Impact case study database

Since its emergence in late 2019, SARS-CoV-2 infection led to 4,144,577 confirmed cases of COVID-19 and 121,747 deaths in the UK alone, with worldwide cases over 83,000,000 and deaths over 1,800,000 by the end of 2020. Rapid and reliable testing is a key tool for controlling the pandemic. Initially this relied on existing testing resources in secondary care settings while centralised laboratories and lateral flow testing programmes were being commissioned. During the first peak of infections in the UK (March-April 2020) national viral PCR testing capacity was rapidly exceeded. Critically, conventional PCR testing requires samples to be sent to a central laboratory that often takes over 24 hours to return results. These slow turnaround times delayed important clinical decisions, such as appropriate therapy and prioritisation for isolation facilities.

The collaboration between the research teams in the Faculty of Engineering and the Faculty of Medicine at Imperial led to the development of a rapid and accurate, true sample-to-answer multiplex RT-PCR diagnosis of SARS-CoV-2 in just over an hour, without the need for any laboratory facilities and trained personnel.

The clinical validation conducted with NHS partners demonstrated high sensitivity (94%) and specificity (100%). Following this trial, the MHRA approved CovidNudge for clinical use in April 2020 [ A]. COVID-19 test machines (“Nudgeboxes”) were first deployed for routine use in NHS settings in late April 2020 and were initially prioritised for cancer wards, A&E and maternity departments to protect those most at risk in eight London hospitals; St Mary’s Hospital in Paddington, Charing Cross Hospital, West Middlesex University Hospital, Chelsea and Westminster Hospital, Royal Hospital Chelsea, Queen Charlotte’s and Chelsea Maternity Hospital, the Renal Transplant Centre at Hammersmith Hospital, and the Tower Hamlets Centre for Mental Health at Mile End Hospital.

From 27 April 2020, the NHS required PCR based testing for all unscheduled admissions to hospital [ B] and the CovidNudge testing platform was able to provide this. The primary impact was in supporting the management of patients in busy acute hospitals, with Chelsea and Westminster Hospital performing up to 200 test per day [ C]. However, an important additional role was the testing of patients admitted by psychiatric services preventing any unnecessary isolation that may exacerbate a patient’s illness. In addition to directly benefitting patients admitted to hospital, rapid CovidNudge testing allowed relatives access to hospitals (e.g. partners of women going into labour were able to attend following a negative test) [ C].

At the beginning of July 2020, the device obtained a CE Mark enabling its additional use in non-clinical locations including care homes and other public emergency services where access to PCR remained limited [ D]. DnaNudge Ltd was indicated on the list of approved coronavirus test providers [ E] and an application for FDA approval began in November 2020. In August 2020 the UK Government placed a £161,000,000 order for DNA Nudgeboxes, to roll out the test UK-wide in urgent NHS patient care and elective surgery settings, plus out-of-hospital locations [ F] at a time when there was very limited availability of rapid viral detection diagnostics.

The lab-free sample-to-answer RT-PCR CovidNudge test, provided the medical community with the means to rapidly diagnose, monitor, and treat disease with high confidence and at a low cost. The rapid deployment of the test continued during the 4^th quarter of 2020, with increasing volumes month on month as more sites adopted the technology with 12,339 point-of-care tests performed in December 2020.

As of the end of December 2020, the system was in use at 87 sites, with over 320 machines deployed and more than 62,000 tests run, complementing other programmes focussed on community settings. The test was designed to detect the emergent B.1.1.7 variant and with the second wave of hospitalised infections, positivity rates rose from 1.1% in September 2020 to 13.7% in December 2020. In December 2020 alone the test identified over 1,600 positive cases allowing rapid and accurate point-of-care clinical decision making.

These Imperial-led studies have resulted in policy changes to the annual ‘flu vaccination programme in the UK, facilitating uptake amongst pre- and primary school age children and contributing to uptake of over 60% in the UK paediatric population.

Following review of the SNIFFLE-1 and -2 studies by the Joint Committee for Vaccination and Immunisation (JCVI; an independent expert advisory committee which provides advice to the UK Departments of Health on matters pertaining to immunisation) in June 2015, JCVI recommended changes to UK vaccine guidance whereby the contraindication of egg allergy was effectively removed. This facilitated the roll out of seasonal influenza vaccination in UK children [ A; see page 4, point 12; B; see page 19]. A similar process was followed for SNIFFLE-4 in 2019, resulting in further changes in guidance with respect to children with asthma [ B; see page 18; and C; see pages 13-14]. The guidance now states, as a result of the SNIFFLE-4 data, “ children with asthma on inhaled corticosteroids may safely be given LAIV, irrespective of the dose prescribed” [ C; see page 18]. Importantly, this has resulted in a shift towards use of LAIV in children of all ages with asthma. Given the evidence that LAIV induces a higher level of immunity than injected influenza in children, this shift may offer better protection to older children with asthma.

Changes in practice were further reinforced through presentations at a number of national and international meetings. Public Health England (PHE) have credited the SNIFFLE studies as having been one factor facilitating the roll-out of LAIV amongst eligible children, achieving uptake exceeding 60% [ D: see page 4].

While there was emerging evidence from the UK and Canada that injected influenza vaccines are safe in children with egg allergy, evidence was lacking for LAIV. Thus, egg-allergic children in USA could only be offered the injected vaccine. Data generated from SNIFFLE-1 and -2 studies were also presented to the Centers for Disease Control and Prevention (CDC), the USA’s health protection agency, in turn resulting in a change in US and Canadian guidance [ E, F, G; see section new developments] whereby LAIV is no longer contraindicated for the majority of egg-allergic children, and so “ Persons reporting symptoms other than hives after exposure to egg (such as angioedema, respiratory distress, lightheadedness, or recurrent emesis; or who required epinephrine or another emergency medical intervention) may also receive any licensed and recommended influenza vaccine [including LAIV] that is otherwise appropriate” [ E].

