Results and submissions : REF 2021

Adoption of stereotactic ablative radiotherapy (SABR) technology for extracranial ...

Submitting institution: King's College London
Unit of assessment: 12 - Engineering
Summary impact type: Health
Is this case study continued from a case study submitted in 2014?: No

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1. Summary of the impact

The multi-disciplinary engineering research in imaging sciences at the School of Biomedical Engineering and Imaging Sciences at King’s College London (King’s) created the environment for the establishment of King’s Technology Evaluation Centre (KiTEC).

KiTEC’s research demonstrated significant improvements in overall survival, local control and cost-effectiveness of stereotactic ablative radiotherapy (SABR) technology in oligometastatic cancer (i.e. cancer that has spread beyond its primary site to a small number of other locations). Previously, SABR appeared promising in this condition, but there was insufficient evidence to justify adoption by the NHS. Our research led directly, and very rapidly, to NHS England changing its policy in 2020 to make SABR available for routine clinical use. This benefits at least 2,200 patients per year in England. It has been particularly useful during the COVID-19 pandemic as it has reduced the number of visits to hospitals by patients.

2. Underpinning research

Underpinning, pioneering engineering research in the School on respiratory motion correction can be traced back to work carried out at King’s by David Hawkes, Derek Hill and colleagues in the 2000s [R1], with substantial follow-on work conducted at King’s by Marsden, King, Prieto and colleagues on respiratory motion modelling and motion reconstruction with application to positron emission tomography (PET) and magnetic resonance (MR) imaging [R2,R3,R4,F1,F2]. These methods include MR-derived motion models for PET respiratory motion correction to improve the accuracy of uptake values and increase lesion detectability and contrast to inform treatment planning [R2,R3], as well as patient-specific breathing motion models that can be used directly for more precise image-guided treatment delivery [R4].

Because of our unique position as an engineering School embedded within an NHS foundation Trust, we were able to establish the King’s Technology Evaluation Centre (KiTEC) as a health technology assessment (HTA) research centre specialising in imaging technology and medical devices in 2011. It combines the School’s strengths in these areas with multidisciplinary expertise in health economics, research methodology, medical statistics, information science and evidence synthesis. KiTEC is embedded in an engineering research environment, but also has ready access to expert collaborators in all clinical and scientific specialisms from across the King’s Health Partners AHSC (Academic Health Sciences Centres). The aim is to perform impactful research that supports the introduction and diffusion of novel health technologies based on innovative engineering. As a result of the strong track records of the School and the wider multidisciplinary team, KiTEC obtained funding from The National Institute for Health and Care Excellence (NICE) for research into a number of medical technologies and interventions. This funding was secured in competition with other universities, healthcare organisations and consultancies.

SABR is an advanced form of radiotherapy technology in which high radiation doses are delivered very precisely (within 1-2mm) to cancerous tumours. It relies on advanced imaging technologies to maximise dose delivery to the target while minimising dose to surrounding healthy tissues. However, translation of this promising SABR technology into routine clinical practice for patients with extracranial oligometastatic cancer was impeded by a lack of sufficient evidence of safety, clinical effectiveness and cost-effectiveness.

In 2015, KiTEC was funded to investigate SABR as part of NHS England’s Commissioning through Evaluation (CtE) programme [F3] . Within this programme, patients are able to access promising treatments that are not normally available through the NHS. Research using data from these patients is used to inform future decisions as to whether the new treatment should be provided routinely.

KiTEC’s research on SABR involved working with 17 NHS Trusts recruiting 1,422 patients with oligometastatic cancer while building a bespoke database and data dictionary. KiTEC carried out assessment on the clinical effectiveness, toxicity, and cost-effectiveness of stereotactic ablative radiotherapy (SABR) as an emerging radiation technology in oligometastatic cancer. KiTEC’s assessment demonstrated significant improvements in overall survival, local control and cost-effectiveness in patients treated by SABR [R5,R6] .

