Impact case study database

Lung cancer accounts for 1,760,000 cancer deaths world-wide each year (World Health Organisation Statistics, 2018). Cambridge University-led research has established ctDNA liquid biopsy as a cornerstone of precision lung cancer medicine, with the aim of reducing this figure.

Impact on practitioners and the delivery of professional services

A clinically approved blood test for managing patients with NSCLC:

In 2018, the International Association for the Study of Lung Cancer (includes 9,000 lung cancer specialists in over 100 countries) convened a multidisciplinary panel of experts in the field of thoracic oncology to produce a set of recommendations for the use of liquid biopsy in the clinical management of advanced NSCLC patients. The panel reviewed a number of studies that had applied liquid biopsy technology to detect cancer-causing mutations (including [2]), and recommended that liquid biopsy be considered at the time of initial diagnosis in all patients with advanced NSCLC who need tumour molecular profiling, particularly when tumour tissue is scarce, unavailable, or for patients in whom invasive procedures may be risky or contraindicated. They also recommended that liquid biopsy be conducted at the time of initial diagnosis if the turnaround time for tissue biopsy is anticipated to be longer than 2 weeks [A].

Subsequently in 2019, IF-LLB received Medicare reimbursement approval in the US, providing the US population with routine access to a comprehensive genomic profiling test for NSCLC (one of only five such approved tests in the US) [B]. In February 2020, the US National Comprehensive Cancer Network guidelines, recommended use of liquid biopsies in advanced or metastatic NSCLC patients when tissue biopsy is not available: “ If there is insufficient tissue to allow testing for all of EGFR, ALK, ROS1, and BRAF, repeat biopsy and/or plasma testing should be done.” [C]. Liquid biopsies are now regarded as routine clinical practice as part of cancer care in the US. Furthermore, a 2020 systematic review which featured Pritchett et al., 2019 [5] noted that: “ctDNA molecular profiling is an accurate and reliable tool for the detection of clinically relevant molecular alterations in advanced NSCLC patients. Clinical outcomes with targeted therapies endorse the use of liquid biopsy by amplicon-based NGS ctDNA analysis in first line and relapse testing for advanced NSCLC patients.” [D].

[Text removed for publication] [B]. Two of these studies, including a large prospective EU clinical trial, investigated the potential of IF-LLB to reduce the time patients waited for treatment and to select treatments [E]. This work has underpinned the increased use of liquid biopsies in the routine management of patients with NSCLC lung cancer.

Leading international lung cancer oncologists attest to the positive impact of Inivata’s assays on treatment selection and patient care; an Associate Professor at the Stanford Cancer Institute says: “Data presented by Inivata has helped demonstrate the validity of their technology. This adds to the supportive data which is important in increasing the awareness and adoption of liquid biopsies for patient benefit.” [F]. An Associate Professor of Medicine at Harvard Medical School commented, “The impact of Inivata is clear. The company, based off your [Cambridge] research, has proven the validity and reliability of amplicon-based plasma NGS…had led the development of methods to monitor cancer noinvasively and use this monitoring to improve patient care..” [F].

The benefit to patients is further illustrated in an interview with the first patient to receive treatment based on his IF-LLB results in 2015, who said: “This test in fact triggered a change in therapy, which gave me almost 18 months of progression free survival until my cancer was mutated again. The liquid biopsies give me visibility, we’re not guessing anymore and can make an informed decision.” [F].

Supporting research of novel patient care pathways and therapies: In addition to use in routine clinical care, IF-LLB is also being used in ongoing studies to improve the NSCLC patient care pathway and develop new therapies. Inivata Ltd has established collaborations with Genomics England to assess ctDNA samples from the 100,000 Genomes Project to explore the potential of liquid biopsies to improve cancer management and patient outcomes in the UK [G]. IF-LLB will also be deployed in a GBP10,000,000 early cancer detection study of 15,000 participants (iDx-LUNG project). This national collaboration between academia and several major diagnostics and informatics companies will test ways to detect cancer at a stage when it can be cured. IF-LLB will be used to analyse blood samples from patients with inconclusive CT scan results participating in NHS England Targeted Lung Health Checks[G].

Impact on commerce and the economy

In 2014, Dr Rosenfeld and colleagues in Cambridge founded the spinout company Inivata Ltd, as a global clinical cancer genomics company developing its proprietary, industry-leading liquid biopsy platform to transform patient care [E]. The company has raised USD129,400,000 (~GBP96,800,000) and employs >80 highly-skilled individuals at its headquarters and R&D centre in Cambridgeshire and its certified clinical laboratory in North Carolina [H]. In March 2015, the further development of Inivata Ltd. technology was enabled through a collaboration with MedStar Health, a US not-for-profit health care provider [I]. To commercialise IF-LLB in the US, in May 2020 Inivata Ltd., then formed a strategic partnership with Neogenomics that made a USD25,000,000 equity investment in UK-based Inivata Ltd., Cambridge [I]. In July 2019, Inivata Ltd., signed a distribution agreement with IPS Genomix, part of the IPS Group, to provide cancer patients and partners in the Middle East and Africa with access to its IF-LLB test and other liquid biopsy tests [I].

Coles and Earl’s research has directly informed clinical practice, sparing major side effects for patients while markedly reducing healthcare costs.

Impact on practitioners and the delivery of professional services

Changing national guidelines and practice for breast cancer therapy: Cambridge research has had a direct impact on national and international clinical practice for the treatment of Stage I-II breast cancer:

• As a result of IMPORT Low, NICE 2018 guidance for early and locally advanced breast cancer: diagnosis and management [A] states: ‘Consider partial breast radiotherapy (as an alternative to whole breast radiotherapy) for women who have had breast conserving surgery for invasive cancer (excluding lobular type) with clear margins and low absolute risk of local recurrence’.

• UK Royal College of Radiologists breast radiotherapy consensus guidelines recommends partial breast radiotherapy for low risk patients (patients 50 years with grade 1-2, 30mm, oestrogen receptor positive and HER2 negative with minimum 1mm surgical resection margins and no lymphovascular invasion) [B].

• As a direct result of IMPORT LOW, regional NHS guidelines have been introduced by the North East Yorkshire and Humber Clinical Alliance and the West Midlands Expert Advisory Group for Breast Cancer, recommending the use of surgical clips on the wall of the tumour bed to enable partial radiotherapy as a standard approach, via increased accuracy of radiotherapy [C].

• As a direct consequence of the PERSEPHONE trial, UK recommendations have been developed by an optimal duration of trastuzumab working group. In a 2020 survey of breast specialists, the majority (78%) agreed with 6 months as a standard option for those receiving single agent trastuzumab [C]. In addition, the 3,200 breast cancer patients treated with single agent trastuzumab each year in the UK could now benefit from reduced-duration 6-month treatment [D].

Changing international breast cancer therapy practice: Internationally, the results of IMPORT Low have motivated numerous countries to change standard practice, implementing partial breast radiotherapy for low risk breast cancer patients. These include the Netherlands and Denmark, where national breast cancer guidelines have been changed to incorporate these new radiotherapy parameters [E]. IMPORT Low partial breast radiotherapy is now being used routinely in some of the largest and most technologically advanced cancer centres worldwide including: Australasia, Canada (Princess Margaret Cancer Centre), Canada Cancer Centres, and USA (Memorial Sloan Kettering Cancer Center) [E].

Impact on health and wellbeing of people

Reducing side effects for woman receiving radiotherapy: The IMPORT Low trial demonstrated that women with low risk breast cancer can be treated safely and effectively with reduced-dose or partial breast radiotherapy, causing fewer side effects than standard treatment. Importantly, this includes halving the number of women reporting marked changes in breast appearance or hardness that are associated with significant psychological sequelae. In the UK alone, 10,000 women per year are eligible for partial breast radiotherapy [F], which annually equates to 1,200 women spared physical changes in breast appearance and 500 patients spared breast hardness because of treatment [1,2]. Partial breast radiotherapy halves the mean heart dose for patients with left-sided cancer, which reduces the predicted absolute lifetime risk of life-threatening cardiac events to less than 0.5%, i.e. reducing from 50 to 25 such events per year (DarbyS *et al.*NEJM 2013). The reduction from 15 to 5 radiotherapy treatments will also have a positive effect on the patient experience, by minimising hospital visits and treatment-associated side-effects.

Reducing side effects for women receiving targeted therapy: The PERSEPHONE trial provides evidence for safe reduction of single agent trastuzumab therapy from 12 to 6 months. This reduced therapy, provides the same excellent survival benefit, but 5% (365/1929 vs 460/1935) fewer patients treated now suffer severe side effects and only 3% (61/1977) of women who receive 6 months of trastuzumab are likely to have to stop treatment because of heart problems, compared with 8% (146/1941) who receive 12 months [D]. Patients on trastuzumab most frequently report severe aches and pains (9.3% - 524/5610) and fatigue (8.2% - 461/5610), which can be minimised by reduced treatment [D].

Establishing therapy-reduction research for patient benefit:** Both IMPORT Low and PERSEPHONE were completed within the NHS Clinical Research Network with active patient advocate partnership throughout design, recruitment, analysis and dissemination [G]. The success of these two trials with non-inferiority design, has been pivotal in establishing a priority theme of treatment reduction in National Cancer Research Institute (NCRI) breast cancer trials and has received consistent and positive feedback from doctors and patients [G]. Benjamin Smith, Professor of Radiation Oncology and Health Services Research at The University of Texas MD Anderson, said regarding IMPORT Low: “ In my opinion, this is one of the most important articles on early breast cancer to be published in this decade.” Maggie Wilcox, who is the patient lead for the PERSEPHONE trial, said “ I am delighted to have been part of this landmark trial which is an important step to reduce the length of treatment whilst not changing effectiveness.” Professor Hywel Williams, Director of the NIHR HTA Programme that funded the PERSEPHONE study said: “ This is a hugely important clinical trial that shows that more is not always better. Women will now have the potential to avoid unnecessary side effects of longer treatment without losing any benefit. In turn, this should help save vital funds for the NHS and prompt more studies in other situations where the optimum duration of treatment is not known. It is unlikely that research like this would ever be done by industry, so I am delighted that the NIHR are able to fund valuable research that has a direct impact on patients.” [H].

Extending excellence in care to Low- and Middle-Income Countries (LMICs): Trastuzumab has had World Health Organisation Essential Medicine designation since November 2015. However, the cost associated with 12 months of treatment precludes its widespread use in LMICs where it is estimated that over 1,000,000 people are diagnosed with breast cancer; ~120,000 of these patients have HER2+ disease. Demonstration by PERSEPHONE that 6 months of treatment are as effective as 12 months has increased directly the use of the drug in several LMICs, resulting in improvement in the uptake of this curative treatment [I]. IMPORT Low uses a simple technique and conventional, widely available radiotherapy equipment, so can be implemented in any centre worldwide.

Impact on commerce and the economy

Standard whole breast radiotherapy consists of 25 fractions over 5 weeks in many countries worldwide. Based on UK tariffs (GBP159 per fraction), a reduction to 15 fractions of partial breast radiotherapy saves GBP1,590 per patient. The 2020 publication of the FAST Forward trial has enabled seamless adoption of just 5 radiation fractions for partial breast radiotherapy in the UK and in countries where 15 fractions are standard of care. Around 10,000 women are eligible for partial breast radiotherapy per year in the UK where the standard of care is 15 fractions: this saves 100,000 fractions of radiotherapy per patient and a saving of ~GBP16,000,000 per year for the NHS. Each year the NHS treats ~3,200 women with 12 months of single agent trastuzumab (GBP22,000/patient) total ~GBP70,000,000). The Health Economic Analysis in PERSEPHONE showed within-trial cost savings of GBP9,793 per patient by reducing treatment to 6-months of trastuzumab [J]. Patients receiving single agent trastuzumab, which accounts for approximately half of all HER2+ cases, equates to an annual cost-saving of ~GBP30,000,000 to the NHS.