SNIFFLE-3 and SNIFFLE-4 studies generated biological samples (nasal swabs, saliva and serum samples) that were used by both Imperial College London researchers and PHE to assess the response to changes in vaccine strains included in LAIV. This was due to concerns in the USA, which had reported that vaccine efficacy might have fallen from >85% pre-2009 to <5% in 2015/16 season, and led to a change in the strains included for the 2017/18 season. The collaboration between Imperial and PHE allowed the collection of biological samples from patients participating in the SNIFFLE and FLUSHED studies (also run at Imperial), which facilitated further mechanistic work evaluating both vaccine efficacy and local mucosal immunity following LAIV [ H, I]. These results contributed to the assessment by the UK’s JCVI that LAIV continued to demonstrate efficacy (midseason vaccine efficacy in 2018/19 of 87%) [ C], thus supporting the ongoing use of LAIV in the UK’s National Immunisation Programme.

Coronary heart disease (CHD) is now the leading cause of death worldwide. An estimated 3,800,000 men and 3,400,000 women die each year from CHD. The primary cause of this is atherosclerosis that reduces blood flow through the coronary arteries to the heart muscle and can result in angina, heart attack and lead to heart failure and arrhythmias.

The diagnostic workup of patients with angina includes a coronary angiogram to view and measure blood flow in the major coronary vessels. Flow through coronary artery stenoses is measured to assess whether patients might benefit from coronary artery bypass grafting or percutaneous coronary intervention (PCI), usually with coronary stenting. More than 5,000,000 PCIs are performed annually worldwide.

It is difficult to differentiate between functionally significant coronary stenosis and a narrowing that is not substantially affecting blood supply using visual assessment of 2D images from coronary angiograms. Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) provide a functional assessment of the stenosis by more accurately measuring if there is a pressure drop across the site of blockage.

Unlike FFR, iFR does not require the use of hyperemic agents such as adenosine. Use of adenosine can cause severe chest pain and is contraindicated in asthmatics as it can cause bronchospasm. Eliminating the need for adenosine means that iFR can be performed more quickly than FFR, since a pressure wire can be advanced instantly during the procedure without waiting for the drug to be injected, and it is more comfortable for patients, as there is no flushing. The iFR SWEDEHEART trial reported that with no hyperemic agent, a 95.7% reduction in patient discomfort could be achieved using an iFR guided strategy [ A]. iFR is also more a cost-effective treatment, with a 10% cost reduction and 25% reduction in hospital readmissions [ A]. The 10% reduction in cost compared to FFR is a saving of approximately $900 per patient [ B].

The iFR technology created by Dr Davies and colleagues at Imperial was patented in 2010 and subsequently licensed to Volcano (a developer and manufacturer of precision guided therapy tools). It was CE marked and received FDA clearance in 2014 [ C]. It is now used in over 5,000 catheter labs around the world [ D].

iFR is recommended in all the major cardiology guidelines, including the 2018 European Society of Cardiology (ESC) and European Association of Cardio-Thoracic Surgery (EACTS) guidelines [ E] in which it is included as a Class IA recommendation “… iwFR are recommended to assess the haemodynamic relevance of intermediate-grade stenosis” [ E]. In the worldwide 2017 ACC/AHA/SCAI guidelines (which include the Appropriate Use Criteria) iFR is included as a measurement tool (described as physiological pressure measurement not requiring hyperemia) [ F].

Since its known emergence in December 2019, there have been over 83,000,000 COVID-19 cases worldwide and over 1,800,000 deaths by the end of 2020, with over 120,000 deaths in the UK alone. From 1 September to end December 2020, during the second wave of COVID-19, there were 12,000 COVID-19 patient admissions to intensive care units in the UK.

Following publication of the REMAP-CAP trial results in September 2020, the WHO published updated treatment guidelines for corticosteroids in COVID-19 [ A]. The number one recommendation was “ *We recommend systemic corticosteroids rather than no corticosteroids for the treatment of patients with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence)*”. The REMAP-CAP trial (2, 3) findings provided critical evidence for the use of hydrocortisone [ A].

NHS Chief Executive, Sir Simon Stevens said, in response to the trial data published in reference (2) above, “ *One of the distinctive benefits of having our NHS is that we've been able to mobilise quickly and at scale to help researchers test and develop proven coronavirus treatments. Just as we did with dexamethasone, the NHS will now take immediate action to ensure that patients who could benefit from treatment with hydrocortisone do so, adding a further weapon in the armoury in the worldwide fight against Covid-19.*” [ B].

A Chief Medical Officer (CMO) Central Alerting System (CAS) alert (Ref: CEM/CMO/2020/033) was issued by the Medicines and Healthcare products Regulatory Agency (MHRA) on 3 September 2020 [ C] stating “ *Corticosteroids, and in particular dexamethasone and hydrocortisone, have been demonstrated to have a place in the management of patients with COVID-19. Following recent publication of the REMAP-CAP trial for hydrocortisone and a meta-analysis of corticosteroids, the World Health Organization (WHO) has recently issued new interim guidance recommending the use of systemic corticosteroids in severe and critical COVID-19 disease.*”

NICE subsequently updated their COVID-19 prescribing briefing for corticosteroids in line with the WHO recommendations [ D]. They recommend to “ Offer dexamethasone or hydrocortisone to people with severe or critical COVID-19”. This briefing directly refers to the MHRA CMO CAS alert quoted above.

Using the UK as an example, there have been 12,000 ICU admissions in England, Wales and Northern Ireland due to COVID-19 from 1 September to 31 December 2020 based on the Intensive Care National Audit & Research Centre (ICNARC) report at that time. In the meta-analysis described above mortality rates for this population were reduced by 8% with the treatment of steroids. This would equate to approximately 960 lives saved in the last 4 months of 2020 in England, Wales and Northern Ireland alone since this research was published. This improvement in survival is reflected in the latest outcome figures. In patients admitted to ICU for COVID-19 before 31 August 2020 survival rates were 61% (95%CI 60.1-61.9) at one month. For patients admitted from September to December 2020 survival increased to 63.4% (95%CI 62.4-64.4) – this excludes patients who are still being cared for in ICU and will therefore change over time.

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Corticosteroids are now considered the standard of care for severely ill patients with COVID-19 who require oxygen or mechanical ventilation. These drugs are inexpensive and widely available, so that all countries around the world can provide them, saving tens of thousands of lives.