3. References to the research

R1. Blackall J, Ahmad S, Miquel M, Landau D, Hawkes D (2004). Techniques for constructing breathing motion models for 4D radiotherapy planning in lung cancer. Radiotherapy and Oncology, 73:S361-S362. DOI: 10.1016/S0167-8140(04)82714-2

R2. Polycarpou I, Tsoumpas C, King AP, Marsden PK (2015). Quantitative Evaluation of PET Respiratory Motion Correction Using MR Derived Simulated Data. IEEE Transactions on Nuclear Science 62(6):3110-3116. DOI: 10.1186/2197-7364-1-S1-A62

R3. Munoz C, Kolbitsch C, Reader AJ, Marsden P, Schaeffter T, Prieto C (2016). MR-based cardiac and respiratory motion-compensation techniques for PET-MR imaging. PET clinics, 11(2):179-191. DOI: 10.1016/j.cpet.2015.09.004

R4. Baumgartner CF, Kolbitsch C, McLelland JR, Rueckert D, King AP (2017). Autoadaptive motion modelling for MR-based respiratory motion estimation. Medical Image Analysis 35 pp85-100. DOI: 10.1016/j.media.2016.06.005

R5. Bourmpaki E, Bunce C, Chalkidou A, Coker B, Eddy S, Elstad M, Goddard K, Jin H, Keevil S, Macmillan,T, Peacock J, Pennington M, Radhakrishnan, M, Reid F, Summers J (2019), Commissioning through Evaluation: Stereotactic ablative body radiotherapy (SABR) for patients with oligometastases report. KiTEC - King's Technology Evaluation Centre

R6. Chalkidou A, Macmillan T, Grzeda MT, Peacock J, Summers J. Eddy S, Coker B, Patrick H, Powell H, Berry L, Webster G, Ostler P, Dickinson PD, Hatton MQ, Henry A, Keevil S, Hawkins MA, Slevin N, van As N (EPub December 2020), Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a national prospective, single-arm, evaluation study, Lancet Oncology, 22(1):98-106. DOI: 10.1016/S1470-2045(20)30537-4

Grants awarded to King’s College London / KiTEC

F1. King, AP, Prieto,C, Marsden, PK, “PET-MR Motion Correction Based Purely on Routine Clinical Scans”, EPSRC. GBP590,238, 31/03/2015-31/10/2018

F2. Hawkes, DJ, Penney, GP, Leach, MO, Alexander, D, Batchelor, P, Atkinson, D, Hajnal, JV, Smith, N, Schaeftter, Razavi, R, Rueckert, D, Prieto, C, Ourselin, S, Webb, “Intelligent Imaging: Motion, Form and Function Across Scale”, EPSRC. GBP6,053,494, 01/06/2010-30/11/2015

F3. External Assessment Centre for NICE Sponsor: NICE, GBP3,310,736.00, 01/04/2014-31/03/2022

4. Details of the impact

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Background: Metastatic cancer is diagnosed in approximately 140,000 patients in England per year. Patients with a relatively small number of metastases (usually no more than 5 in a maximum of 3 separate locations) are considered to have oligometastatic cancer. Although there is scarce evidence from randomised controlled trials on the treatment of extracranial oligometastatic cancer (that is oligometastases outside the head), there is a growing body of evidence from multiple non-comparative studies to suggest that patients may be cured if all lesions are eradicated using SABR, an emerging treatment that uses external beam radiation therapy to deliver a high dose of radiation with high precision (within 1-2 mm) to a cancerous lesion. In addition, a course of SABR treatment involves fewer fractions of radiotherapy (and, consequently, requires fewer hospital visits) than standard radiotherapy – approximately 8 or fewer for SABR compared with 20 to 30 sessions for standard radiotherapy.

Pathway to Impact: KiTEC’s research on SABR included the following components.

Working with 17 NHS Trusts to recruit 1,422 patients with oligometastatic cancer, the largest cohort recruited internationally.
Development of analysis protocols and target outcomes, requiring synthesis of input from NHS England, NICE and numerous clinical stakeholders.
Development of a bespoke database and data dictionary, in collaboration with University Hospitals Birmingham.
Analysis of patient-level data to determine overall survival, local control, and safety. To improve outcome detection, KiTEC linked this data to the Hospital Episode Statistics (HES) and Office for National Statistics (ONS) registries. Cost-effectiveness analysis compared SABR with alternative treatments such as surgery and radiofrequency ablation.
Qualitative analysis of the experience of the 17 centres.
Systematic review of the evidence base regarding clinical effectiveness, toxicity, and cost-effectiveness.

The research showed clinically and statistically significant improvement in overall survival (92.3% at 1 year and 79.2% at 2 years) and local control rates (86.9% at 1 year and 72.3% at 2 years) using SABR. It further showed that the treatment is safe (less than 5% of patients experienced severe toxicity). In health economics, the value of a medical intervention is often expressed in terms of the number of additional years of life gained weighted to reflect quality of life, producing a measure known as a QALY (Quality Adjusted Life Year). In our study, we found that in comparison with surgery, SABR results in both a gain in QALYs (0.0214 per person on average) and a cost saving (GBP2,912 per person on average) [R5].