Impact on the health and wellbeing of people

Re-inventing the primary-tertiary care pathway to prevent OAC: Cytosponge®-TFF3 has provided patients at risk of OAC with a simple, convenient test in primary care allowing earlier intervention; thereby improving likelihood of survival and reducing both treatment side-effects and healthcare costs. The BEST3 trial was conducted in 109 GP surgeries, covering a patient population of >800,000 and this led to curative treatment for early cancer that would not have been identified otherwise [A]. Cytosponge®-TFF3 has been licensed to Medtronic to commercialise the technology and make it widely available: it received FDA marketing approval in 2018 and CE mark status in 2020 [B]. Medtronic figures indicate that Cytosponge®-TFF3 has now been used in the management of >1,000 patients in addition to those treated on clinical trials and will be administered to >10,000 patients by end of 2021[B], with expansion to Canada and Western Europe reaching >40,000 individuals by 2022 and >100,000 by 2023.

Patient and public involvement has been critical in developing Cytosponge®-TFF3. Over 4,000 people have now had the Cytosponge®-TFF3 test and their feedback has been overwhelmingly positive, for example : “If I hadn’t taken the Cytosponge test, I would now be walking around with cancer… the fact I am clear of cancer is fantastic… I believe this trial saved my life.” [A]. A video demonstrating the test received over 22,500,000 views and 2,837 comments on Facebook within a four-month period [A]. Fitzgerald has ongoing, long-term support of Heartburn Cancer UK, which “is a passionate advocate of the Cytosponge…the device will reduce the need for unnecessary endoscopies, an invasive procedure, which can only be of benefit to patients and an overburdened health system.”[A]

Impact on practitioners and the delivery of professional services

Clinical implementation in primary care:** Cytosponge®-TFF3 is the first diagnostic test for BE available to GPs in primary care. Therefore, following support by Eastern Academic Health Science Network [D], Innovate UK funded the ‘Delta Project’ to accelerate the use of Cytosponge™-TFF3 in primary and secondary care and to make the identification of patients eligible for Cytosponge®-TFF3 clearer to GPs. This system alerts GPs to test patients with Cytosponge®-TFF3 who request repeat prescription for acid-suppressants [C] –1,300,000 patients in the UK are on long-term proton pump inhibitor (PPI) medication. To ensure further that clinicians are widely informed about Cytosponge®-TFF3, in December 2020, NICE published a Medtech Innovation Briefing, designed to support NHS and social care commissioners and staff who are considering using new medical devices and other medical or diagnostic technologies [D]. Cytosponge®-TFF3 has also been promoted as simple cost-effective test for BE by the Canadian Agency for Drugs and Technologies in Health, “Use of the Cytosponge with biomarker analysis could improve identification of individuals with BE through a test that is less onerous for patients than endoscopy, as well as less costly” [D]. Cytosponge is also an exemplar for the 2020 Early Detection and Diagnosis Roadmap produced by Cancer Research in collaboration with the Department of Health and Social Care [D] .

Maintaining services during the Covid-19 pandemic:* The Covid-19 pandemic disrupted routine NHS services and screening on an unprecedented scale. Routine endoscopy lists – an ‘aerosol generating procedure’ – presented a high COVID-risk and were subject to major delays and cancellations. Therefore, Cambridge University Hospital NHS Trust accelerated commissioning of the Cytosponge®-TFF3 during the pandemic demonstrating its value to investigate patients who could not access endoscopy [E]. This led the Scottish Government from October 2020 to invest GBP500,000 to implement Cytosponge®-TFF3 across all ten of its mainland health boards [E]. By the end of December 2020, NHS Scotland were performing 100 Cytosponge procedures/week and NHS Scotland have stated they are scaling up these services with the expectation that 40% of the >65,000 patients undergoing upper gastrointestinal endoscopy each year will meet the criteria to undergo Cytosponge. Scottish Health Secretary Jeane Freeman stated: “Cytosponge is part of an accelerated roll-out of innovative technologies being embraced by Scotland’s NHS to support the resumption and recovery of vital health services that had to be paused because of the pandemic. It is a much simpler and more patient friendly test than endoscopy that enables faster diagnosis of patients at risk of pre or early cancer, without the need for them to undergo a more invasive procedure. The Scottish Government is working at pace with Health Boards, National Services Scotland (NSS), and industry partners to safely resume NHS services and this new tool further strengthens our ability to provide vital health services, and protect patients across Scotland” . NHS England are also implementing Cytosponge®-TFF3 through a pilot project to reduce the Covid-19 related backlog in secondary care. 700 patients (phase 1) will be tested first, expanding to 30,000 in 2021/22 [E], with a clear path to NICE approval and commissioning. Testing in a mobile van will start in 2021 to pilot the community implementation which will fulfil the recommendation to move routine diagnostics out of secondary care, and assist in providing a Covid-19 safe service during the pandemic [E] .

Impact on commerce and the economy

Established a companion diagnostics company: To commercialise the sample processing and reporting of cells obtained through Cytosponge®-TFF3, in 2018 Fitzgerald co-founded the Cambridge spin-out Cyted that secured GBP8,700,000 investment from Morningside Capital Management. Cyted is providing the sample processing and reporting for Cytosponge procedures, and pioneering AI innovations for smart reporting [F]. In October 2020 Cyted acquired Pathognomics Limited, a provider of digital pathology and clinical diagnostic laboratory services, bringing the total number of Cyted employees to 23 [F].

Healthcare savings for the NHS: The cost of using Cytosponge®-TFF3 is approximately GBP280 – two thirds the cost of standard endoscopy (GBP407 [D(i)]). Based on 2016 UK population data (Office of National Statistics), assuming an uptake of the test in 50% of the 16,500,000 people aged 50-70 years who have gastro-oesophageal reflux (10% of a given age bracket), at least 800,000 people will be tested resulting in an estimated GBP240,000,000 screening savings to the NHS [G] .

Impact on the health and wellbeing of people

Routine genetic testing of patients with PAH: Prior to the research published by Morrell and his colleagues, only patients with PAH who had a positive family history (<5% of cases) had access to routine genetic testing. This meant that around 190 of the 200 people diagnosed with idiopathic or familial PAH in the UK each year had no known underlying cause for their disease; delaying diagnosis and impeding precise and early treatment intervention. Cambridge University-led research has directly influenced clinical recommendations and implemented genetic screening leading to early diagnosis and more appropriate management for patients worldwide [A, B, C, D]. To set this in context, in 2014-2015 no patients with idiopathic PAH in the UK were referred for genetic testing. Currently, at least 25% and in some centres around 50% of PAH patients presenting with idiopathic PAH and no family history are now referred routinely for genetic testing of PAH [H]. A UK PAH centres informal survey in early 2020 showed that all eight National Pulmonary Hypertension Centres discuss the likelihood of a genetic diagnosis with patients and offer referral for genetic counselling and testing. The finding of a mutation in an index case has a major impact on patient prognosis and can help tailor management options. As part of the National Cohort Study of Idiopathic and Heritable PAH, unaffected relatives of PAH patients with a germline mutation are now offered annual screening for PAH. This service has screened over 60 unaffected relatives of BMPR2 index cases, allowing early diagnosis intervention therapy for five newly detected patients[H]. It is well established that early intervention improves survival in PAH patients (Hachulla & Denton 2010, Burger et al 2019).

Rapid access to novel treatment and risk-stratified treatments for patients: Widespread genetic testing for the different types of BMPR2 mutation has opened up the possibility of recruiting patients to clinical trials aimed at restoring BMPR2 function. Increasingly, the BMPR2 status of patients is included as part of clinical trial design (Sitbon O et al, Eur Respir J. 2019). Indeed, in January 2020 Morrell’s research group received an MRC Developmental Pathway Funding Scheme award to conduct a clinical trial of hydroxychloroquine in PAH patients with BMPR2 mutations, as well as a precision medicine approach using 4-phenylbutyrate in patients with cysteine substitutions in the extracellular domain of BMPR2, based on their preclinical research. These trials are connected to the UK British Heart Foundation (BHF)/MRC PAH Cohort, which is being used to identify patients for precision medicine trials. Their research has also provided a definitive test for those patients that have a particularly poor prognosis, justifying more intensive therapy and early referral for lung transplantation. In addition, the company Acceleron have recently published positive Phase 2 trial data using ‘sotatercept’, a drug that targets the BMPR2 pathway, in patients with PAH, providing further support for the use of genetic testing [E].

Patient education and empowerment: Significant mechanistic discoveries by Cambridge research has given patients with PAH an understanding of their fatal disease and the prospect of development of a cure a reality. Morrell and his team have presented their findings to UK patient groups) (most recently at the annual UK Pulmonary Hypertension Association meeting May 2019) and their families to raise awareness of genetic testing in this disease. In February 2020, the Pulmonary Hypertension Association (UK) conducted a survey, in collaboration with Morrell, to identify the need for genetic testing in PAH patients (n=211 patients) [F]. One of the key findings was that “74% of respondents said they would want to be referred for genetic testing if they knew there was a chance of their PAH being caused by a faulty gene” [F].

Impact on practitioners and the delivery of professional services

Refining the patient care pathway in the UK: Prior to the Cambridge-led research described in Section 1, the absence of evidence supporting routine genetic testing for BMPR2 and other mutations in patients with suspected PAH meant that healthcare professionals did not have access to accurate diagnostic tests for most patients. Their research has led directly to a step change in the number of idiopathic and familial PAH patients being tested across the UK (up to 50%). They have added PAH genetic testing to the NHS testing directory [G]. The finding of a genetic mutation in a patient with PAH immediately establishes the diagnosis of heritable PAH, which means that additional testing to ascertain other causes of PAH become unnecessary, saving resources and time in the NHS [H]. The research suggests that patients with mutations have a particularly poor prognosis and justify more intensive therapy and early referral for lung transplantation. These recommendations have been incorporated into the 2018 international global guidance on the clinical management of PAH [A], and should improve outcomes for these patients.

Genetic testing of PAH across the world: Several European countries have now adopted routine genetic testing in PAH, most notably in France [B], and Germany. In 2019 Morrell established an International Consortium for the Genetics of PAH, a collaborative network of 34 institutions from 10 countries in Europe and North America [I, G], to encourage appropriate genetic testing, to curate causative mutations to inform clinicians, and to provide a platform for further genetic discovery.

Impact on commerce and the economy

Although existing drugs are licensed to treat PAH, their impact on the disease is modest. Based on Morrell’s genetic and lab-based research identifying BMP9 as a potential new therapy, patents have been awarded to protect this discovery in the United States and Europe [7]. Working with the University technology transfer office, Cambridge Enterprise, Cambridge academics (Morrell, Upton and Li) established a spin-out biotech company to commercialise the BMP9 approach [J, K]. The venture capital firm, Medicxi, along with Cambridge Innovation Capital and Cambridge Enterprise have invested GBP19,800,000 in the company, Morphogen-IX [K].

In October 2018 the company announced the nomination of its clinical development candidate, MGX292 [L]. The company is now undertaking manufacturing of MGX292 to support planned Phase 1 and Phase 2 studies in patients.

The existing PAH drug market, despite being a rare disease, is worth in excess of USD5 billion per year. As recent national audit data commented: “ While there are currently 12 marketed PAH therapies available, they only serve to slow disease progression. There is no marketed drug that addresses the underlying disease mechanism and targets to cure patients.” The expectation is that the BMP9 approach could be a potential cure, as highlighted in a Guardian article [K].

Morphogen-IX has led to the creation of 10 new jobs. Based on the Babraham Research Campus, the company employs one full time employee, with a subcontract of its drug development activities to a local contract testing research organisation (RxCelerate). The RxCelerate team working with Morphogen-IX comprises 5 senior research scientists, 1 administrator and 3 researchers/technicians. In addition, the company employs consultants in safety, regulatory affairs and manufacturing across the UK.