Ripple Mapping is a novel technique that permits 3D visual representation of cardiac tachycardias during patient electrophysiological studies. It facilitates the accurate localization of the origin of the arrhythmia and guides curative thermo-ablation without the need for an experienced computer-operator assistant.

The Patent (reference US8838216B2) for this novel technique was filed by Prof Kanagaratnam with Imperial Innovations in May 2008 and granted in the United States in September 2014 [ A]. The presentation of the initial concept (1) led to an intellectual property license agreement between Imperial Innovations and Biosense-Webster, a Johnson & Johnson company, in 2013. The agreement obtained exclusive rights to Ripple Mapping to commercialise the technique and distribute a licensed product. It also covered future costs and patent maintenance. Johnson & Johnson then incorporated Ripple Mapping as a permanent feature of their commercial CARTO® CONFIDENSE® Module with seamless access using a drop-down tab procedure [ B]. This was introduced to the market in 2015 and it has now been rolled-out to 3,000 hospitals worldwide.

Johnson & Johnson offer a Ripple Mapping Training program at their Education Centre in Hamburg and ad hoc courses have also run in the UK, US, China, Singapore. The company also features ‘The Value of Ripple Mapping’ as one of their on-demand learning modules for healthcare professionals [ C], describing the technique as ‘resulting in a greater understanding in complex arrhythmia diagnosis’. There are several on-demand learning videos available through the training platform [ D].

The studies conducted by the Imperial team (5) are referenced in the 2019 European Society of Cardiology Guidelines for the Management of Supraventricular tachycardia [ E]. It has been adopted and exhibited by cardiac electrophysiology laboratories outside of Imperial College, using patient case studies to demonstrate the advantages of the technique for optimising identification of suitable sites for ablation. These case studies, available on YouTube, have been viewed several thousand times [ F, G]. Ripple Mapping is the only technology that has been tested in a randomised controlled study of acute outcomes (6). Competing technologies such as Precision® (Abbot Medical) and Rhythmia® (Boston Scientific) have not been tested in any prospective, randomised controlled studies.

Ovarian masses are extremely common, with an incidence of 5% – 15% in post-menopausal women. The large majority are benign. The underlying management strategy, therefore, is to distinguish between those that are benign and those that are potentially malignant, allowing conservative management where possible for those that are benign, and rapid referral to a gynaecological oncologist for those that are potentially malignant.

Ultrasound scanning is a critical test in the investigation of such ovarian masses. The IOTA Simple Rules is proven to result in a 2.6-fold reduction in the rate of surgery compared to use of the Risk of Malignancy Index (RMI) in the previous 2003 Royal College of Obstetricians and Gynaecologists (RCOG) guidelines, with, critically, no delay in cancer diagnosis at 12 months. The absolute 16% difference in rates of surgery means that, with 40,000 women being considered for ovarian cyst surgery in the UK each year, 6,500 fewer operations would take place after assessment by Simple Rules compared to assessment via RMI [ A]. The IOTA Simple Rules algorithm can be used in routine clinical practice by junior doctors and ultra-sonographers to distinguish cancers from benign cysts, with significant impact upon patient care worldwide.

The IOTA Simple Rules were included in the revised UK Royal College of Obstetricians and Gynaecologists (RCOG) guidelines for management of ovarian cysts in premenopausal women in 2014 [ B; pages 6-7]. IOTA Simple Rules have also been included in the RCOG guidance for diagnosis and management of cysts in postmenopausal women since 2016 [ C; pages 17-18]. IOTA Simple Rules were included in the British Medical Ultrasound Society guidance in 2019 [ D; page 66] and the British Gynaecological Cancer Society guidelines in 2017 [ E; page 8].

In 2019, the IOTA Simple Rules formed the basis of the French national guidelines for the initial diagnosis of ovarian cancer, containing six citations to IOTA studies [ F]. In 2020, the American College of Radiology and the Society of Radiologists in Ultrasound published the ultrasound risk stratification and management system. This lays out a guideline for the diagnosis and management of ovarian masses in the USA that is based on simple ultrasound descriptors and the IOTA ADNEX model [ G; this guidance contains 15 citations to IOTA studies].

The IOTA ADNEX model has now been incorporated into the most commonly used high-end ultrasound machines for diagnostics internationally, including GE and Samsung [ H].

To ensure the models are accessible, the Imperial team has developed two apps, available for Android and iOS [ I]. The first app contains the logistic regression (LR)1 and LR2 models, as well as Simple Rules, and has been downloaded over 10,000 times. The second app features the ADNEX model and has been downloaded approximately 8,000 times. These apps are designed for use in routine clinical practice, as not all users will have access to high-end ultrasound machines, especially those working in low and middle-income countries.

The researchers at Imperial have implemented IOTA courses to teach IOTA ADNEX and Simple Rules, and IOTA exams to investigate the ability of clinicians to use the models. Over 10,300 people have passed the IOTA certification and are listed on the IOTA website [ J].

There are one million new CRC diagnoses annually worldwide. It is the fourth most common cancer (c.45,000 new cases/year) and second most frequent cause of cancer mortality (c.17,000 deaths/year) in the UK. It is estimated that the overall cost of CRC to the NHS exceeds £1 billion annually.

Most CRCs develop from a type of polyp called an adenoma, and removal of adenomas reduces the risk of CRC. National guidelines recommend surveillance colonoscopy for patients thought to remain at increased CRC risk following polyp removal. Colonoscopy is an invasive procedure that is burdensome for patients, requires intensive bowel preparation and carries a small risk of serious complications. Post-polypectomy surveillance places enormous pressure on NHS resources, accounting for approximately 75,000-100,000 colonoscopies every year (20% of all colonoscopies) in the UK. For intermediate-risk patients alone, surveillance (as recommended in the 2002 UK guidelines) costs the NHS approximately £2,500,000 over each surveillance three-year cycle.