Evidence synthesis of these results at King’s with the published literature led NHS England to conclude that there is sufficient evidence to support the routine use of SABR for patients with extracranial oligometastatic disease [S1].

The NHS England Policy Working Group estimates that approximately 2,200 patients per year with extracranial oligometastases would be suitable for SABR treatment, in line with the criteria established by KiTEC’s research [S1] . Our qualitative research has helped to define the main priority areas for future commissioning of SABR and in particular has highlighted workforce implications and emphasised the benefits of providing SABR treatments at a larger number of NHS organisations so that they are more accessible to patients. In the words of the Medical Director of The Royal Marsden NHS Foundation Trust, “The design of this programme and the data analysis has therefore been transformative for delivery of this novel radiation technology in the UK and will have a significant impact on both patient outcome and appropriate use of healthcare resources within the NHS” [S2].

A new technology has been adopted in routine use as a result of KiTEC’s work

The National Institute of Health and Care Excellence (NICE) updated the guidelines for radical radiotherapy (including SABR) for people with non-small-cell lung cancer in March 2019 [S4] . Quoting the guidance 1.4.27 “For people with stage I–IIA (T1a–T2b, N0, M0) NSCLC who decline surgery or in whom any surgery is contraindicated, offer SABR”.

Impact on professional practice

Our work in collaboration with University Hospitals Birmingham NHS Foundation Trust (UHB) resulted in the first registry in the UK, developed to collect imaging and outcomes data from multi-centre radiotherapy studies in a single framework, implemented as the Platform for Radiotherapy Plan Evaluation and Learning (PROPEL) [S3] . KiTEC engineered PROPEL based on feedback from various stakeholders - clinical experts, NHS England, NICE and the Radiotherapy Trials Quality Assurance (RTTQA) group. PROPEL is now fit for purpose to host data from future national and international radiotherapy trials, including radiotherapy treatment planning images as well as textual data. This assures the quality of treatment planning as SABR is implemented at a wider range of centres in keeping with the results of our qualitative research. Professor Stuart Green, Director of Medical Physics at UHB, says, “Analysis of the data stored in PROPEL from the Commission through Evaluation programme is continuing and focused on the derivation of guidance for treatment planners to ensure that future patients have a high quality treatment regardless of the experience of the clinical team and the treating centre. This is particularly important now that these treatments are being rolled-out nationally. Further impact comes from the wider and continuing use of PROPEL and its development as platform for plan quality analysis” [S5] .

Helped serve more patients during the COVID crisis

Because SABR treatment involves fewer visits to hospitals by patients, it is particularly valuable during the COVID-19 pandemic when there is a desire to minimise hospital visits and risk of infection. According to Dr Nicholas van As, a leading clinical oncologist and the Medical Director, The Royal Marsden NHS Foundation Trust, “SABR is a technology that is delivered in a small number of fractions and then therefore extremely efficient treatment; this has been crucial as a method of getting more patients through treatment in the COVID crisis.” [S2] . This aspect is also commented on in a testimonial from NICE [S6] . The approach adopted by KiTEC to managing and delivering this complex project will readily translate to similar real-world data collection and analysis exercises in the context of NHS commissioning, bringing additional future impact. To quote from the testimonial received from NICE, “The principles used to achieve high data quality are being used in subsequent CtE and are useful in planning ‘Managed Access’ projects undertaken by KiTEC on behalf of NICE” [S6] .

In summary, the impact of this work was a change in NHS policy leading to availability of a novel cancer treatment based on innovative engineering, resulting in improved health outcomes for many patients. This was achieved by combining underpinning engineering expertise with a multidisciplinary approach to medical device HTA to ensure that novel technology is not just translated into healthcare but is firmly embedded and diffused through effecting evidence-based changes to national policy.

COVID Symptom Study App

Submitting institution: King's College London
Unit of assessment: 12 - Engineering
Summary impact type: Health
Is this case study continued from a case study submitted in 2014?: No

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1. Summary of the impact

In March 2020, as the global COVID-19 pandemic was declared, King’s College London (King’s) researchers together with ZOE Global rapidly engineered the COVID Symptom Study smartphone app. This was used to capture real-time data on known and potential symptoms of COVID-19 from residents of the UK, USA and Sweden. Endorsed by the Welsh, English and Scottish Governments, over 4,000,000 people signed up to the app globally, with 2,000,000 of those registering in the first two weeks it was available (24 March 2020). Analysis of the data generated led to:

The World Health Organisation (WHO), UK government and the UK Office for National Statistics updating their guidance on anosmia and delirium as key symptoms of COVID-19.
Identification of rate and location of new infections in real time, which informed the UK Government’s national strategy for containing infection.
Helping the UK government identify hot-spots across the nation.
Identification of the symptoms and duration of Long COVID for the first time in a non-clinical population, informing UK government policy and NICE guidelines.