Peacock’s work applying WGS to infection control has had a profound impact on UK and international policy, placing the UK at the forefront of genomic pathogen sequencing. By establishing and leading COG-UK, she has demonstrated the power of viral WGS to guide disease control and minimise harm to people [A]. COG-UK has positioned the UK as world leaders in COVID-19 genomics, and in September 2020, the Secretary of State for Health and Social Care announced the launch of a new national genomic healthcare strategy, ‘Genome UK’, the development of which will be based on, and informed by, COG-UK [A].

Impact on practitioners and the delivery of professional services

Establishing routine sequencing services for infection control: Between January and March 2013, Peacock chaired the working group that made recommendations on infectious disease sequencing for the 100,000 Genomes Project in the UK [B]. This led to recommendation for the sequencing of Mycobacterium tuberculosis (TB), Hepatitis C, and deep sequencing of HIV to detect drug resistant variants which emerge during treatment. The 2013 report also proposed the need for a devolved network of pathogen sequencing laboratories. As a direct result of these recommendations by Peacock and the committee, in 2017 Public Health England (PHE) announced the launch of a National Mycobacterial Reference Whole Genome Sequencing service [B]. Since its launch, WGS has been performed on culture confirmed TB from 6,479 individuals (1,151 in 2017; 2,693 in 2018; 2,635 in 2019). This information has been used to determine appropriate treatment regimens, and identify clusters of infection [B]. HIV (since 2017) and Hepatitis C (since 2018) sequencing are also now offered through PHE’s Antiviral Unit [B].

SARS-CoV-2 sequencing: In March 2020 in response to the COVID-19 pandemic, Peacock obtained GBP20,000,000 to establish COG-UK, overseeing the legal, ethical and governance framework. COG-UK has developed the methods for SARS-CoV-2 sequencing and software tools for data interpretation and integration, including methods for real-time mutation and outbreak detection [C]. These research tools and all genome data generated have been deposited to open access repositories including GISAID (to which 1,000 institutions deposit data and 7,500 researchers participate) and MRC-CLIMB (which serves over 300 research groups across at least 85 research institutions in the UK) [C]. By the end of December 2020, COG-UK had generated more than 200,000 UK SARS-CoV-2 genomes [C] – around 45% of all SARS-CoV-2 genomes sequenced worldwide. These data are actively utilised each day by the four UK Public Health Agencies and government to monitor the spread and evolution of the virus. In November 2020 Sir Patrick Vallance (the UK Chief Scientific Officer) noted the critical role played by COG-UK stating: “ On behalf of the Government, I wanted to acknowledge the scientists and technicians of COG-UK. By mapping over 90,000 genomes you’ve helped us better understand the virus, identified routes of introduction and transmission, and paved the way for improved treatments and vaccines.” [C]. This unprecedented effort – not previously performed for any pathogen, anywhere in the world – has placed the UK at the forefront of pathogen genomics.

Impact on policy and the health and wellbeing of people

Infection control during the COVID-19 pandemic: In December 2020, COG-UK enabled the discovery of a new, more transmissible SARS-CoV-2 variant (lineage B1.1.7, termed VOI 202012/01 by Public Health England) [D], associated with an outbreak of COVID-19 in Kent that spread rapidly across the UK and beyond. This work informed directly a major change in government policy aimed at saving lives and protecting the NHS: (i) on 19^th December 2020, new Tier 4 measures were introduced for 6,000,000 people in the South East of England and London; (ii) previously sanctioned 5-day Christmas ‘bubbles’ were restricted to Tier 3 or below areas, only on Christmas day; (iii) on Boxing Day 2020, a further 20,000,000 people were brought into Tier 4 [D]. The identification of the new variant also resulted in the closure of borders to the UK by almost all of the EU member states as well as suspension of flights from the UK to India, Iran, and Canada [D].

*Prospective tracking of SARS-CoV-2 variants: During the first and second waves of the pandemic, COG-UK identified the origins of viral importations into the UK [E]. These data showed that during the first wave, more than 1,000 introductions occurred between February and March from Spain, Italy and France. Furthermore, studies in Scotland and Wales showed that viral lineages became largely extinct during the first lockdown, with second waves being driven by new introductions [E]. These data refuted the alternative hypotheses that the virus had been important solely from SE Asia or that there existed a single index case. This work contributed to UK government policy discussions relating to border control and viral sequencing from people arriving in the UK from overseas [E].

COG-UK data was also critical for modelling dispersal of the new VOI 202012/01 variant, informing directly the government’s New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) assessment of viral transmission [E] Similar work allowed assessment of the transmissibility of the D614G variant which subsequently became ubiquitous around the world [E]. Modelling methods developed by COG-UK for studying these variants remain instrumental for real-time assessment of the pandemic.

**Impact on future genomic sequencing services for infection control: In recognition of the crucial role of COG-UK in the response to the COVID-19 pandemic, in November 2020 Peacock secured GBP12,200,000 of additional funds (Testing Innovation Fund) to increase sequencing capacity from 10,000 to 20,000 viral genomes per week by March 2021. She is also supporting the planning, training and handover of a new nationwide sequencing network which will be embedded in the NHS and public health agencies. This national network will sequence SARS-CoV-2 and other pathogens (e.g., TB) to detect and control future infection outbreaks, representing a lasting legacy of the COG-UK for the UK [F].

Impact on public awareness and understanding: Peacock has led numerous events using COG-UK data to educate that public (e.g. Science Showcase, an open access recording viewed 57,234 times by 18^th December 2020 [G]). Peacock has also participated in Science Media Centre events, producing numerous articles on pathogen sequencing for leading news outlets including the BBC and The Guardian – a commenter on the latter noted: ‘We can be really grateful that Britain has such expertise in genome sequencing. The article above provides real insight as to the purpose and benefits of the work of the Genomics UK consortium and others.’ [G].

*Policy relating to control of other pathogens: In 2016, Peacock led chapter nine (Pathogen Genomics) of the Annual Report of the Chief Medical Officer on Genomics (Generation Genome) [H]. This chapter articulated the many benefits of sequencing of bacteria and viruses, and specifically its importance controlling epidemics and pandemics, citing case studies including Foot and Mouth and Ebola. This text continued to raise the profile of pathogen sequencing for disease control. A review written by Peacock was also included by a WHO Global Antimicrobial Resistance Surveillance System (GLASS) report as evidence for the use of WGS in the surveillance of antimicrobial resistance [I].

Each year, around 3,000 babies are lost to stillbirth in the UK. More than 90% do not have a congenital anomaly and more than three quarters occur at 28 weeks of gestational age or beyond, when survival is the norm if a baby is delivered. Hence, on the basis of lack of an anomaly and viable gestational age, more than half of the losses are potentially preventable by medically-indicated delivery if the baby had been known to be at risk of stillbirth. Prior to August 2013, Smith made substantial contributions to raising the public profile of stillbirth as a problem in the UK; in particular, a series of high-profile papers in the Lancet including Smith’s 2007 Seminar on Stillbirth, and the 2011 Lancet Stillbirth Series to which Smith contributed significantly. The latter demonstrated that the UK had the 3^rd highest stillbirth rate out of 35 high income countries. Smith also featured heavily in a 2014 BBC Panorama documentary of stillbirth (“Born Asleep”) [A]. In July 2015, in response to Smith’s review in The Obstetrician & Gynaecologist calling for better monitoring of women during their pregnancy to prevent stillbirth, stillbirth & neonatal death charity (Sands) released a press release that “ welcomes Professor Smith’s clear overview and critique of recent developments in stillbirth prevention” and called for better monitoring to prevent stillbirth [B].

Impact on public policy

The increasing profile of stillbirth as an issue and the UK’s poor record in this area led to action from the UK government. The Health Secretary, Jeremy Hunt, announced on 13 November 2015 an ambition to reduce stillbirth rates by 50% by 2030. Reducing stillbirths was also included in the NHS Outcomes Framework and was included in the NHS England Business Plan for 2015-16. The Government’s mandate to NHS England 2016-17 (section 2.1) requires “ measurable progress towards reducing the rate of stillbirths, neonatal and maternal deaths and brain injuries that are caused during or soon after birth by 50% by 2030 with a measurable reduction by 2020.” [C].

Impact on practitioners and the delivery of professional services

This political ambition led NHS England to produce a care bundle aimed at reducing stillbirth rates articulated in “Saving Babies’ Lives” published on 21 March 2016 [D]. The target audience was all staff delivering maternity care as well as Clinical Commissioning Group Clinical Leaders, Medical Directors, Directors of Nursing and Allied Health Professionals. The care bundle was supported by key stakeholders, such as the Royal College of Obstetricians and Gynaecologists and the Royal College of Midwives, as well as charities representing consumers. The bundle included the recommendation that all women with a low level of PAPP-A in early pregnancy should have serial ultrasound scans from 26-28 weeks, including umbilical artery Doppler, until delivery and this is recommended to reduce the risk of stillbirth. As discussed above, ultrasound can be used to detect FGR and placental insufficiency, hence the demonstration that the association between low PAPP-A and stillbirth was due to these causes was key to informing the subsequent use of serial ultrasound in these women. There is level 1 evidence that use of umbilical artery Doppler in high risk pregnancies reduces the risk of perinatal death (stillbirth or early neonatal death) (Alfirevic Z et al, Cochrane Database Syst Rev2017).

Impact on the health and wellbeing of people

The beneficiaries were pregnant women, their families, health care professionals and the NHS in England. In May 2016 NHS England commissioned the Tommy’s Stillbirth Research Centre at the University of Manchester to evaluate the impact of the Saving Babies Lives care bundle on stillbirth rates. The result was the “Saving Babies Lives Project Impact and Results Evaluation (SPiRE) study (www.clinicaltrials.gov NCT03231007) [E]. The SPiRE study report (published in July 2018) concluded “ During the time period analysed in the early adopter Trusts there was a statistically significant reduction in stillbirth of 20%; this reduction was also seen in term stillbirths. Due to variations in the timing and level of implementation of the various elements of the care bundle this reduction cannot be unambiguously related to its implementation. However, it is highly plausible that the care bundle contributed to the fall in stillbirths.” [F]

As the report states, it is impossible to prove that the Care Bundle was responsible for the fall in stillbirth rates but the report does state that it is “highly plausible”. Moreover, it is impossible to separate out the individual contributions of different elements of the Care Bundle to the fall in stillbirths. However, approximately 90% of Trusts implemented the risk assessment tool, which included serial scanning of women with low early pregnancy PAPP-A, either fully or partially. Moreover, the SPiRE study reported that antenatal detection of small babies increased by approximately 60% over the period of implementation, which was associated with a 31% increase in the use of serial ultrasound. The rate of induction of labour, the primary method for preventing stillbirth of the high-risk foetus, also increased from 26.3% to 31.4%. Hence, it is also highly plausible that implementation of serial scanning to assess foetal growth in women with a low PAPP-A increased detection of small babies and prevented stillbirths.

NHS England produced version 2 of the Saving Babies’ Lives Care Bundle in 2019 and it continues to recommend serial ultrasonic surveillance of women with low first trimester PAPP-A. [G]. Smith was one of seven experts who oversaw the development of the care bundle and was one of only two experts who was on the contributory panels of all five elements of the care bundle.

International impact

Smith’s work on stillbirth prediction is recognised internationally, for example, through the International Stillbirth Alliance Distinguished Researcher Award (presented in Sydney, Australia, 2010). In relation to PAPP-A, although the evidence for impact is strongest in the UK, using low PAPP-A to guide the assessment of risk of stillbirth in pregnant women is also described in international guidelines, from bodies including the New Zealand Maternal Fetal Medicine Network (‘Low PAPP-A is associated with increased risks of SGA [Small for gestational age]’) [H], the South Australian Maternal & Neonatal Community of Practice (“Women who have a low PAPP A on 1st trimester screening should be counselled by the medical practitioner ordering the test about the risk of complications of pregnancy associated with low PAPP-A”) [I], the Government of the State of Queensland, Australia (low PAPP-A at the time of first trimester screen is listed as a risk factor to take into consideration for stillbirth) [J].

