgement on the initial judicial review was upheld in March 2020 after Bayer PLC and Novartis Pharmaceuticals UK Limited appealed it [ 5.12], paving the way for the use of bevacizumab in treating AMD in the NHS.

In 2019 Southampton clinicians administered 540 bevacizumab doses instead of ranibizumab. Based on current costs of bevacizumab at GBP50 per dose, the Southampton team saved approximately GBP243,000.

4.1.4 Influence on MHRA policy

In September 2019 the MHRA changed its position on bevacizumab following a request from Mrs Justice Whipple. They stated: “The Agency accepts that when prescribed and/or used by a healthcare professional, this does not create an unlicensed medicine and falls under the scope of ‘off-label’ use.” They also state: “Professional governance bodies have published advice to prescribers that should be taken into account.” This is a significant change in their position following the initial Judicial Review and guidance from the Royal College of Ophthalmologists and allows clinicians the freedom to choose to use bevacizumab without any legal complications. Lotery was heavily involved in both of these processes [ 5.13].

4.2 Bevacizumab for the treatment of Sorsby Fundus Dystrophy

Research by Lotery’s team [ 3.6] has led to new treatments for Sorsby Fundus Dystrophy (SFD). In previous studies, treatment with bevacizumab allowed stabilisation or improvement in SFD patients. The Southampton research showed that intravitreal bevacizumab should be considered as a safe and effective treatment for choroidal neovascularization secondary to SFD, with 5 patients reported so far. It prevented blindness in these rare disease patients, so the impact on their quality of life was significant [ 5.14]. One patient said: “If it wasn’t for [bevacizumab] I would have lost my eyesight over 10 years ago. I have been having this treatment for over 13 years and it has reduced the deterioration of my vision by 90%. I can still read large print and do what I need to. I consider this treatment miraculous and am so thankful for its availability.” [ 5.15] It is now an accepted treatment in University Hospital Southampton NHS Foundation Trust, and Southampton have provided the evidence base for this treatment to be used elsewhere in the NHS for this small but deeply affected patient group.