2. Underpinning research

At King’s School of Biomedical Engineering & Imaging Sciences (BMEIS) we have been engineering methods and tools to deal with large scale imaging clinical trials and clinical studies. Ourselin, Modat, and Cardoso have led the development of computational platforms to host, curate and process imaging and associated clinical data for large-scale neurodegenerative studies. An exemplar is the deployment of a validated, unsupervised, automated algorithm in the Insight 46 study [R1]. Our know-how and research has contributed to the development and deployment of the Dementia Platform UK infrastructure and portal [R2]. This portal now hosts 3 million patients’ data, completely curated, and enables researchers to access the combined information from over 40 dementia studies. Additionally, our combined research expertise in machine learning led to the development of some the most popular open-source toolboxes dedicated to the process of healthcare data analysis with machine learning techniques, NiftyNet [R3], and more recently MONAI.io, co-developed with NVIDIA.

Zoe Global is a health technology spin-out from King’s, co-founded by Spector, that develops a mobile platform to gather nutrition data from its users. As the COVID-19 pandemic began, Zoe repurposed their platform to create a smartphone app that gathers self-reported data on COVID-19 from the general population, collaborating with clinicians and epidemiologists from the King’s Department of Twins Research to analyse the data.

The COVID Symptom Study App was launched in three countries (UK, US, Sweden) on 24 March 2020. After more than 1.5 million users downloaded the app within days of its launch, several engineering challenges emerged that we solved because of our expertise in algorithm engineering and development and deployment of software at scale.

The sheer scale of the data generated by millions of users meant that researchers were not able to analyse it using the hardware and software available to them. With billions of rows of reports, the data from the COVID Symptom study became quickly too large to load and process on typical analysis software. We developed the open-source ExeTera software package [R4] based on our expertise. This open-source software package was designed to address scalability challenges and allows researchers to analyse large datasets, with billions of rows of data, without the need to load the full dataset into memory, taking care of the curation and imputation at scale to enable reproducible research.
The non-traditional acquisition of the data compared to classical epidemiological studies required the development of new analysis methods to extract insight from the rich, although non-curated, data produced by the study. New machine learning and statistical analysis algorithms were engineered and deployed in order to allow for insight to be extracted from the Symptom Study data. Traditional disease surveillance methods perform tests on many people to build an idea of disease levels in the population; we developed a novel approach that combines information from a small number of tests with predictive models applied to self-reported symptoms from a large number of app users to track the pandemic. While demonstrating similar accuracy as traditional methods, this approach allowed for greater geographic granularity, enabling notably the identification of emerging disease hotspots [R5]. The self-reported and voluntary nature of the study introduces potential bias that can undermine the validity of any insights extracted from it. To address this, we developed a number of selection processes that allow us to extract reliable insight from the data, leveraging its unique dense longitudinal nature, such as differential weighting, as some parts of the population are sampled with unequal probabilities of selection. Such techniques allowed us to develop robust predictive models, producing one of the earliest pieces of evidence that anosmia is a key symptom of COVID-19 [R6], that delirium is an important symptom in older patients, and enabling us to carry out one of the largest studies on Long COVID, significantly furthering our understanding of the disease and its presentation [R7].

4. Details of the impact

King’s researchers leveraged their expertise in algorithm engineering, big data, and artificial intelligence to rapidly engineer the COVID Symptom Study App in response to the COVID-19 pandemic. Rapid deployment and analysis of the data generated key evidence which widened the understanding of core symptoms for COVID-19 worldwide, helped with the identification of hotspots in the UK, contributed to a better understanding of Long COVID-19 both in the UK and internationally, and supported the UK government and the public to navigate the pandemic.

Endorsements lead to widespread adoption of the app by UK public.