Impact on the health and wellbeing of people

Lives saved through earlier diagnosis: Symptoms of vasculitis are easily confused with other illnesses, so the disease can go unrecognised for a long time. Decades of Cambridge University research has contributed to earlier diagnosis of patients by increasing awareness of AAV and training physicians with interest in this disease. The improvement of quality of services for patients in the UK, 1,000 of whom receive treatment from the Cambridge Vasculitis Service, has enhanced wellbeing and saved lives. As such, Vasculitis UK notes, “the loss or reduction of this service [Cambridge-based research and treatment] would represent the loss of a valuable resource and leave a huge gap in provision of care nationally for patients suffering from systemic vasculitis” [A].

Lives saved by optimising treatment strategies: Infection related to high-dose steroid use is the major cause of treatment-related death, owing to organ damage and hospital readmission among patients with AAV. Cambridge-led trials, spanning two decades, have tested and led to the use of alternative, less toxic maintenance treatments [1-3]. The results of the Cambridge led PEXIVAS Study in 2020 [4] led to an immediate change in practice, with physicians reducing steroid dose more rapidly across the NHS. This has reduced hospital readmissions by 20% and has become the new standard of care for patients with AAV [B]. The optimisation of these conventional AAV therapies has seen first year fatality rates fall from 50% in 2007 to under 25% in 2020 [4,B].

Access to novel therapies: In March 2013, Cambridge-led research was pivotal to the licensing of rituximab by the European Medicines Agency (EMA). In 2018 new patient use of rituximab was 36% [C]. Use continues to grow as 63% of patients treated in Cambridge were using rituximab in 2020 [C]. In 2019, the EMA announced that mepolizumab is under investigation for the treatment of the specific AAV disease EGPA [D]. As a result, this offers the first licensed therapy to the approximately 3,000 patients with EGPA in the UK [C]. In the same year, the FDA licensed mepolizumab as the first drug in the US to treat EGPA [10; D]. Furthermore, the avacopan programme has led to licensing applications and the availability of this novel treatment on a compassionate basis [9].

Impact on practitioners and the delivery of professional services

Establishment of national policy and guidelines: The January 2015 NHS Clinical Commissioning Policy, Rituximab for the treatment of AAV in adults [E], was directly informed and shaped by Cambridge-led research [6]. The Policy ensures the equitable and cost-effective use of rituximab as a treatment for AAV, both as a remission-induction and maintenance agent.

Cambridge researchers also contributed significantly to the writing of the 2014 National Institute for Health and Care Excellence (NICE) accredited British Guideline for the management of adults with AAV [E], and the first international Recommendations for the management of ANCA-associated vasculitis (2016, European League Against Rheumatism [EULAR]) [E]. Cambridge-led research into rituximab has produced the first recommendations specifically formulated for B cell targeted therapies in autoimmune rheumatic diseases. The 2018 recommendations aid healthcare professionals with clinical decision-making in order to minimise infection risks for patients with drug induced immune deficiency [E].

NICE also drew on Cambridge research [6] to shape its March 2014 Guideline, Rituximab in combination with glucocorticoids for treating AAV (TA308) [F]. As a direct consequence, clinicians are now able to implement best practice efficiently within treatment centres where patients and clinicians benefit from a unified practice across the UK, reducing significantly the risk of low quality, ‘postcode lottery’ management experiences that have been typical among rare diseases.

Networks, training and development: Cambridge researchers have been instrumental in establishing both national and international research and training networks for healthcare professionals caring for patients with AAV. Jayne was the founder of EUVAS in 2011 and remains its President. EUVAS has over 200 members across Europe and Australasia, facilitating international collaboration and sharing best practice. The success of EUVAS has led to the founding of similar clinical trial networks across the globe. The Chair of the NHS England Clinical Reference Group for Specialised Rheumatology, and President of the British Society for Rheumatology, notes that through Jayne’s “international leadership of clinical trials as President of EUVAS, his work has created the evidence base that has directly ‘paved the way’ for revolutionary new treatments for people living with Vasculitis” [G].

Additionally, Cambridge researchers run a number of training courses for clinicians, including the annual EUVAS Course for senior trainees, consultants and allied health professionals. Established in 2017, the Course has been well-attended each year (720 attendees to date), and has received positive feedback: in its first year 92% of attendees stated they would implement their learning in clinical practice [H].

The national vasculitis registry, UKIVAS, was established in 2012 with input from Cambridge researchers, and Cambridge is the highest recruiter to the registry (over 950 patients at present). UKIVAS ensures that clinicians, providers and commissioners working in the field of vasculitis have robust and meaningful data to inform decision-making for vasculitis services and patients.

Regional Vasculitis Service: The Vasculitis and Lupus Service at Addenbrooke’s Hospital is a nationally eminent treatment centre for sufferers of AAV. Under the directorship of Jayne, the Service provides optimal AAV treatment based on Cambridge-led research. Between 2015 and 2019, the service hosted ~4,500 outpatient appointments per year for ~1,000 patients [I].

Impacts on understanding, learning and participation

Patient engagement: Jayne is a Medical Advisor to Vasculitis UK, the UK’s leading vasculitis charity. In this role, Jayne uses his expertise to support and inform patients about their disease and therapies. Jayne contributed to the Fertility and Vasculitis section of the Vasculitis UK Route Map [J], published in 2014, which serves as a guide to living with vasculitis. In acknowledging Cambridge’s pivotal role in patient and clinician education and engagement through its world-leading service, Vasculitis UK stated: “ the [Cambridge] clinic has become the UK’s institution of ultimate recourse for unusual & complex cases with secondary & tertiary referrals from around the UK. ” [B].

Impact on commerce and the economy

Healthcare savings for the NHS: By decreasing relapse and improving the management of patients with AAV, Cambridge research has significantly reduced the financial burden on the NHS. Approximately 50% of AAV patients relapse within the five years of treatment, which is particularly costly to the NHS, through hospitalisation, additional treatment, and immunosuppression-associated infection. Significant costs can accrue at relapse from further organ damage, particularly renal damage leading to costly renal replacement therapy [K]. Indeed, the estimated cost savings for the NHS resulting directly from Cambridge-led introduction of rituximab therapy alone are GBP45,000,000 per year (2018/2019) [K]. In the US, healthcare savings are estimated at USD41,400 per major relapse [K].

Cambridge research demonstrating that two 1g infusions of rituximab is as effective as four infusions of 375mg/m² at weekly intervals has also produced cost savings to the NHS in terms of reduced clinical activity (50%) and drug costs (40%) [F]. Rituximab also generates more quality-adjusted life years (QALY) than cyclophosphamide; noted by the NICE Evidence Review group to produce an incremental cost-effectiveness ratio of GBP6,006 per QALY gained [F].

Impact on industry and production: Cambridge research has been a major contributor to the licensing of novel treatments for AAV. Since its FDA licensing of mepolizumab for the treatment of EGPA, GlaxoSmithKline (GSK) has reported a 23% increase in sales of mepolizumab in the USA [L].

Chemocentryx Inc has recently invested USD100,000,000 to develop the novel therapy, avacopan. Jayne is providing scientific advice based on novel work from Cambridge [7]. The drug is now in a Phase III trial and is on a pathway to licensing with the EMA, with the FDA recently accepting the New Drug Application (NDA) for avacopan [C and L; 8].

Impact on the health and wellbeing of people

Innovative Treatments: Cox and colleagues drove the successful clinical trials of the first compound, miglustat, for the treatment of sphingolipid diseases: this led directly to clinical approval in Europe in 2009 and subsequently in 44 additional countries, including the USA in August 2014 [A]. In 2018, the FDA approved a miglustat generic for the treatment of sphingolipid-driven diseases [A]. The effectiveness of oral miglustat treatment for Gaucher disease motivated the development of eliglustat as a second generation, potent oral treatment (Genzyme Corp, later Sanofi Genzyme). Cox was involved as an advisor, a member of the safety monitoring committee and then Chief Investigator of the pivotal, large Phase III that showed the efficacy of eliglustat [5] and ultimately led to its European Medicines Agency recommendation in 2018 [A].

As a direct result of Cox’s research, Sanofi Genzyme has supplied eliglustat (approved as Cerdelga™) for clinical use since 2014 and was approved for prescription by The National Institute for Health and Care Excellence (NICE) (HST5) [B] and the Scottish Medicines Consortium (1277/17) in 2017. Eliglustat was made available in NHS England (September 2017) and NHS Scotland (February 2018) [C]. Of the 250 Gaucher patients in the UK national cohort study, within the first two years since UK authorization, 70 patients are taking the oral substrate-reduction therapy. Worldwide, of 7,000 patients in the international registry, more than 1,200 are now taking eliglustat and it has been approved in more than 55 countries, demonstrably improving the quality of life of these patients [D] and [4,5]; following one year of eliglustat, 98% of patients expressed a preference for oral therapy and the main reason cited was convenience [5]. Patient testimony has demonstrated the improved quality of life for patients, as Adele, a Gauchers Type I patient describes her experience in the Gaucher’s Association April 2017 Newsletter: “ Presently I am still taking Eliglustat and […] I can honestly say that I have never felt better, which allows me to do all the things I have always wanted to do. Mostly this involves daily long walks with my dog.” [G].

Novel Diagnostics: The PARC-CCL-18 biomarker discovered by Cox is now used widely within standardised assays for clinical monitoring of Gaucher disease. This Gaucher biomarker has positively affected clinical practice, as clinicians have been able to use these proteins as biomarkers in diagnosing disease and importantly, in following treatment response in Gaucher disease and other lysosomal diseases. This has had a global impact on treatment and patient benefit for those suffering from these lysosomal diseases, because it provides clinicians with the means to compare and monitor dynamic therapeutic responses to a range of treatments with distinct modes of action [E and F]. Indeed, Jeremy Manuel OBE LLB, Founder of the UK Gaucher’s Association and Honorary President and co-Founder of the International Gaucher Alliance, notes that “ It was Prof Cox who initiated the national strategy of centres for the treatment Gaucher patients which subsequently expanded to cover all Lysosomal diseases patients and he continues to be a clear and guiding voice on the ongoing advisory groups responsible for developing and delivering National Protocols and the best possible for treatment for patients (where this a treatment and management of conditions) where there is none.” [F]

Patient education and empowerment: Building on decades of support for the UK Gaucher’s Association since its inception, Cox helped generate a forum and advocacy group for families and patients suffering from Tay-Sachs and Sandhoff diseases. As a Patron, Cox supported establishment of the UK Cure Tay-Sachs Foundation in 2011 and subsequently in 2014 the formation of the European Tay-Sachs and Sandhoff disease Charity Consortium. He now serves as the Consortium’s Medical Advisor [F].

Cox was also instrumental in the establishing the International Gaucher Alliance in 2018. The Alliance is an umbrella group representing the interests of Gaucher patients in 55 countries. Cox has consistently raised public awareness of this disease and supported the formation of EU Charities (Europe and elsewhere) [F], as verified by Jeremy Manuel, who has described Cox’s influence as follows: “ He has always championed the involvement of Patient advocates in all areas of clinical, scientific and public life and inspired the patient community to partner with the clinical and scientific community in their efforts to improve the lot of Gaucher patients, and promoted the involvement of patients to industry, regulators and those responsible for managing the delivery of healthcare and paying for access to treatment. All Doctors promote the cause of the patient before them not all seek to improve and enhance the position of their cohort on a National and Global basis.” Cox remains actively involved with these groups and provides education and updates to patients via their communication channels [G].

Impact on practitioners and the delivery of professional services

Cox’s research and policy creation has provided clinicians with new treatments, ways of monitoring these diseases and better guidelines for clinical management. Patients have benefitted from the following impacts on practitioners:

• In 2014 the FDA approved eliglustat.

• In 2018 the FDA approved a miglustat generic from Amerigen Pharmaceuticals for the treatment of Type I Gaucher disease [A].

• In 2018, the European Medicines Agency recommended eliglustat (tartrate) for the treatment of Type I Gaucher disease [A].

• Eliglustat is now a first-line oral treatment of choice for patients for adults with Type I Gaucher disease [B and C].