To reduce this burden on patients and the NHS, Professor Cross and colleagues at Imperial College reassessed these surveillance requirements to inform revisions to the 2002 UK post-polypectomy guidelines. Dissemination of the findings from this work (refs 1-2 above) highlighted potential beneficial impact on both patients and the NHS and resulted in Professor Cross playing a leading role in the revision of the UK surveillance guidelines and being co-senior author of the revised guidelines, published in Gut in 2020 [ A].

Imperial research findings were used to determine which patients require surveillance and are cited >60 times in the guidelines to support the evidence statements. Surveillance is no longer recommended for nearly all the low-risk group and approximately half of the intermediate-risk group. For the high-risk group, one surveillance colonoscopy at three years is recommended, compared to a minimum of three examinations in the 2002 guidelines [ A, page 219; Figure 1, page 205]; this largely aligns with the recommendations from the Imperial team of researchers (ref 4 above).

The Imperial findings were also incorporated into the latest EU guidelines, which similarly recommend surveillance after three years for the high-risk group [ B, cited 17 times pages 689-690, 692-694].

The main impact of the new guidelines is a substantial reduction in the number of patients requiring surveillance colonscopy. It is estimated that total colonoscopic surveillance workload will fall by 80% [ A, page 219], potentially saving approximately 60,000-80,000 colonoscopies per year. Under the new guidelines, surveillance is already being directed specifically towards patients who remain at increased risk of CRC following polyp removal. Conversely, patients not at increased CRC risk compared to the general population are returning to routine CRC screening based on stool-based tests.

In summary, the new guidelines are minimising patient exposure to unnecessary invasive procedures and alleviating the burden of colonoscopy surveillance on NHS endoscopy services.

The reduction in colonoscopy surveillance that has already taken place reflects the efficient dissemination and implementation of the new guidelines. Professor Cross, other guideline authors and national endoscopy stakeholders have used various electronic and web-based communication, conference presentations, and workshops to disseminate the guidelines. The Imperial researchers have promoted their data and the guidelines via Twitter (@CSPRG_Imperial), and their website (https://csprg.org.uk/\), by press releases [ C, D, E], blog articles [ F], as well as at national and international meetings. Dissemination of the guidelines has been further aided by their endorsement from the British Society of Gastroenterology, the Association of Coloproctology of Great Britain and Ireland, and Public Health England.

Public Health England has sent communications to screening services to encourage implementation of the guidelines and the new guidelines are currently being built into the National Bowel Cancer Screening Programme software. NHS England have worked with cancer alliances, asking NHS trusts to nominate a consultant surveillance lead responsible for guideline implementation [ G]. The 2002 guidelines were formally withdrawn from gov.uk webpages in July 2020 [ H].

As the WHO Collaborating Centre for Infectious Disease modelling, the Imperial team provided real-time analyses (and direct support via deployed personnel) to WHO and governments during the 2013-16 West African Ebola epidemic and three subsequent epidemics in DRC. In 2014-15, a key aspect was direct support for the UK Government via the Scientific Advisory Group for Emergencies (SAGE) and the then Departments for International Development (DFID) and Health (DH) [ A, B]. Much of the work made use of confidential data shared by the affected countries, and so was only summarised in confidential reports and presentations shared with WHO, countries and key other stakeholders throughout each epidemic. UK modelling is referred to, though not explicitly described, in UK SAGE minutes [ A, B]. Additional letters of support are therefore provided to confirm the impact.

West African Ebola epidemic

The initial assessment of the epidemic in research reference (1) (co-authored with WHO) directly informed the WHO declaration of the epidemic as a Public Health Emergency of International Concern (PHEIC); [ C] states “ this study provides the evidence needed for an urgent wakeup call requiring intensive scaling up of control measures” and this is confirmed in supporting letter from Bruce Aylward, then the WHO lead for the response [ D]: “ These estimates informed … WHO to declare the epidemic a Public Health Emergency of International Concern in 2014”.

It additionally prompted a rapid scale-up of funding for the international response (“ Importantly, the technical credibility of these early forecasts added further urgency to the response and informed the strategic and operational planning of WHO and the broader national and international response” [ D]) .

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The team’s estimates of the case fatality ratio and how it varied with age, sex, and location (references 1, 3) “were instrumental in shaping the understanding of the risk of death by programme managers, donors, politicians, and others, and adjusting the response priorities accordingly” [ D].

The team shared transmission estimates and short-term incidence projections with WHO and other stakeholders (including UK government [ A, B]) every one to two weeks. These reports improved situational awareness, the monitoring of progress in epidemic control and consequent adjustments to interventions and associated logistical planning [ D- F].

Projections made as the epidemic declined were used to plan progressive withdrawal of international staff and equipment and the dismantling of Ebola Treatment Units (ETUs) and mobile laboratories [ D, F].

The team generated reasonable worst-case scenario projections for the UK government and projected bed capacity requirements [ A]. Investigations into the drivers of transmissibility (reference 4) were used to establish which interventions would be most effective. Safe burials were highlighted in modelling presented to UK SAGE: “ Modelling: the risk of transmission at burials was highlighted as a continued area of concern” [ A] and “ The need to focus on transmission that occurs in the few days before death, in addition to transmission during burials, was highlighted” [ B]. The need for earlier hospitalisation was also noted in [ A] as an output from the modelling.

Incubation period distribution estimates (research reference 1) were used by WHO to support the recommendation to follow up contacts of Ebola cases for 21 days [ D]. Estimates of the typical duration of hospital stays were used by WHO for logistical planning of bed capacity and food requirements for ETUs [ D, G, cites reference 1].

Ebola epidemics in DRC (2017-)

Following promising trial results demonstrating safety and high efficacy of the rVSV Ebola vaccine, the Imperial team used mathematical modelling to quantify the potential impact of different vaccination strategies on Ebola epidemics. This evidence was presented at WHO/SAGE working groups and used by WHO to inform policy recommendations regarding Ebola vaccination [ H, I]; compassionate use of vaccination was added to the traditional Ebola intervention toolkit in 2018 [ H].