The Scottish and Welsh Governments and prominent health charities endorsed the COVID Symptoms Study App. The Welsh Government and NHS Wales [S1] were the first to make an appeal for the public to download and use the app. In April 2020, they released a press release where Welsh First Minister, Mark Drakeford, stated: “ Having a range of evidence and data is crucial in helping us build a clear picture of how the virus is behaving and affecting everyone’s lives. Crucially this app can help us anticipate potential COVID hot spots and get our NHS services ready. I’m asking everyone in Wales to download the new COVID Symptom Tracker App, so you can help protect our workers and save lives [S1a] *.*” The Scottish Government also encouraged people to use the app in their official social media channels. They stated: “ The COVID Symptom Tracker is an app, approved by Scotland’s top clinicians, designed to study the symptoms of #coronavirus and track how it spreads. We need as many people as possible to take part including people who are feeling well [S2] .” Several key health charities in the UK also urged members and the general public to use our app such as the British Heart Foundation, British Lung Foundation, National Rheumatoid Arthritis Society, and Stand Up to Cancer [S3]. By July 2020, the app had been downloaded by over 4,000,000 users [S11]. In August 2020, the UK government further recognised the importance of the app by awarding ZOE Global a GBP2,000,000 grant [S9]. They said [S9] the app is “ the largest public science project of its kind anywhere in the world” and that it “ will help control the spread of the virus by providing vital new intelligence on the scale of local outbreaks, inform our understanding of the virus and how it affects different demographics.”

King’s research on data collected from COVID Symptom Study App led the WHO and the UK Government to include anosmia in official COVID-19 symptoms lists. Data from our COVID Symptom Study App confirmed, for the first time in non-clinical patients, the loss of taste and smell as the most predictive symptom of COVID-19 - 10 times more so than the initial officially listed symptoms, fever or cough . As a result, the World Health Organisation (WHO) [S5] and UK Government [S6] added anosmia to the official list of COVID-19 symptoms. This increased the medical community’s diagnostic capability, and ensured the public recognised this symptom as a sign that they may have COVID and took appropriate action to protect themselves and their community. [Text removed for publication], said [S5b]: “ *Your [King’s] work, particularly in relation to anosmia, was really important in informing the discussions behind this and is much appreciated.*” [Text removed for publication], confirmed that data from the app was one of the pieces of evidence reviewed which led to anosmia being added to the official case definition symptoms list for COVID-19 in May 2020. [Text removed for publication] [S6b]: “ As estimated by NERVTAG (The New and Emerging Respiratory Virus Threats Advisory Group) *at the time, this will have helped pick up 93% of symptomatic cases, up from 91% previously, which may have led to significant benefit over time.*” [Text removed for publication] said “ These reports have been part of a range of information that is received, which has influenced the management of the COVID-19 pandemic in Scotland. …..estimated prevalence data has informed SARS-CoV-2 testing strategy; the app provided clear evidence of that anosmia was a cardinal symptom of COVID-19…..” [S6c]

King’s research led the UK Government to include delirium in the official COVID-19 symptoms list for the elderly. The COVID Symptom Study showed that delirium - a state of sudden confusion - is a key symptom of COVID-19 in older people . As a result, UK government updated its guidance, outlining the addition of delirium to the UK’s official list of COVID-19 symptoms in the elderly, and advising doctors to test elderly people presenting with acute confusion for COVID-19 [S6a]. This helped healthcare professionals in diagnosis, and increased awareness amongst the public and in care homes to recognise this symptom and take appropriate action to test and avoid spread.

Research by King’s allowed the UK government to identify hot spots across the nation. Thanks to over 4,200,000 people logging their symptoms and location in the app daily, our daily reports to the UK government were able to show the rates of infection in real time across the UK, allowing identification of areas where rates of infection were increasing rapidly. This information was used by the different government bodies in England [S6b], Wales [S1c] and Scotland [S2a], to inform policies intended to slow rates of infection and allow health services to cope. [Text removed for publication] stated [S6b]: “ (…) the app has been very useful in tracking the progress of the disease. Since March 2020 [Text removed for publication] *to identify hot spots across the nation showing the rates of infection in real time all over the UK, allowing identification of areas where rates of infection were growing rapidly. These data have also contributed to increased public awareness and facilitated better management of the disease, which has had an impact on the UK population, the NHS and COVID-19 patients.*”

King’s research informed NICE and the UK government about Long COVID-19. Data from our COVID Symptom Study suggests that while most people recover from COVID-19 within two weeks, one in ten people will suffer symptoms after three weeks, and some may suffer for months . In December 2020, The National Institute for Health and Care Excellence (NICE) published guidelines on the management of long-term COVID [S7a] informed by King’s research. [Text removed for publication]: “ COVID Symptom Study data was [Text removed for publication] at a critical moment in the development of the guideline, allowing the advisory panel to consider it when making recommendations on the identification and management of post COVID-19 syndrome [S7b].”