• Phase I/II Trials are underway with a derivative called venglustat, an oral treatment which is more effective at penetrating the brain in patients with sphingolipid derangements in Fabry disease and neuronopathic Gaucher disease (Cox is PI). In addition, he leads the European initiative with EMA as CI in the Phase I/II trial in late-onset Tay-Sachs and Sandhoff diseases (announced Jan 2020). Phase I and II clinical trials for Venglustat in adults with Late-onset Tay-Sachs and Sandhoff diseases are currently being conducted and Phase III extension studies in Neuronopathic Gaucher disease type 3 are currently being run (AMETHSIST [ClinicalTrials.gov Identifier: NCT04221451] and LEAP [NCT02843035] trials).

Impact on commerce and the economy

Global drug sales: Initial approval of miglustat (Zavesca®) priced at USD26,820 per month, per patient, had 2016 world sales of USD104,000,000 [H]. Actelion (makers of Miglustat) were then bought by Johnson & Johnson for USD30,000,000,000 [H]. In April 2018 the U.S. FDA approved Amerigen Pharmaceuticals’ generic form of Miglustat; and its partner Miglustat Dipharma, a generic, is used in 33 countries – the first generic approval for miglustat (Zavesca®) [H].

Commercial impact has also been generated through the global sales of eliglustat (Cerdelga®) as sales over the REF impact assessment period have eclipsed EUR773,000,000 [H]. Following its FDA approval in August 2014, eliglustat sales totalled EUR4,000,000 in Qs 3 and 4 of that year. Sales have continued to rise year on year, and in Q1 of 2020, total sales were EUR53,000,000, of which 53% was in the USA and 41% was in Europe [H].

Biotech spinoff company: Cox established Cambridge Gene Therapy (Companies House No. 11112130) in December 2017, which aims to develop and broaden the clinical programmes targeting lysosomal diseases and in particular using pioneering gene therapy as a treatment for Tay-Sachs disease, which is currently incurable [I]. He has secured seed funds of GBP500,000 from Cambridge Enterprise to support pivotal clinical trials and full translational development of this research [J].

Over 3,000,000 people in the UK have osteoporosis, leading to 500,000 fragility fractures each year. Vertebral, hip and other osteoporotic fractures are estimated to cost the UK around GBP4,500,000,000 each year, with hip fractures alone accounting for 69,000 emergency admissions into English hospitals (Source: National Institute for Health and Care Excellence, ‘ Falls and fragility fractures’, 2018). Many of these fractures could be prevented with earlier intervention. The pain and deformity of osteoporotic vertebral fractures accounts for an additional 14 GP visits in the year after the injury [A]. Once diagnosed, treatment for osteoporosis is both clinically and cost-effective for preventing more fractures. Improving the identification of vertebral fractures and osteoporosis is critical to reducing these enormous medical and fiscal costs [A].

Impact on the health and wellbeing of people

Romosozumab (EVENITY™) treatment has improved health and wellbeing of women with severe osteoporosis: Since romosozumab was first produced in 2005, Ken Poole has provided 15 years of expert advice to the drug companies co-developing the drug; UCB (Union Chimique Belge) and Amgen. The Executive Vice-President of UCB described Poole’s research and expert advice as ‘valuable and critical…in the recent EU regulatory process which has led to the Committee for Medicinal Products for Human Use (CHMP) positive opinion regarding romosozumab’ [B] **. This filing culminated in approval of romosozumab by the European Medicine’s Agency (EMA) and Federal Drug Administration (FDA, USA) in 2019. Romosozumab is now being used to treat >60,000 patients across the world including in Europe, USA, Japan, Canada and Australia [B, C]. Extrapolating the numbers of fractures prevented during the pivotal trial (Saag KG, et al . N Engl J Med. 2017) to these 60,000 women provides an estimate of the impact of romosozumab on women’s health globally. Within one year of starting romosozumab instead of alendronate, 1,123 fewer vertebral fractures and 611 fewer hip fractures are expected to have occurred. Romosozumab increased cortical thickness by 10.3%± 4.9 over 12 months; a significant (p ≤ 0.05 ) increase over the next best treatment, teriparatide, which increased cortical thickness 4.3% ± 3.4 [D]. Hisoko N. from Kyoto, Japan was pleased to benefit, “When my 88-year-old mother fell and fractured her spine, we feared she would stay bedridden for life. Thankfully, her doctor prescribed EVENITY^®. After several months of treatment, her bone mineral density has increased and her risk for another fracture has been greatly reduced” [E]

Impact on practitioners and the delivery of professional services

An improved tool was developed to diagnose osteoporosis in the clinic: QCT Pro devices – new effective tools for diagnostic discordance of osteoporosis – have been used worldwide [text removed for publication]. [F]. Cambridge University research was critical for the approval of the QCT Pro method to diagnose osteoporosis in routine clinical practice [6-8], via the International Society of Clinical Densitometry (ISCD) official position statement [G] which cited five papers from the University of Cambridge. A further health impact of improved diagnosis occurred as QCT Pro measurements of bone density were then incorporated into FRAX, the online fracture risk prediction tool and App. Developed by Sheffield University, FRAX evaluation of fracture risk was restricted to clinical risk factors and hip bone density values alone hip (from Dual-energy X-ray Absorptiometry, DXA) [H]. With the introduction of QCT Pro, FRAX now has the facility, in 66 countries worldwide, to calculate patient risk estimates from QCT Pro measurements of bone density as well as DXA [H]. Dr Brown, President of Mindways QCT Pro commented, “ Your work demonstrating superiority of QCT-based hip measurements to DXA-based hip measurements for assessment of hip fracture risk assessment has been pivotal in obtaining recognition within ISCD position statements of the clinical utility of QCT-based assessments of the hip in predicting hip fracture risk.” [F] .

Improved care of osteoporosis patients in the Cambridgeshire regional referral centre: In 2016 with the support of an NHS Innovation Award, the Cambridge team established the QCT Pro Opportunistic Osteoporosis Screening Service at Cambridge University Hospitals. This service, endorsed by the Clinical Director of Radiology [I], deploys routine clinically acquired medical CT scans to diagnose osteoporosis as an ‘added-extra’ to mitigate the devastating effect of late diagnosis. Automated letters are then sent to patients’ GPs to give specific advice on treating osteoporosis to prevent future fractures. The service was audited in 2019 [I] and showed that 581 patients had been detected and benefited from specific osteoporosis intervention. A meta-analysis of fracture risk found that treatment of 28 high-risk individuals would prevent one hip fracture in that population (Merlijn T. et. al. Osteoporosis Int. 2020; 31;251: 257). Accordingly, the service is estimated to have prevented 20 hip fractures, preserving people’s health and wellbeing. Similarly, vertebral fracture detection rates increased from 10-30% in 2013 to 79% in 2018 through local audits [I]. This service is now being tested across the Eastern region in other NHS hospitals including Bury St Edmunds, Peterborough, Huntingdon and Bedford. The benefit of implementing this service was explained by one patient, a retired engineer: " During my annual bowel CT check-up in December 2019 I was found to have severe osteoporosis in my spine and hips. I am so grateful that this was picked up and treated before any damage occurred. I know all too well the agony of spine fractures having broken a lumbar vertebra falling from a ladder some years ago" [I]. Patients suffering from the intense pain of osteoporotic vertebral fractures are often left unable to work and may need years of therapy during recovery (Al-Sari et al. Osteoporosis Int. 2016; 27: 2891 ). Improved osteoporosis care not only reduces the risk of osteoporotic fractures but also could reduce osteoporosis-related health care costs (by for example reducing hip fractures, which cost health and social services over GBP1,000,000,000 each year – National Hip Fracture Database 2019 annual report). The 2019 Royal Osteoporosis Society Bone Academy Patient Insight Survey showed that 92.5% of respondents (n=7,237) with osteoporosis considered a programme of opportunistic detection of osteoporosis using CT to yield either 'extremely beneficial' (70%) or 'very beneficial' (22.5%) outcomes for patients [I].

Impact on commerce and the economy

Romosozumab. Since Romosozumab launched in May 2019, Amgen has generated revenue of USD189,000,000 to year-end 2019 [E]. Over 60,000 women have received romosozumab for severe osteoporosis worldwide, at an average wholesale price of USD26,243 for 12 months [B], equating to approximately USD13,000,000 in sales.

QCT Pro diagnostic software. Screening for osteoporosis is estimated to have reduced Cambridgeshire hip fracture-associated costs by GBP283,260 (GPB14,163 for each of 20 fractures averted from Leal et al. *Osteoporosis Int. * 2016; 27:549 ) versus screening costs and the annual treatment costs.

Cortical Bone Mapping. The Lilly-commissioned Cambridge CBM research programme allayed growing clinical concerns that teriparatide treatment for osteoporosis might worsen hip strength. The research demonstrated the converse; that hip 3D structure improved substantially after treatment with teriparatide for 18-24 months. Cambridge CBM hip maps subsequently featured in product literature to reassure prescribers worldwide, aiding commercial sales [4]. Teriparatide had US sales of USD1,800,000,000 in 2018. In osteoporotic women, Cambridge CBM research found that denosumab (a monoclonal antibody used to treat osteoporosis in >80 countries worldwide) enhanced bone accrual in parts of the hip that commonly break during a fall to the side [2], enhancing claims of drug efficacy. Denosumab had combined worldwide net sales of USD3,200,000,000 in 2016 [J].

Impact on pharmaceutical education strategy: Testimonials from the Head of Bone, at Lilly and Head of Bone at Amgen & UCB describe how Cambridge CBM research has influenced understanding, learning and pharmaceutical strategy [K]. With drugs that add new bone structure or mineral, it is important to discover where and how much new bone is formed. The research identified the treatment effects of denosumab, teriparatide and romosozumab [2-5] which had impacts on physician understanding and learning, and in turn prescribing of the drugs. Teriparatide CBM results allowed Lilly to reassure prescribers using CBM images in prescriber handouts to show precisely where bone accrual was occurring with the drug [L]. This allowed the pharmaceutical industry to educate prescribers on the benefits of denosumab and teriparatide on preventing fractures through targeted bone accrual at sites of known vulnerability. The testimonial from Amgen describes how the Cambridge research has influenced educational strategy: “The work has also been used in education initiatives, not only by Amgen but I have witnessed related work by other pharmaceutical companies to understand and educate practitioners on the effects of bone anabolic treatments” [K].

Impact on clinical practice

Incorporation into UK guidelines:

• In 2018, PREDICT Breast became the only tool recommended by UK NICE for planning the use of adjuvant therapy for breast cancer and the management of early and locally advanced disease (Guideline NG101): “Use the PREDICT tool to estimate prognosis and the absolute benefits of adjuvant therapy for women with invasive breast cancer” [A].

• NICE also recommend the use of PREDICT Breast for all patients with early breast cancer prior to other advanced molecular profiling (Guideline NG34, 2018) [A].

• PREDICT Breast is also endorsed by the Breast Cancer Clinical Expert Group [A].

• In 2019, NICE endorsed PREDICT Prostate as a resource to support decision making in the management of prostate cancer (Guideline NG131) [B].

• The East of England Cancer Alliance (EOECA) also proposed PREDICT Prostate for clinical consideration in the Best Practice Prostate Pathway ‘ ...to provide a standardised personalised tool to help men make decisions via the MDT and clinic’.

• Both PREDICT Breast and PREDICT Prostate are suggested by Cancer Research UK (CRUK) as tools to help patients make treatment decisions [A, B].

Incorporation into international guidelines: In 2016, the American Joint Committee on Cancer (AJCC) established 13 criteria against which any new prognostic model should be evaluated before use in the clinical setting. PREDICT Breast was the only model to pass all criteria. It has since been officially endorsed in the 2018 edition of the AJCC: Cancer Staging manual : “Thirty prognostication tools for breast cancer were identified and reviewed against a checklist derived from the PMC guidelines. Only two tools, Adjuvant! Online [no longer available] and PREDICTv1.2 (incorporation of HER2 into PREDICT, also known as PREDICT-Plus) were found to have met all predefined AJCC inclusion and none of the exclusion criteria” [C].