During each Ebola epidemic since West Africa, the team has continued to provide regular situation reports to WHO, DFID and other partners, including real-time quantification of severity and transmissibility, short term projection of case incidence, bed capacity needed, number of vaccine doses required, as well as measures of the risk of spatial spread. These analyses have been critical in assisting decision-making during these outbreaks and contributed to the evidence WHO used to declare the 2018-19 Ebola epidemic a PHEIC [ D].

Cystic fibrosis affects almost 11,000 people in the UK and an estimated 100,000 worldwide, and causes excessive airway mucus secretion, early and recurrent bacterial infection and inflammation leading to irreversible lung damage. Furthermore, the majority (>85%) of people experience digestive malfunction leading to poor weight gain and require digestive enzymes to be taken with all food and drink.

Until recently, all treatments for CF were directed at disease symptoms such as airway clearance (physiotherapy and muco-active inhaled drugs), antibiotics, nutritional supplements and treatments for complications such as diabetes and liver disease. During periods of stability, pwCF spend 1-2 hours daily on their treatments. Periods of ill-health frequently necessitate hospital admission (average 14 days) for intravenous antibiotics. Patients also experience acute loss of lung function, painful procedures (e.g. repeated venous access) and consequences of high dose antibiotics (allergies, gastrointestinal disturbance, development of antimicrobial resistance and drug toxicity including kidney damage and deafness). Despite this huge burden of treatment and healthcare costs, CF is progressive and relentless. Lung health is lost progressively and life expectancy severely reduced; even with advances in diagnosis and therapy over the last decades, median age of death in the UK is approximately 30 years. The only option for end-stage lung disease is transplantation, if available, but this is not curative and only has a 50% 5-yr survival.

CFTR modulators restore the defective cellular processes underlying key symptoms, significantly changing the approach to CF management and thus have been genuinely transformative.

Professor Davies’ programme provided the critical clinical evidence for licensing the first of these drugs, ivacaftor (Kalydeco), by the European Medicines Agency (EMA) for ≥12 year olds in 2012, and younger children in 2015 [ A]. Although only suitable for a minority (5-8%) of patients, its impacts have a far wider reach, as they provide evidence of the long-term benefits of CFTR functional restoration. Indeed, 4-5 year observational data collected through national (US and UK) patient registries confirm the acute improvements in lung function [ B], but also describe slowing the rate of lung function loss; reduction in lung infection; hospitalisation and treatment for exacerbations; optimisation in nutritional health and quality of life scores with reduced frequency of diabetes. These benefits translated into prolonged survival and a reduced need for lung transplantation.

The dual combination Orkambi (lumacaftor/ivacaftor) was approved by the EMA in 2015 (≥12 years old) and in 2017, for patients ≥ 6 years old [ C]. Findings from the EXPAND trial provided pivotal efficacy evidence that contributed to the approval of Symkevi (tezacaftor/ivacaftor) for 12 year olds in 2018 [ D]. These dual combinations demonstrate a significant reduction in pulmonary exacerbation and improvements in LCI. Orkambi, Symkevi and Kalydeco were commissioned in England and Northern Ireland (October 2019); Orkambi and Symkevi were made available in Scotland (September 2019) and Wales (November 2019) [ E].

The triple combination Trikafta/Kaftrio (elexacaftor/tezacaftor/ivacaftor) was approved for pwCF ≥12 years old by the FDA in 2019 and EMA in 2020 [ F]. NHS England immediately announced availability of the drug to all eligible patients, giving >7,000 patients access to a CFTR modulator, subsequently followed by Wales, Northern Ireland and Scotland [ G]. Data from the phase 3 trial in 6-11 year olds has been announced, with regulatory approval expected in Q4 2021 [ H]. Trikafta/Kaftrio leads to greater restoration of CFTR function than ivacaftor in both laboratory and clinical assessments. Trials also demonstrated even greater acute benefits (lung function- FEV₁ increasing by 14%-, admissions to hospital, weight gain). The fact that this combination is suitable for approximately 80-85% of pwCF worldwide who possess 1 or 2 F508del mutations amplifies these impacts substantially.

The major impacts described thus far accrue in patients commencing these drugs as adolescents or adults. There is accumulating evidence that restoring CFTR function in early life, before end-organ damage is irreversible, could be even more impactful. The design of paediatric modulator trials, led globally by Davies, allowed rapid translation of early data from older cohorts in to younger/healthier children. The EMA has recently approved ivacaftor to treat babies as young as 4 months of age, shortly after their diagnosis [ I].

Furthermore, for the first time, the field of treating CF has witnessed a substantial proportion of children demonstrating restored function of the pancreas, an organ hitherto considered irreversibly destroyed antenatally. For some children, early access to highly effective modulators, may lead to a complete change in the way CF manifests as a disease, with the possibility that life span could approach that of healthy people.

In the UK Kalydeco is available to infants ≥4 months with gating/ residual function mutations (~7-8%), Orkambi to children aged ≥ 2yrs with 2 copies of F508del (~45%), Symkevi to people aged ≥ 6 with 2 copies of F508del (~45%) or residual function mutations (~10%) and Kaftrio to individuals aged ≥ 12 years old with 1 or 2 copies of F508del (80-85%).

Studies at Imperial identified CDK7 as a potential therapeutic target in ER-positive breast cancer as well as other cancers, including prostate and colorectal. Imperial researchers subsequently developed ICEC0942 as the first-in-class selective inhibitor of CDK7. This work has moved from basic cancer biology through drug discovery and development to commercial partnership and clinical trials evaluation. Patents concerning the pharmaceutical composition of these compounds and their use to treat disorders associated with CDK7 activity were filed in 2014 [ A].

The research undertaken at Imperial College London has had significant economic and commercial impact with benefit to the pharmaceutical industry in the UK and EU. ICEC0942 and related compound families were licensed by Cancer Research UK and Imperial College London to Carrick Therapeutics Ltd in 2017.

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As a result of this funding, Carrick was able to develop an on-going clinical development programme for ICEC0942. This included full toxicology and re-confirmation of Imperial College data in additional in vivo cancer models. Phase 1 studies of ICEC0942, which began in 2017 (ClinicalTrials.gov Identifier: NCT03363893) [ C] under the drug name CT7001 [ D, E] (now also known as sumaraciclib), have been completed in Manchester, Oxford and Imperial College, and four parallel phase 2 studies (hormone therapy-resistant and triple-negative breast cancers, non-small cell lung cancer and acute myelois leukaemia) have been started in US and UK.