[Text removed for publication] mentioned, “In both of these roles I am grateful for the work of the COVID Symptom Study. Its data has informed early understanding of Long-COVID, being the first dataset to show the extent of the problem, and characterise the syndrome. […] We have seen how the findings of the COVID Symptom Study App have had an important impact on our understanding of the natural history of COVID, both in the UK and internationally.” [S5d]

Furthermore, the Health and Social Care Secretary Matt Hancock confirmed: " The findings of the Covid Symptom Study are stark and this should be a sharp reminder to the public, including to young people, that COVID-19 is indiscriminate and can have long-term and potentially devastating effects [S8]." The [Text removed for publication] data from the app will continue to help track the symptoms of those suffering from Long COVID, to help understand more about its course and the long-term impact of this disease on people’s lives [S6b].

Members of the public have benefitted from using the app. The app is free of charge and has been available since March 2020. It’s rated 4.7 out of 5 stars based on over 276,500 user ratings in the Apple [S10a] and Google Play App Store [S10b]. Anonymous reviews illustrate how well the app has been received by the public and what difference it has made in their lives while living through a pandemic. An anonymous review from April 2020 revealed [S10b]: “ In our isolation feels like we are helping to stop the spread of COVID-19 and the research into its spread with this app.”

Reviews have also shown the difference the app has made in people with Long COVID symptoms [S10a]: “ This app is very welcome both for its potential to enable better understanding of the illness, and for the fact that it makes those of us isolating with long term symptoms feel less alone.” (May 2020) “ My youngest daughter is showing signs of long COVID like myself, so this app is great for me to keep track of my symptoms and hers.” (November 2020).

CYDAR, an AI driven image guidance system for minimally invasive endovascular aortic ...

Submitting institution: King's College London
Unit of assessment: 12 - Engineering
Summary impact type: Technological
Is this case study continued from a case study submitted in 2014?: No

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1. Summary of the impact

Minimally invasive endovascular surgery is quicker and safer for patients; however, it comes at the cost of exposing the patient to high doses of harmful ionising radiation and kidney-toxic contrast agents. Researchers at King’s College London (King’s) have developed a cloud-based, artificial intelligence-driven image guidance system (Cydar-EV) for endovascular surgery, which minimises exposure to radiation and kidney-toxic contrast by shortening the duration of surgery.

Cydar-EV has the European Union (EU) certification mark for health and safety standards, is Food and Drug Association (FDA) cleared, and has been commercialised in the UK, Europe, and the USA by Cydar Medical, a spin-out company of King’s College London. Cydar Medical has benefitted approximately 2,000 patients [Text removed for publication] by December 2020. Since 2014, the company has raised approximately [Text removed for publication] and in July 2020 it had 39 employees across the UK, Europe, and the USA.

2. Underpinning research

Minimally invasive procedures are revolutionising the management of cardiovascular diseases, which has previously been dominated by open surgery. Endovascular aortic repair (EVAR) is a successful example of this, and it has replaced open aortic surgery owing to advantages in patient survival, reduced postoperative complications, and shorter length of hospital stay.

EVAR planning is done using high-resolution 3D images from pre-operative CT scans; however, the surgery itself is performed under image-guidance using 2D X-ray fluoroscopy. This loss of dimensional spatial information between 3D pre-operative images and a 2D operating field makes the operation more complex to perform as the surgeon must try to visualise the 3D anatomy to accurately position the device. This slows down the procedure and leads to three challenges:

Concern regarding the amount of ionising radiation, which is associated with the duration of the procedure
Concern regarding the amount of kidney-toxic contrast used during the procedure to delineate the blood vessels
Imprecise visualisation of the anatomy and positioning of the device leading to high rates of re-intervention (≥20%), requiring further patient hospital admissions and cost to the health service

The School of Biomedical Engineering and Imaging Science at King’s has devised methods to align 3D computed tomography (CT) images and 2D X-ray images. Previous solutions to improve visualisation during EVAR include manually aligned, operating table-tracked 3D-2D image overlay; however, this is costly, disrupts the clinical workflow, and has clinically significant image positioning errors.

The King’s-developed image guided surgery system matches CT and X-ray images based on their similarity and automatically links the images using a process called image registration. The technology has been proven to be fast, accurate, and robust. The technology has been developed in a step-wise fashion based on advancement in image processing and matching (R1) to automation in the endovascular clinical environment (R2), thereby increasing the speed of registration (R3) and improving the accuracy of the matching algorithm (R4), with full automation and verification of accuracy in the specific use case (R5).The system is now cloud based to take advantage of the high compute power infrastructure available, allowing the technology to run quickly and smoothly at multiple hospital sites simultaneously, with 2,000 patients treated to date. Machine learning algorithms have been developed in-house and are used for increasing the speed of 3D image segmentation, contour generation for intra-operative guidance, and image matching.