Impact on patient health and wellbeing

Breast cancer affects >2,000,000 women globally each year, while around 1,300,000 new cases of prostate cancer are diagnosed globally each year. PREDICT Breast and PREDICT Prostate are both provided as free online tools by Public Health England ( https://breast.predict.nhs.uk/ and https://prostate.predict.nhs.uk) to help cancer patients and physicians across the world make an informed decision about treatment options. Since 2014, PREDICT Breast received over 1,250,000 visits across the UK, North America, Europe, Australasia and South America [D]. Between its launch in March 2019 and November 2020, the PREDICT Prostate tool has been visited 28,000 times by 19,000 independent users from over 110 countries, and as of November 2020, it is averaging 250 visits a month with 51.5% as new users [D].

In the breast units of most UK hospitals, PREDICT Breast has, as recommended by NICE guidelines [A], been adopted as the clinical management decision tool of choice; as of 2018, according to NICE, ‘ most healthcare professionals […] use the PREDICT [Breast] tool’ [E]. The effectiveness and user-friendly nature of the PREDICT Breast online tool is evidenced by qualitative user feedback from oncologists, such as that provided by clinicians to the Cambridge Winton Centre for Risk and Evidence Communication [E], for example:

• “I like the different ways of presenting the data to patients and the addition of the risk of death from causes other than breast cancer which provides a context for discussion.”

• “*We use PREDICT tool often in clinic and find it very helpful in order to help patients understand and make informed decisions about their adjuvant treatment. Thank you!*”

Patients have also provided feedback on PREDICT Breast [E]:

• 24th Feb 2020: “ *Thank you, you have made my decision easier.*”

• 23rd January 2019: “ Hello. Thank you for this wonderful online tool for woman such as myself. By the way, I reside in Bangkok, Thailand.”

Similarly, PREDICT Prostate has received positive user feedback from UK based Consultant Urologists and Prostate Cancer International, a cancer support website [E]:

• “Predict is simply brilliant, Using it on my iPad with patients on a daily basis. Well done for producing such a great patient aid “– JA, Stevenage, May 2019.

• “ *I use it and it’s a fantastic tool to guide discussions and help reassure patients!*” -HY, Kent, July 2020.

• “*Men ask me all the time, What is my risk for ED / incontinence / bowel dysfunction. My answer now will be that, "That's impossible to project accurately on an individualized basis, but the PREDICT Prostate system can give you a decent estimate of that risk at 3 years post-diagnosis". I live in the very real world of "What do you think I should I do?" You've just made answering that question a lot easier for tens of thousands of men every year!*” – Prostate Cancer International website , April 2019.

Impact on treatment planning: A clinical review of 200 patients managed by the Cambridge Breast Unit Multidisciplinary Team found 7.5% of breast cancer patients who would have been classified as low risk and not offered chemotherapy, were classified as high risk by PREDICT Breast and offered chemotherapy. Conversely, 11% of patients who would have been classified as high risk and offered chemotherapy, were reclassified as low risk and spared chemotherapy [F]. A conservative estimate – based on PREDICT Breast being the only tool recommended for adjuvant therapy planning by NICE and the number of online recorded visits to the website – is PREDICT Breast was used for at least 25% (100,000) of 400,000 new UK breast cancer cases recorded between 2013 and 2020. Extrapolation suggests that in the UK since 2013, PREDICT Breast will have resulted in ~7,500 women being offered chemotherapy who would otherwise not have been, and ~11,000 women being spared unnecessary chemotherapy.

A significant impact of PREDICT Prostate on treatment planning was shown also in a study of ~200 doctors and specialist nurses. This revealed PREDICT Prostate led to a ~60% reduction in the likelihood of recommending radical treatment to patients, with 80% of clinicians stating PREDICT Prostate is a useful clinical tool [G].

The PREDICT Prostate patient impact study (2018-2020) further demonstrated benefit to patients. This study involved 156 patients across eight UK centres, randomised to either standard of care (SOC) information (n=75), or SOC and the PREDICT Prostate web-tool (n=81). Mean decisional conflict scores (a measure of perception of uncertainty in choosing options) were 21.5 and 15.9 in the SOC and PREDICT Prostate groups respectively, representing a 26% reduction (p=0.01). Anxiety was not increased in the PREDICT arm. In total, 58% of men reported PREDICT Prostate estimates for prostate cancer specific mortality were lower than expected and 35% were less likely to select radical treatment. Over 90% of patients in the PREDICT Prostate group found it useful and would recommend it to others [H].

Impact on the economy

Cost savings due to reduction in overtreatment of cancer: Overtreatment of cancer incurs unnecessary costs for the NHS, principally through avoidable treatment expenses and the management of any side effects. As detailed above, it is estimated that PREDICT Breast has resulted in ~7,500 more women with breast cancer in the UK being offered chemotherapy, and ~11,000 women being spared unnecessary treatment, with associated cost savings to the NHS relating to the cost of adjuvant chemotherapy for 4,500 women.

Overtreatment of prostate cancer can result in significant costs for unnecessary therapy (e.g. prostatectomy costs ~GBP7,000 [2020/21 NHS National Tariff Payment System]) and side effect management (e.g. incontinence, erectile failure, bowel dysfunction) without any clear benefit to patient survival. Data from the National Prostate Cancer Audit shows that 4-8% of men with low-risk disease and 30-40% of men with intermediate risk disease for whom use of PREDICT Prostate would be suitable, are receiving potentially unnecessary radical therapy every year [G]. Based on 19,000 UK visitors to PREDICT Prostate since 2019 [A, H], and on the figures from the PREDICT Prostate Study [G] in which 35% (approximately 6,600) decided not to proceed with radical treatment, such as prostatectomy, this would equate to NHS savings of approximately GBP46,000,000 per year.

**Licensing of PREDICT algorithm: the PREDICT Breast algorithm has been licensed to Portable Medical Technologies and is incorporated into their OncoAssist app. The PREDICT algorithm has been licensed by Cambridge Enterprise to Portable Medical Technologies (whose clients include Microsoft, AMGEN, Dorset Healthcare NHS Foundation Trust and The Clatterbridge NHS Cancer Centre) and it is incorporated into their OncoAssist app. [text removed for publication] [I]. In March 2020 PREDICT Breast and PREDICT Prostate were approved as medical devices under EU Directive 93/42/EEC allowing for rollout and use in clinical settings across Europe [J].

Ebola is spread by direct human-human or animal-human contact and on average kills more than 50% of patients who contract the disease. During the 2013-2016 Ebola outbreak in Guinea, Liberia and Sierra Leone, >28,500 cases were recorded and >11,000 patients died. The WHO declared the outbreak a ‘Public Health Emergency of International Concern’, reserved only for events with a risk of international spread or that require an international response. In November 2014, Goodfellow led an international team that set up one of the first rapid diagnostic laboratories for Ebola treatment and holding centres in Sierra Leone.

Impact on the health and wellbeing of people

Accurate, rapid diagnosis of Ebola: Makeni, in northern Sierra Leone, was a hotspot for new Ebola cases. However, at the start of the epidemic the lack of rapid diagnosis and laboratory infrastructure allowed the disease to spread at an unprecedented rate. During this time, Ebola infected patients and suspected cases were quarantined together with increased opportunity for transmission. By establishing the first Ebola diagnostic laboratory in Northern Sierra Leone, Goodfellow reduced the *'*in the field ' diagnosis time from up to seven days down to 4 - 6 hours for patients at the treatment centre and ~24 hours for samples received from surrounding districts [A]. During its operation, the mobile diagnostic laboratory processed more than 25,000 patient samples [A,B], diagnosing more than 20,000 patients [A]. Their work provided the scientific basis for the WHO coordinated quarantine and treatment response for the 325 patients who tested positive for Ebola at the Makeni treatment centre [B]. Critically, the rapidity of the diagnosis also allowed non-infected patients, who would ordinarily be co-quarantined and potentially infected by diseased patients – to be discharged, directly reducing mortality and Ebola transmission rates. 40 individuals survived their infections. In addition, this process detected cases of unrelated but treatable infectious diseases, including over 750 patients with malaria who were provided with appropriate therapy [A].

Improving public understanding of infectious diseases: During the Ebola outbreak, rumors often hampered control efforts, prompting Goodfellow to establish a public engagement programme in 2016 to increase understanding of infectious diseases and how to protect oneself. The programme employs three people and has engaged >4,000 students at >50 schools across Sierra Leone. By simulating real-time outbreaks students are prompted to identify the pathogen and the chain of transmission by comparing genetic sequences to reference ones, highlighting the need for expediency in implementing control measures. During the Covid-19 pandemic the team have continued to engage local students with information on the pandemic and how to protect themselves and their families. The programme has also benefitted those employed by it: one member of the engagement team subsequently obtained a fully funded scholarship to undertake a degree programme in Japan, and another completed a degree in Public Health [C].

Impact on practitioners and the delivery of professional services

Impact on disease control policy: Little is known about how Ebola emerges, evolves and spreads, severely hampering the efforts of medical and public health staff to manage epidemics. By establishing the first 'in the field' genetic sequencing facility in Sierra Leone – Ebola Outbreak Sequencing Service (EOSS) – Goodfellow and collaborators at the University of Edinburgh provided the WHO with reports on clusters of infection, unmasking sources of ‘cryptic’ Ebola cases [A]. This was the first time WHO had supported the deployment of genomic sequencing during an Ebola outbreak and at the time, this laboratory was the only in-country sequencing capacity available. Their results directly informed the local government, Centres for Disease Control and WHO quarantine, road block and surveillance policies. For example, following development of Ebola in a 13-month old baby who had been quarantined for the standard 21 days, the WHO were considering increasing the quarantine period across the region, fearful that this case reflected an increase in the Ebola incubation period [A]. This would have had major workforce, resource and containment implications for the response effort. However, sequencing at the EOSS established that the Ebola transmission route in this case was via breastmilk in an otherwise clinically healthy mother [2]. Reassured by these results, the WHO maintained the existing 21-day quarantine period [A], and this research informed WHO guidelines for breastfeeding women in the context of Ebola virus disease [D]. A Technical Officer from the WHO Health Emergencies Programme stated: “Professor Goodfellow arrived in Sierra Leone in 2014, and his research expertise was invaluable in establishing and running the Ebola diagnostic laboratory in Makeni. The diagnostic laboratory served the 100 bed Ebola treatment centre (ETC) in Makeni at which it was based, as well as the surrounding district. During its operation, the laboratory processed more than 25,000 patient samples…The mobile laboratory established by Professor Goodfellow led to the diagnosis of >20,000 patients. Their work had a significant impact on improving the laboratory response by decreasing the diagnosis time of patients…The Ebola Outbreak Sequencing Service (EOSS), established by Professor Goodfellow in 2015 provided further crucial data to the WHO, allowing us to identify sources of sporadic cases of Ebola during the tail-end of the epidemic. This was the first time WHO had supported the deployment of genomic sequencing during an Ebola outbreak and at the time, this laboratory was the only in-country sequencing capacity available….The UniMak Infectious Disease Research Laboratory (IDRL) established by Professor Goodfellow at the University of Makeni and the training they have given staff, has also provided much needed local expertise, allowing Sierra Leone to react quickly in response to any new, sporadic Ebola cases…Professor Goodfellow’s contribution formed a crucial role in helping to bring the epidemic in Sierra Leone to a close and his ongoing work at the UniMak IDRL has allowed us to maintain effective local disease surveillance since.” [A].