Although the full clinical impact of ICEC0942 is still emerging, the drug has already had a positive impact in cancer care: during the phase-1 trial, several patients with advanced breast and prostate cancers achieved either durable remissions or stabilisation of disease with minimal toxicity. These patients were enrolled in the study because they had no other treatment options and thus ICEC0942 has offered these patients the potential for additional length and quality of life that they would not otherwise had. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

The prevention of overt TB in latently infected subjects through use of prophylactic isoniazid was widely recognised prior to the HIV epidemic. However, the findings of the research led by Prof Wilkinson demonstrated for the first time in a randomised trial that concurrent ART plus IPT could be safely and effectively combined to reduce the reactivation of latent TB in HIV-infected subjects, leading to a 37% reduction in overt TB disease. Previous reports of the use of IPT in HIV infection to prevent LTBI had been small and observational only, without randomisation. The independent TEMPRANO randomised trial subsequently confirmed Wilkinson’s teams’ result, reporting a 35% reduced risk of death in a similar population intervention [ A].

In the Western Cape of South Africa, a peak TB incidence of 1,024 per 100,000 in 2006, fell substantially (by 39%) to 625 per 100,000 by 2015; this reduction occurred almost exclusively in HIV-infected persons. Whilst overall TB incidence in South Africa peaked in 2010-11, it still remains exceptionally high. It is difficult to disentangle the multiple interventions which led to this reduction in TB incidence and especially the contribution of ART alone; however, the research work by Prof Wilkinson was widely disseminated in the Western Cape from 2012 onwards, was a substantial and novel catalyst in this achievement and underpinned the change to national and international treatment guidelines.

Changes to international guidelines as a result of this research:

The provision of at least 9 months of IPT to HIV-infected persons receiving ART in high TB incidence areas has become a policy guideline worldwide as a result of the research findings at Imperial College plus those generated from contemporary and subsequent randomised studies by colleagues. These guidelines include:

• The South African HIV Society ART guidelines for adults in 2017 recommend that all patients receiving ART should be considered for IPT [ C, see page 22]

• The British HIV Association (BHIVA) guidelines for the management of TB/HIV co-infection in 2019 recommends testing for, and treatment of, LTBI with IPT for all HIV-positive individuals who are close contacts of people with infectious TB [ D]

• The WHO guidelines were updated in 2018 and recommend: “ Adults and adolescents living with HIV, with unknown or a positive tuberculin skin test (TST) and are unlikely to have active TB should receive preventive treatment of TB as part of a comprehensive package of HIV care. Treatment should be given to these individuals irrespective of the degree of immunosuppression and also to those on antiretroviral treatment (ART), those who have previously been treated for TB and pregnant women. (Strong recommendation, high-quality evidence)” [ E].

The underpinning work by the Imperial researchers has been specifically highlighted by leaders in the field of TB as particularly important work [ F] and included as advice in recent US NCA and CDC guidelines [ G]. The research has been incorporated to a single-stage meta-analysis of isoniazid prophylaxis using individual participant data through stratified Cox-proportional hazards models [ H]. This analysis concluded that IPT, concurrent with ART, prevents overt TB disease across demographic and HIV-specific and TB-specific subgroups, aligning with current guidelines and thus supporting efforts to further increase use of IPT plus ART broadly among people living with HIV.

Roll-out of IPT beyond South Africa:

ART plus IPT is now being scaled up widely in and beyond South Africa; in 2016, the US President’s Emergency Plan for AIDS Relief (PEPfAR) Scientific Advisory Board recommended the promotion of concurrent IPT with ART [ B]; subsequently in 2019, PEPfAR committed to targets of 14,600,000 people living with HIV and AIDS and in care and taking ART also receiving concurrent IPT. PEPfAR has now led successful scale up elsewhere in sub-Saharan Africa most notably in Kenya, Uganda and Nigeria – a direct consequence of the evidence underpinning the WHO guidelines [ E], to which Wilkinson’s research contributed significantly.

Largely in recognition of this work Wilkinson was awarded the International Union against Tuberculosis and Lung Disease Scientific prize in 2020 [ I].

Dr Seddon and colleagues estimated that, globally each year, 1.2 million children develop TB of which 250,000 die. Until the described modelling work was undertaken, this burden was not recognised. These estimates have underpinned global and national estimates of burden. From 2015 onwards they have been directly incorporated into the annual World Health Organization (WHO) estimates of childhood TB disease and mortality [ A]. As a result of this research, for the first time, childhood TB is now recognised as one of the top 10 causes of under 5 mortality [ B] – it was previously unrecognised. As under 5 mortality is seen as a key metric in the funding agenda for research and operational investment globally, this is crucial for childhood TB funding [ B].

The burden estimates in children from this modelling work and reported by WHO have been used by Ministries of Health and National TB Programmes to carry out national and regional service evaluations. A recent example is the FIKIA Project in Kenya, which seeks to increase case-finding in children. It uses as its justification the fact that the WHO estimates suggest that 10-15% of the overall TB burden is in children, while in Kenya, only 8.7% is in children. This has led to the use of enhanced case-finding to look for these missing children [ C]. A similar justification for case-finding is seen in national TB guidelines, for example [ D] which cites reference (1) above. The burden estimates have also led to childhood TB being prioritised in global and national TB planning due to increased perception of burden of disease and death. In the 232-page WHO Global TB Report in 2010 the terms “child” or “children” were used 5 times. In the same report in 2020 they were used 163 times [ A]. The WHO carries out reviews of country TB Programmes and it is now mandatory to include a reviewer with paediatric TB expertise on these panels. These reviewers use the modelled estimates to evaluate the discrepancies between expected and diagnosed cases of childhood TB.