The system has been tested in interdisciplinary clinical studies involving engineers, mathematicians, and clinicians. This work has shown patient benefit by a significant reduction in the amount of X-rays used, with a mean reduction in X-ray fluoroscopy screening time of 35% (p = 0.013), a 41% reduction in the amount of iodinated contrast used (p = 0.008), and a nearly one-hour reduction in mean operating time (17%, p = 0.06) (data submitted for EU certification mark (MHRA ref: 5334)[S7]). Superiority to commercial competitors (Siemens Artis Zeego) was demonstrated, with a significant reduction in radiation exposure [S1a], with significant clinical and technical improvements shown compared to standard practice in studies in both the UK and US [S1b, S1c, S1d].

The development and automation of the image registration technology was funded by Guy’s and St Thomas’ Charity (GBP183,500, 2010–2013), with subsequent funding from Innovate UK (GBP250,000, 2014, 2018) and approximately GBP18,000,000 in equity funding tranches (2014–2020) to develop the product, collect clinical data in a pivotal trial, gain regulatory clearances (CE, FDA, TGA), and build the platform, along with operational and support capabilities.

The National Institute for Health Research have awarded GBP1,740,000 (NIHR201004) this year to fund a trial to investigate the clinical and cost effectiveness of Cydar-EV (the name of the product from Cydar Medical) compared to the current reference standard: 2D X-ray fluoroscopy. The trial will run for 3 years and the data will be used for an application to The National Institute for Health and Care Excellence (NICE) for appraisal. A positive report from NICE would support national adoption of the technology.

4. Details of the impact

Image-guided, minimally invasive surgery is growing rapidly. The global market for EVAR is approximately GBP2,000,000,000 [S10], with a compound annual growth rate of 6.2% and is an increasing burden on health spending. 4,396 EVAR procedures were performed in UK alone between 2017-2019 [S11a, S11b], with an average cost of approximately GBP19,000. EVAR is under an existing NHS care pathway and reduces mortality from 4.7% to 1.7% compared to open surgery [S13], with faster return to normal activities on discharge.

Enterprise: The demonstrated success of the technology led to the development of the King’s spin-out company Cydar Medical in 2012. Since 2014, Cydar Medical has raised [Text removed for publication] and by July 2020 had 39 employees across the UK, Europe and the US, in science, development, sales & implementation and central, with approximately 2,000 patients having benefitted in the current REF period [S5]. The system has been installed and is in regular clinical use [Text removed for publication] across the UK (8), France (5), US (5), Germany (2), Netherlands (1) and Spain (1). The product has undergone safety and performance testing under an ISO13485 certified Quality Management System and is CE marked (MHRA ref: 5334, CE conformity application dated November 20, 2015) and FDA 510(k) cleared (dated: July 7, 2016).

Cost and efficiency improvement for NHS: Cydar-EV can be easily implemented without the need for linked capital expenditure on a new fixed imaging or hybrid operating room, which is associated with cost-saving across 6 NHS centres of approximately GBP21,000,000 (GBP2,000,000–GBP5,000,000 per centre [S12]) and in the 12 centres worldwide, approximately GBP42,000,000. Use of Cydar-EV is associated with a reduction in procedure time that has health economic benefit by improving productivity, allowing one additional aneurysm repair per day, valued at GBP8,157 per procedure [S4].

Benefit to patients: Over 2,000 patients have been treated by 2020 using Cydar-EV. In sites where Cydar-EV is installed, the surgeons have real-time, fully integrated 3D visualisation throughout the EVAR procedure, with much greater spatial accuracy than was achieved by previous technology (median error 3.9 mm versus 8.64 mm [p = .001]). This means less kidney-toxic contrast is used during the procedure (41% reduction with Cydar-EV [p = 0.008]) to position the device accurately (data submitted for EU certification mark (MHRA ref: 5334) [S7b]).

Benefit to medical staff: Many of the early pioneers of X-ray guided endovascular surgery died due to cancer-related causes. Operators today may perform thousands of these procedures during the course of their career. In our installations there has been a reduction of 31% in the number of X-rays used, hence reducing the chance of radiation-induced disease [S1]. In words of some users: Cynthia K. Shortell of Duke University Medical Center in the US said: “It has been an instant, blockbuster hit with everyone involved in these procedures. Every operating room participant has a story about the way Cydar technology benefits our team-shorter procedures, lower radiation, less contrast agent, and much greater accuracy.” Dr Peter Goverde, ZNA Stuivenberg Hospital, Belgium said: “This will expand extensively the possibilities of our mobile C-arms and reduce contrast and radiation exposure!” [S9].