**Preparedness for future epidemics: It is highly likely that future epidemics of Ebola will occur. Therefore, to enhance epidemic preparedness in the wider region, in 2017 Goodfellow joined with collaborators from the University of Edinburgh, Birmingham and Oxford, KU Leuven, UCLA and the Fred Hutchinson Cancer Centre to form the Wellcome Trust funded ARTIC Network, aiming to develop real-time genomic surveillance in field settings. This collaboration has led to the delivery of training workshops and sequencing protocols that have had a profound impact on public health. For example, in December 2018 Goodfellow acted as a tutor on a five-day workshop attended by 21 researchers and staff from public health laboratories in 13 countries, including Botswana, Kenya, Ghana, Nigeria, Tanzania and Zimbabwe. Separately, in December 2019, Goodfellow visited the national laboratory in the Democratic Republic of the Congo ( Institut National pour la Recherche Biomédicale, INRB) to provide training on virus genome sequencing as part of the ongoing efforts to control the Ebola epidemic [E]. The team trained by Goodfellow and colleagues from the University of Birmingham have since deployed their lab to North Kivu, where it is now providing real-time sequencing support to the DRC outbreak [E]. Goodfellow and colleagues continue to provide support remotely as the work is being undertaken by scientists from INRB. The open source ‘blueprints’ the ARTIC team developed to enable the setting up of diagnostic sequencing services in resource limited settings have since been used by researchers in Glasgow to respond to outbreaks of Rabies virus in Kenya, Tanzania and the Philippines [F]. This experience resulted in the rapid provision of an optimised protocol for sequencing the pandemic SARS-CoV-2 virus, used by labs in Hangzhou CDC in China, and subsequently by labs across 4 continents [F].

Impact on commerce and the economy

During the 2013-2016 epidemic, Goodfellow also worked with the University of Makeni to establish a permanent Infectious Disease Research Laboratory (UniMak-IDRL) within Sierra Leone; thereby training local staff to provide diagnostics and state-of-the-art research methods. The UniMak-IDRL was already serving as the host lab for the EOSS by the end of the 2013-2016 epidemic and has since played a key role in researching, diagnosing and monitoring Ebola for the world. Since opening in September 2014, the UniMak-IDRL has [C]:

• Provided employment to approximately 40 local staff as a direct result of lab activities.

• Received external funding of >USD3,000,000 from multiple international donors.

• Coordinated regional training biosafety and epidemic preparedness training courses for the WHO and US Centre for Disease Control.

• Expanded the UniMak School of Public Health from 12 students/year in 2014 to 72 students/year in 2019. 280 students are currently enrolled. The best students train in the UniMak-IDRL with a view to supporting and growing local public health expertise. Graduates have gone on to successful careers as laboratory technicians and managers, and nursing managers.

The outcomes of these capacity building activities at the IDRL have resulted in:

• On 14^th January 2016, following a 42-day period where no new cases were identified, the WHO declared the Ebola epidemic in Sierra Leone over. The same day, a postmortem sample tested positive, raising concerns around the possible origin, whether this was a new imported case or a part of an unmonitored chain of transmission which would necessitate the immediate re-escalation of control measures, taking up valuable resources. The national IDRL lab staff were able to sequence the virus within 48 hours and determine that it was most likely linked to the persistence of Ebola virus in the individual’s sexual partner [A,C].

• The laboratory played a key role in the characterisation of an outbreak for African Swine Fever virus (ASFV) in November 2019, allowing for earlier introduction of prevention and control measures [G].

• The facilitation of ongoing clinical trials in the treatment and prevention of Ebola: the EboVac vaccination trial and the TKM Ebola therapeutic trial which started during the epidemic [6, 7] and [C,G].

Impact on health and wellbeing of people

An NHS commissioned, national service for patients with severe insulin resistance: Grounded in 20 years of Cambridge University research and based on expertise acquired during their laboratory and clinical investigation, in 2011 Savage, O’Rahilly and colleagues established an NHS commissioned and funded National Severe Insulin Resistance Service (NSIRS) which includes medical, paediatric, specialist nursing and dietetic expertise [A]. Unique in the world, this service provides patients with syndromes of severe insulin resistance, including the lipodystrophies, with accurate diagnoses, optimised therapy and educational support. Between August 2013 and September 2020, the NSIRS provided care to 414 adult and 66 paediatric patients referred from across the UK. Patients received comprehensive genetic diagnostic testing, genetic counselling, specialist nutritional support, optimised drug therapy and, in some cases, bariatric surgery [A]. The NSIRS provided a precise diagnosis to 84% of patients, with around 30% receiving a specific genetic diagnosis [A]; this has brought about a step change in the management of patients with these rare diseases, providing them access to coordinated, expert care, wherever they live. Since its inception, the Cambridge NSIRS has been the only centre in the UK providing metreleptin therapy to patients (n=35) with the metabolic complications of lipodystrophy on a compassionate use basis [A]. Cambridge University researchers support the NSIRS by testing patients for anti-insulin receptor antibodies that can cause Type B insulin resistance; thereby, enabling accurate diagnosis and the use of immunosuppressive therapies which provide dramatic clinical benefits for patients [A].

Improving the patient care pathway for severe obesity and PROS: Genomics England’s gene panel for severe early-onset obesity, which is now available to all relevant NHS specialists [B] was based substantially on Cambridge University discoveries and the ‘45 gene obesity panel’ developed by the Cambridge team. The panel was approved by the UK Genetics Testing Network in Feb 2018 and now provides patients with severe obesity and their physicians across the UK with an accurate diagnostic service: in Cambridge University Hospitals Genomic Laboratory alone, the panel has been used to generate clinical reports for over 600 patients [B]. Further, these discoveries underpin the new Endocrine Society Clinical Practice Guidelines for the assessment, treatment and prevention of paediatric obesity (which Farooqi co-authored) that are now used around the world [B].

The Cambridge discovery that mutations in PIK3CA cause PROS [8] has been incorporated into NHS diagnostic services for this condition in Cambridge and Manchester [C]. Importantly, this discovery has also enabled the repurposing of Alpelisib – a PI3 kinase inhibitor – by Novartis as the first treatment option for PROS, leading to Alpelisib being designated an orphan drug by the FDA (November 2019) available on a compassionate use basis [D].

Metreleptin therapy for leptin deficiency: The Cambridge University team were the first to demonstrate that recombinant leptin is an effective therapy of congenital leptin deficiency (CLD), reversing the severe obesity, and multiple endocrine and immune deficiencies experienced by these children and restoring them to normal health [8]. These initial observations underpinned the development and licensing of metreleptin as a therapy for this disorder throughout the world. The condition is extremely rare, with only around 30 cases reported worldwide. Currently, more than 20 children with CLD from eight countries receive daily metreleptin injections [E]. In 2018, the NHS England Specialised Commissioning Team commissioned metreleptin for the treatment of NHS patients with CLD in the UK [E]. Currently, all 10 UK children treated with metreleptin for this disorder are well, no longer obese, and have completed their education. Five patients who were treated as children are now young adults in higher education or employment and can expect to live a normal life. The first CLD patient in the world to receive metreleptin (commenced 20 years ago age 9 years) gave birth to a healthy baby girl in 2016 [E].

Metreleptin therapy for lipodystrophy: The work of O’Rahilly and Farooqi [9] showed for the first time that correction of a state of leptin deficiency by recombinant leptin had a dramatic effect on appetite and metabolism. This work was also a critical step underpinning the development of metreleptin for states of leptin deficiency due to the lack of functional fat tissue that is found in the lipodystrophies. Savage was an expert adviser to Astra Zeneca during the submission to the US Food and Drug Administration (FDA) in 2014, and to Aegerion in 2018 for their submission to the European Medicines Agency (EMA) for evaluation and approval of metreleptin for the treatment of lipodystrophy [F]. Subsequently, also underpinned by Cambridge-led research, in December 2020 the National Institute for Health and Care Excellence (NICE) provisionally approved metreleptin for the treatment of the metabolic complications of lipodystrophy in the NHS [F]. Metreleptin therapy improves the diabetes, hypertriglyceridaemia and fatty liver disease common in lipodystrophy patients, in whom these conditions are otherwise refractory to treatment and often lead to severe complications such as cirrhosis and pancreatitis [10]. Therapy can also greatly improve patients’ quality of life: “It’s starvation-level hunger. It consumes your every waking moment…It is impossible to exaggerate my experienced benefit of Metreleptin treatment. It has literally changed my life. Indeed, it has saved my life..The NSIRS has been a beacon in the darkness. Its talented and dedicated team have provided an anchor in a sea of uncertainty. Without them I would never have had access to Metreleptin” [F]. Of the estimated 200 people in England, who have lipodystrophy complicated by the severe metabolic effects of the resultant relative leptin deficiency, the majority will now be eligible for metreleptin treatment [F].

Setmelanotide, the second licensed targeted therapy for obesity: In November 2020, setmelanotide – an appetite suppressant that acts downstream of the leptin receptor in neurons of the hypothalamus – was licensed by the FDA for the treatment of patients with severe obesity due to mutations in PCSK1, POMC or LEPR [G]. Although difficult to estimate prevalence, it is thought that these mutations affect a few thousand individuals worldwide. The first of these conditions was originally discovered and characterised by the Cambridge team [1] and Farooqi co-led the clinical trials which established the efficacy of setmelanotide in LEPR deficiency [11]. Data from these trials was included in the filing to the FDA [G].

Enabling and strengthening the voice of patients: The NSIRS team worked with patients to establish a new patient-led charity and support group, Lipodystophy-UK. Cambridge hosts its website [H] providing patients with a voice to share their experiences and highlight the issues specific to these conditions. For example: “ After finding myself in hospital with severe diabetes, out-of-control cholesterol, and several other issues my diagnosis of Familial Partial Lipodystrophy left me feeling alone and frightened. Thanks to LDUK I have connected with other patients”

Impact on commerce and the economy

The commercialisation of the drug metreleptin by Novelion Therapeutics for the treatment of lipodystrophy generated net revenues of USD146,200,000 from sales between 2016-2018 across 10 countries in the US, EU and Asia [I]. This increased to USD85,400,000 sales in 2019 under new owner Amryt Pharma PLC [I].

Impact on practitioners and delivery of professional services

*Establishing genetic testing as standard of care: As detailed above, Cambridge research has pioneered the discovery of genetic causes of rare metabolic disorders. As a direct consequence, genetic tests implementing these discoveries are now standard of care around the world. In 2017 the Expert Panel of the American Endocrine Society, of which Farooqi was a member, formally recommended genetic testing in severe early onset obesity for the first time: “ We suggest genetic testing in patients with extreme early onset obesity (before 5 years of age) and that have clinical features of genetic obesity syndromes (in particular extreme hyperphagia) and/or a family history of extreme obesity” [B]. The 2016 Consensus Document on Diagnosis and Management of the Lipodystrophies produced by the Paediatric Endocrine Society (USA) on behalf of nine endocrine societies from four continents, a document in which Cambridge research represents >10% of all the cited references, cites [5] and states “ *Confirmatory genetic testing is helpful in suspected familial lipodystrophies...Genetic testing should be considered in at-risk family members.*” [F]. In a testimonial from a NSIRS referring clinician: “ The accurate diagnosis and management of these patients would not be possible without the expert services provided by the insulin resistance unit at Cambridge’ [A].

Educating medical practitioners: The European Association for the Study of Obesity (EASO) includes over 20,000 scientists, health care professionals, researchers, students and patients drawn from 36 countries. EASO organises several teaching courses annually with partner stakeholders e.g., Royal College of General Practitioners in the UK: in 2019, over 2,000 professionals participated EASO courses. The Executive Director of EASO noted ‘ *given their seminal contributions to this field, course content on the genetic causes of obesity invariably features the work of Professors Farooqi and O’Rahilly.*’ [J]. Each year the NSIRS also delivers 10 or more educational seminars throughout the UK, each attracting an average of ~50 health care professionals. These are aimed at raising awareness of rare genetic metabolic disorders, highlighting diagnostic advances, guiding use of novel therapies (particularly leptin) and offering support via referrals [A]. In 2016, together with EU partners, the Cambridge team established an EU-wide registry of patients with lipodystrophy in an effort to share expertise [K]. The registry has recruited 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) [K]. The Cambridge team have also changed the education and training of healthcare professionals in obesity medicine globally. These include the Blackburn Course in Obesity Medicine at Harvard Medical School which prepares physicians and surgeons for the American Board of Obesity Medicine (ABOM) certification examination that features a core module on the genetics and biology of obesity, richly citing Cambridge research [J].