The estimates from Dr Seddon’s work have been cited in multiple advocacy materials, especially in the run up to the first UN high level meeting on TB in September 2018 [ E]. When competing for scarce resources for both child TB service implementation and research, burden estimates have proved crucial. For example, Dr Seddon’s work has been included in WHO advocacy material (‘ At least 1 million children fall ill with tuberculosis (TB) each year. Children represent about 11% of all TB cases’) [ F] and the 2018 revised Roadmap for childhood TB (‘ *We now know that 10% of all TB affects and manifests in children – over half of that among children under five years of age.*’) [ B], as well as the 2018 Union advocacy document, the silent epidemic [ G]. The estimates have resulted in changes to attitudes and awareness around childhood TB for the public as well as for policymakers – this body of work has influenced the development of strategic research priorities [ H] and best practices [ I] for childhood TB at a WHO level.

Dr Seddon has also worked with industry to develop new drugs for children. The TB Alliance is a product development partnership that works to develop new TB drugs. They received a grant of USD16,700,000 from Unitaid in 2013 to develop child-friendly drug formulations. A key first step was to develop market estimates for TB in children to strengthen negotiations with drug companies [ J]. Dr Seddon and Dr Dodd worked with Unitaid and TB Alliance to ensure that their estimates could be used for these negotiations (acknowledged in [ J]). The first ever fixed-dose, fully dispersible, palatable TB drug formulation was subsequently developed by Macleods and these formulations have now been rolled out to >90 countries, making it much easier to treat children with TB [ J].

Finally, children with TB ultimately benefit from the increased funding and prioritisation of diagnosis and treatment. This has benefits for families and communities in high TB burden countries. The number of children diagnosed with TB and notified to WHO increased from 327,000 in 2011 to 523,000 in 2019 [ A]. In 2015, 87,242 children <5 years were given preventive therapy following household exposure to TB. In 2019, this figure was 433,196 [ A].

Burden and Global Strategies

Estimates of the burden of viral hepatitis (1) were used by WHO to make the case for their new advocacy strategy [ A]. Model-based strategies for eliminating hepatitis as a public health threat and the associated programmatic and epidemiological targets were provided to WHO as an unpublished report (reference 2 in document [ A]) and subsequently published (2, 3 above). The resulting WHO strategy to achieve elimination of hepatitis B and C by 2030 [ A] directly cites the outputs from this work - specifically the targets and their associated estimated impact. The construction of the five pillars of the strategy (“ Reaching five prevention and treatment service coverage targets would eliminate hepatitis B and C as public health threats”, page 6 ) directly refers to the modelling research. The economic analyses presented as part of the strategy ([ A], Section F) directly reproduces analyses undertaken by the researchers. The strategy was presented to the WHO Executive Board in 2015 and subsequently adopted by WHO as the Global Health Sector strategy on viral hepatitis 2016-2021 [ B]. These programmatic areas and targets are the benchmarks by which WHO monitors progress of countries in respect of its aim to combat hepatitis, as confirmed in a WHO-authored article [ C]. Today 87% of persons living with hepatitis reside in a country with a national plan for hepatitis [ D] that is based on, or draws reference from, the WHO health sector strategy [ B] that the Imperial research directly contributed to. The WHO authors of [ C] confirm that the targets have led to the initiation of action plans in many countries: “ As a result, many countries have initiated work to formulate national action plans, starting with initial assessments”.

Introduction of Birth Dose Vaccination

As one of three independent modelling teams, the Imperial researchers adapted their model developed in academic references (2,3) and worked with GAVI to provide projections of the impact of the timely birth dose to inform their hepatitis B birth dose vaccine investment case [ E]. In this it was shown that GAVI support for birth dose introduction could avert between 300,000 and 1,200,000 perinatal infection-related deaths between 2021 and 2035 and that this would be highly cost-effective (USD72-USD403 per death averted). The GAVI investment strategy relied on five primary criteria when ranking proposed new vaccine introductions - two of which (health impact and value for money) directly used the impact and cost-effectiveness estimates that the Imperial team provided [ F]. Birth-dose hepatitis B vaccine was recommended to the Gavi board for introduction from 2021 and adopted at its November 2018 meeting subject to successful replenishment that has now been confirmed.

Introduction of Tenofovir in Chinese National Insurance Program

Imperial modelling of the need to invest in hepatitis B control in China formed one of the case studies in the WHO advocacy strategy [ A, Box 4 page 10]. This work was expanded to explore the impact and cost-effectiveness of introducing tenofovir into the Chinese national insurance program. A preprint of this work (subsequently published academic reference 4) was shared with the WHO China office and formed part of a WHO (China) policy brief to government [ G]. This was the major piece of research motivating a policy change [ H] whereby tenofovir became included within the Chinese national insurance program [ I] leading to the reduction in cost of tenofovir for patients from ¥ 49.0 to ¥ 16.6 per day, or less [ I]. In a study of patients at selected hospitals, the proportion of patients being treated with first-line recommended drugs increased from 41.9% (2010) to 92.8% (2019).

Population-wide screening for HBV in West Africa

The Imperial-led PROLIFICA trial is cited as a case study in the WHO advocacy strategy [ A, Box 5 page 11]. The evidence that this trial generated on the efficacy and cost-effectiveness of population wide screening for HBV in West Africa is cited in the WHO Guidelines for screening of hepatitis B and C [ J]. The WHO is required to consider the cost and feasibility of a strategy it may recommend, and the research at Imperial was the only such information available for low-income countries [ J, pages 40 and 50]. This research is also reproduced as supporting evidence on cost-effectiveness in the Annex [ J]. As a consequence of the research, these guidelines gave, for the first time, a ‘conditional recommendation’ that testing should be made available to the general population in low-income settings with high prevalence of hepatitis B.

By demonstrating that the criteria used to diagnose miscarriage were unsafe, the initial development study conducted by Prof Bourne and colleagues in 2010/2011 prompted a consensus meeting attended by Prof Bourne in the United States. This meeting led directly to the publication of a review paper in the New England Journal of Medicine that used the Imperial data to propose new safe diagnostic criteria (research reference 1 above). The Royal College of Obstetrics and Gynaecology (RCOG) in the UK published an addendum to its guidance within a week of the initial development study being published following an urgent meeting of its ultrasound committee [ A].