There are currently (2020) around 6,000 people on the UK Transplant Waiting List. Of those, approximately 600 are awaiting a liver transplant, and approximately 4,600 awaiting a kidney transplant. Cambridge University, through its transplant personnel, continues to be at the forefront of national transplantation research and has an international reputation for excellence [A]. Research has led to the following impacts:

Impact on the health and wellbeing of people

Increasing access to kidney transplantation nationally: Watson, Chair of the National Health Service Blood and Transplant (NHSBT) Kidney Advisory Group, led a team to design an updated policy for kidney allocation [A]. From September 2019 a new national kidney offering scheme was introduced in the UK, which addresses some of the inequities resulting from the previous 2006 kidney allocation scheme. Recognising Cambridge University research showing the good long-term outcomes of DCD kidneys [2], this scheme now allows for offering of DCD kidneys as well as DBD kidneys.

Development of the UK Kidney Fast-Track scheme (KFTS): Having identified that usable kidneys were being declined by transplant centres, in 2012 Cambridge led the development of a national fast-track offering scheme to rapidly place rejected kidneys in centres willing to transplant them. Declined deceased donor kidneys meeting defined entry criteria for the KFTS are simultaneously offered to all participating transplant centres. Kidneys are allocated through existing algorithms, but with the added flexibility that the accepting centre can implant the kidneys into the recipients of their choosing. An initial outcomes study published in 2017 reported that 286 DBD kidneys (Nov 2012-Apr 2015) and 237 DCD kidneys were transplanted (Mar 2013-Apr 2015), with results as good as non-fast track kidneys (1 year graft survival >90%) [B]. As of November 2020, the scheme continues to run UK-wide.

Increased number of patients receiving organ transplants: By demonstrating the quality and suitability of kidneys donated after DCD, Cambridge University research has contributed to the 25% (n=191) increase in number of patients receiving a DCD renal transplant between 2013/2014 and 2018/2019, with 6053 patients receiving kidneys from DCD donors since 2013, and 970 in 2018/2019 alone. From the Medical Director of NHSBT “Research at the University of Cambridge…has contributed to an increasing acceptance in UK transplant centres of DCD kidneys, observable in an overall upwards trend of DCD kidney transplants since 2014” [A].

Decreased waiting times for transplantation: Cambridge University research demonstrating safety and quality of organs has resulted in Cambridge patients waiting less time for a kidney transplant (2014-17 median waiting time 360 days vs UK median 603 days [A]). This has particularly benefitted elderly patients listed for a kidney transplant, who generally wait longer for transplantation: 60% of Cambridge patients listed when 65 years or older received a transplant by five years, compared with only 38% of the equivalent patient group nationally. Elsewhere a higher proportion either died or were delisted before receiving a transplant [C].

Patient education and empowerment: Cambridge University research has engaged potential kidney transplant recipients in more informed discussions around the transplantation of kidneys from high-risk donors by quantifying the risks. In recognition of the need to discuss risk with patients, Cambridge co-led, with the Directorate for Organ and Tissue Donation and Transplantation NHS Blood and Transplant and key stakeholders, the development in 2015 of the first UK guidelines for consent for transplantation [D]. Consequently, common practices are now shared across UK NHS trusts, meaning that patients should be equally well informed when making decisions and receive parity of care wherever they are treated.

Impact on commerce and the economy

Healthcare savings by increasing the number of transplants: ATTOM confirmed that kidney transplantation is cheaper than dialysis, saving GBP15,000 per transplant in the first 6 years [E]. Cambridge University research has contributed to an additional 191 DCD kidney transplants in the UK between 2013/14 and 2018/19. A conservative estimate of healthcare savings to the NHS arising from these additional transplants is therefore at least GBP2,850,000. This is likely to continue to increase given the upward trajectory of use of DCD donor organs and other previously declined organs for transplantation.

Healthcare savings by increasing the success of transplants: The utilisation of biopsy information and functional assessment of kidneys by normothermic perfusion, together with the identification of the shorter tolerance of DCD kidneys to cold storage, all reduce the chance of unsuccessful transplants which are associated with prolonged inpatient stay and increased resource utilisation. The use of in situ normothermic perfusion and EVNP of livers has had a similar impact on liver transplantation locally, and this is likely to be translated nationally.

Impact on practitioners and the delivery of professional services

Improving international practice in organ selection and quality: Research into the risks of transmission of donor diseases has been incorporated into national and international guidance:

• Cambridge University researchers have co-authored guidance from the UK Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO). From the Chair of SaBTO: “By removing uncertainty, and providing some estimation of risk, this body of work has made a major contribution not only to an increased acceptance and uptake of organs for transplantation but also provides both patients and health care professionals the best available evidence on which to make decisions about the use of scarce, life-saving organs.” [F].

• Professor Watson formed part of the working group that developed the 7^th Edition of the Guide to the quality and safety of organs for transplantation by the European Directorate for the Quality of Medicines & HealthCare of the Council of Europe (EDQM). In October 2020 the Council of Europe issued a recommendation that the governments of member States ensure that quality and safety standards for organ donation and transplantation are set in place in accordance with these guidelines. The guidelines are used not only by the UK and member states of Europe but have been accessed over 1000 times by non-EU countries [F].

Pioneering technology to improve uptake of organs:

Cambridge University researchers have pioneered the introduction of normothermic organ perfusion into clinical practice. In January 2019, NICE issued guidance (from evidence which cited [10]) recommending ex situ machine perfusion (EVNP) for extracorporeal preservation of livers for transplantation, under special arrangements as more data is gathered into its efficacy [G]. EVNP technology is now used clinically in at least three kidney transplant centres in the UK and the Cambridge perfusion protocol has been adapted for clinical use in The Netherlands and the USA [H]. Early work has shown a more rapid resumption of kidney function in DCD kidneys than those not undergoing normothermic perfusion, reducing the need for post-operative dialysis and reducing inpatient stay [I].

The UK National Protocol for direct procurement of cardiothoracic organs and in situ normothermic regional perfusion (NRP) of the abdominal organs, co-written by Professor Watson, was published in May 2019 [J]. Cambridge research on in situ NRP was used by NHSBT to apply for funding to commission a national service for NRP in all DCD donors. In 2020 Professor Watson was invited by NHSBT to lead a committee implementing roll out of NRP in the UK [A]. Funding for the service has been granted in Scotland and Wales in 2019/20. Calculations on the cost benefit of this technology to the NHS show a substantial economic benefit: GBP2,380,000 cost of 100 retrievals using NRP vs GBP3,550,000 for 100 retrievals without NRP [A]. These cost savings are due to lower rates of post-transplant complications and higher rates of graft survival. In Cambridge alone between 2013 and 2020 the use of in situ NRP has led to the transplantation of 78 livers of which two-thirds would have otherwise been discarded, while maintaining high survival rates (April 2015 - March 2019 risk-adjusted 1 year survival rates for Cambridge liver transplants was 96.8% (CI 94.4 - 98.2)) [A].

Impact on practitioners and the delivery of professional services

Endosonography techniques are now the front-line test for lung cancer staging in the UK:

Cambridge University-led development and validation of the combined endosonography techniques EBUS/EUS through the ASTER study has transformed the way clinicians in the UK stage lung cancer. Prior to this work, lung cancer staging of the mediastinum was performed by surgical mediastinoscopy. Based on the results of the ASTER trial and associated healthcare economic modelling led by Rintoul, the updated March 2019 National Institute for Health and Care Excellence (NICE) guidelines for lung cancer have replaced surgical mediastinoscopy with endosonography methods as the first line test for lung cancer lymph node staging; guideline NG122, 2019 recommendation 1.3.19 specifically states: ‘ Offer PET-CT followed by EBUSTBNA [Endobronchial Ultrasound Transbronchial Needle Aspiration] and/or EUSFNA [Endoscopic Ultrasound Fine Needle Aspiration] , to people with suspected lung cancer who have enlarged intrathoracic lymph nodes and who could potentially have treatment with curative intent.’ [A]. The Royal College of Physicians, London, National Lung Cancer 2017 & 2019 Organisational Audit reports show the incorporation of endosonography techniques into national guidelines for staging of lung cancer has led to widespread adoption of endosonography in clinical practice, with 108 (76%) of responding NHS Hospital Trusts in England and Wales now undertaking EBUS, an increase from 44 % since 2014, representing around 1,500 patients per year benefiting from this less invasive test [B].

Rintoul’s research has also substantially influenced new clinical guidelines in Scotland (2014) and service specification recommendations from the NHS England Lung Cancer Clinical Expert Group (2019) [C]. The latter sets out guidance to Cancer Alliances, commissioners of lung cancer services and lung cancer service leads on how to set the best standards of care for EBUS endosonography. This guidance, in conjunction with NHS England’s ‘Clinical advice to Cancer Alliances for the commissioning of the whole lung cancer pathway’, is further driving formal implementation of endosonography techniques as a front-line test throughout the NHS [C].

Impact on international clinical practice and training: Rintoul's endosonography approach has been incorporated into multiple lung cancer clinical guidelines across the world [D]:

• American College of Chest Physicians evidence based clinical practice guidelines for management of lung cancer, May 2013.

• European Society of Medical Oncology (ESMO) clinical practice guidelines for diagnosis, treatment and follow up, October 2013.

• European Society of Thoracic Surgery guidelines for preoperative mediastinal lymph node staging for non-small cell lung cancer, May 2014.

• European Respiratory Journal guidelines for combined endobronchial and oesophageal endosonography for the diagnosis and staging of lung cancer, July 2015.

• Irish National Clinical Guideline for diagnosis, staging and treatment of lung cancer, November 2017.

• New Zealand National Lung Cancer Working Group Standards of Service Provision for lung cancer patients in New Zealand, 2016.

Practitioner training: As endosonography techniques have become standard of care, appropriate training of clinical practitioners has been established to guarantee competency and successful patient outcomes [E].

Impact on the health and wellbeing of people

The widespread implementation of endosonography techniques has led to significant improvements in patient quality-of-life during lung cancer staging [F]. Rintoul’s research has led directly to a decrease in surgical mediastinoscopies, with Bailey et al., noting: ‘ Importantly, in NSCLC, when EBUS-TBNA was performed as primary diagnostic and staging investigation, less patients underwent subsequent invasive procedures’ [F]. Therefore, patients now experience staging under sedation as day-cases, rather than under general anaesthetics as inpatients for one to two days. In addition, it has been shown that the median time to treatment decision is shorter with EBUS-TBNA endosonography (14 days; 95% CI 14-15) than with prior diagnostic investigations including mediastinoscopy (29 days; 23-35) resulting in a hazard ratio of 1.98 (1.39-2.82, p<0.0001) [F]. Data from the UK Society of Cardiothoracic Surgeons shows that prior to the introduction of combined EBUS/EUS endosonography in 2007/8, 3,100 surgical mediastinoscopies were performed each year in the UK; as of 2018/19 this figure has fallen by 70% to 918, avoiding 2,170 operations each year [F]. A recent prospective study from France showed that using EBUS endosonography for lung cancer staging in the pre-operative setting avoided the need for surgical mediastinoscopy in 80% of 163 cases [G].

Impact on commerce and the economy

Work led by Rintoul has demonstrated the cost-effectiveness of endosonography techniques relative to mediastinoscopy across all countries engaged in the ASTER study [2, 4], and similar analyses have shown that endosonography saves approximately GBP900 per procedure over mediastinoscopy [G]. The reduction in annual surgical mediastinoscopies observed by the UK Society of Cardiothoracic Surgeons therefore translates into savings of approximately GBP1,900,000 per year for the NHS. Similar savings of EUR1,450 per patient have been demonstrated in the French healthcare system [G].

The main manufacturers of endosonography equipment in the UK are Olympus UK, Hitachi Pentax and Fujifilm. Implementation of EBUS endosonography has led to increased business and sales of endosonography equipment and consumables for manufacturers and distributors nationally and globally. [text removed for publication] [G].