Data reported in the validation study published in the BMJ in 2015 enabled recommendations to be made on the follow up of women deemed at risk of a miscarriage, providing information on how long to wait before repeating ultrasound examinations and what to expect to see on those examinations.

Following the publication of the validation study in the BMJ, the American College of Obstetricians and Gynecologists published a practice bulletin in 2016 citing the Imperial-led research as the driver behind changing the diagnostic guidelines for miscarriage in the United States [ B]. In 2018, the Australasian Society for Ultrasound in Medicine also published new guidelines for miscarriage diagnosis using the Imperial criteria [ C]. In the same year, the American College of Radiology updated their guideline by adopting the updated criteria [ D]. Now countries throughout the world, including France and Italy, have changed to the new criteria for miscarriage diagnosis based on the data generated by the Imperial College team [ E, F]. These changes in guidance were prompted by Imperial data showing existing diagnostic criteria were unsafe and have resulted in the implementation of safer criteria based on the Imperial study.

Prior to these guideline changes, it is possible that thousands of wanted pregnancies throughout the world may have had surgical or medical treatment for a miscarriage based on a misdiagnosis. The data generated from the research at Imperial College has shown that, using the existing guidelines, the risk of a misdiagnosis using embryo size measurements and an apparent lack of a visible heartbeat on ultrasonography was at least 8% (just over 1 in 12), leading in many cases to unnecessary termination of a wanted pregnancy.

An American study suggested that for women presenting with a possible miscarriage, about 12% may have been given an incorrect diagnosis of miscarriage using the guidance that existed in the United States prior to the Imperial study [ G]. Applying such calculations to the UK, as many as 1,200 healthy wanted pregnancies could have been terminated each year owing to an incorrect diagnosis of miscarriage.

Furthermore, the novel findings from the Imperial study investigating post-traumatic stress in women following early pregnancy loss attracted intense media interest and were presented at the “All Parliamentary Group on Baby Loss” in the House of Commons [ H]. This work directly resulted in the inclusion of early pregnancy loss in the National Bereavement Care Pathway [ I], an initiative that is dedicated to ensuring that bereaved parents are offered equal, high quality, individualised, safe and sensitive care in all hospitals in the UK.

The publication of the full paper in 2020 describing the psychological impact of miscarriage and ectopic pregnancy received one the biggest media coverage of any story from Imperial College and trended on social media in the UK. It was covered throughout the world, increasing awareness of the important long-term psychological consequences of ectopic pregnancy and miscarriage and enabling women to tell their stories. This was exemplified by two leading articles in the Guardian in which readers described their experiences of the pain of miscarriage (>120,000 print subscribers > 350,000 digital subscribers) [ J].

COPD, the third leading cause of death globally after cardiovascular disease and cancer is a combination of chronic bronchitis and emphysema. In emphysema, the alveolar walls and small airways are destroyed, causing the lung tissue to become baggy and trap air. This gas trapping increases the work of breathing, restricts vital capacity and cardiac function and manifests as disabling breathlessness, impaired ability to do physical activity, reduced capacity to withstand acute exacerbations of the condition and premature death. Inhaled medication can relieve symptoms but does not alter the natural history of the disease and lung hyperinflation has been an intractable problem.

There are an estimated 16,000 people in the UK and 660,000 in Europe, who might be eligible for a lung volume reduction procedure, equating to approximately 1% of people with COPD. These procedures, indicated in patients with severe COPD who are highly symptomatic, improve breathlessness, exercise capacity and quality of life, as well as prolonging survival in a condition that is otherwise progressive and relentless. The scale of benefit with lung volume reduction is dramatic and typically far exceeds those seen with inhaled medications.

Initial case series investigations by the Imperial team generated a body of work on the physiological mechanisms and data on mortality benefit from successful valve placement - previously the only other interventions shown to improve survival in COPD were smoking cessation and supplemental oxygen in individuals with respiratory failure.

This led to funding of the BeLieVeR-HIFi trial, the first device study supported by the NIHR-MRC EME programme. The results of this RCT and the individual patient meta-analysis performed by the Imperial team, combined with data from the Dutch STELVIO trial, informed a Cochrane review [ A]. Importantly the improvements in quality of life seen were double that observed with inhaled medication. Collectively this formed the evidence base on which the National Institute for Health and Care Excellence (NICE) health technology appraisal [IPG600] approved the use of endobronchial valve placement within the NHS in 2017 [ B]. These data also informed international guidelines and clinical practice, with their inclusion in the international GOLD COPD guidelines.

These data, together with that from the Imperial-led multi-centre TRANSFORM trial contributed to the NICE COPD guideline committee making a clear recommendation that endobronchial valve therapy should be offered to appropriately selected patients in 2018 (NG115 recommendation 1.2.88) [ C]. The decision was supported by data estimating the cost per quality-adjusted life years of endobronchial valve placement at approximately £22,500, putting it within an acceptable range for NICE [ D].

This evidence of efficacy together with data gathered on inequity of access to the procedures led NHSE to approve endobronchial valve placement for Specialist Commissioning (November 2020) so that all patients within the NHS who are suitable should be able to access it [ E].

Data from the UKLVR registry show that our work has led to 14 centres performing LVR procedures in the UK with around 500 lung volume reduction procedures performed since 2017. The Specialist Commissioning with associated funding and support for referral pathways, will lead to a substantial further increase in patient access and benefit.

Endobronchial valve placement is also now recognised in international guidelines for the management of COPD (e.g. the GOLD guidelines 2020, p63, “endobronchial valve placement shows comparable benefits to LVRS but with fewer complications”), meaning that the impact has been global [ F]. According to the website of one valve manufacturer >19,000 emphysema patients worldwide have already undergone an endobronchial valve placement procedure using their product [ G]. Another manufacturer, Olympus, estimates that globally over 11,000 patients have been treated using their valve product [ H].

The UK Taskforce for Lung Health states that lung volume reduction procedures remain an underused therapy. Newer and less invasive lung volume reduction technologies, such as valves, broaden the pool of eligible people to as many as 16,300 people in England who could benefit from such a procedure [ I].