Intellectual property: The computer vision is a form of artificial intelligence, which uses NHS Digital-approved, GDPR compliant, high-performance cloud computing. Patents have been granted protecting the 2D-3D image registration (China, EPO, Japan, the USA) and tomosynthesis imaging (the UK, France, Germany, Netherlands, the USA) [S2]. In the period between August 2013 to December 2020, King’s has received reimbursement of patenting expenses incurred, amounting to GBP14,548.67 [S6]

In summary, Cydar is the first company in the world with a CE marked, FDA-cleared product using cloud and AI technology to inform and influence surgery in real-time [S8][S7a,S7b,S7c]. There are traditional imaging companies that use hardware to achieve less accurate and reliable image fusion, but these are not considered competitors as they do not aggregate data, and therefore, cannot develop the same intelligent insights and channel for new products. In recognition of its pioneering work, Cydar was the winner of the Cambridge Business Innovation Award and runner-up for Cambridge AI Company of the Year in 2018 [S3].

5. Sources to corroborate the impact

S1. Peer-reviewed, published evidence demonstrating superiority over existing (hardware) systems and user acceptance:

a. Rolls AE, Maurel B, David M, Constantinou J, Hamilton G, Mastracci TM (2016). A Comparison of Accuracy of Image- versus Hardware-based Tracking Technologies in 3D Fusion in Aortic Endografting. Eur J Vasc Endovasc Surg, 52(3):323–31. DOI: 10.1016/j.ejvs.2016.05.001

b. Maurel B, Martin-Gonzalez T, Chong D, Irwin A, Guimbretiere G, Davis M, Mastracci TM (2018). A prospective observational trial of fusion imaging in infrarenal aneurysms. J Vasc Surg, 68(6):1706-13.e1. DOI: 10.1016/j.jvs.2018.04.015

c. Southerland KW, Nag U, Turner M, Gilmore B, McCann R, Long C, Cox M, Shortell C (2018). IF09. Image-Based Three-Dimensional Fusion Computed Tomography Decreases Radiation Exposure, Fluoroscopy Time, and Procedure Time During Endovascular Aortic Aneurysm Repair. J Vasc Surg, 67(6):e61. DOI: 10.1016/j.jvs.2018.03.037

d. Martin-Gonzalez T, Penney G, Chong D, Davis M, Mastracci TM (2018). Accuracy of implementing principles of fusion imaging in the follow up and surveillance of complex aneurysm repair. Vasc Med,18;23:461-466. DOI: 10.1177/1358863X18768885

S2. Patent details: Cydar IP portfolio status summary

S3. Awards:

a. Cydar recognised at 2018 Cambridge AI company awards

b. Cydar medical winners of the business innovation award 2018

S4. NHS National Tariff Workbook: procedure reference YR04Z – Tab APC & OPROC

S5. Testimonial from Paul Mussenden, CEO of Cydar, 24^th February 2021

S6. Letter from Kings IP and Licencing,

S7. Regulatory documentation for Cydar

a. US FDA 510(k) cleared letter

b. MHRA notification

c. Cydar’s declaration of conformity

S8. Press release, CISION PR Newswire with news of being the first company to have a CE marked, FDA-cleared product using cloud and AI technology to inform and influence surgery in real-time.

S9. Praise from users of Cydar.- Business Weekly 13 February, 2018.

S10. Market research report on endovascular aneurysm repair market

S11. Illustrations from Vascular Services Improvement Program (VSQUIP) for 2017-19 (Total 4396 procedures)

a. Repair of elective complex aortic aneurysms to prevent rupture 2306 procedures

b. Repair of abdominal aortic aneurysm (AAA) to prevent rupture 2090 procedures

S12. News Article reporting costs

S13. Greenhalgh R M, Brown L C, Kwong G P S, Powell J T, Thompson S G, EVAR trial participants, (2004), Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial Lancet, 364(9437):843-8 DOI: 10.1016/S0140-6736(04)16979-1

Galliprost - Democratisation of PET imaging technology for prostate cancer patients ...

Submitting institution: King's College London
Unit of assessment: 12 - Engineering
Summary impact type: Technological
Is this case study continued from a case study submitted in 2014?: No

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1. Summary of the impact

Prostate cancer kills over 10,000 men annually in the United Kingdom alone. Positron Emission Tomography (PET) imaging is central to managing prostate cancer. Synthesis of radiotracers for PET imaging is usually complex and time-consuming, limiting availability for patients.

At the School of Biomedical Engineering and Imaging Sciences of King’s College London (King’s) we engineered tris-hydroxypyridinone (THP), a patented chelator for gallium-68 which helped synthesise a PET tracer using a simple and quick single-vial kit, named Galliprost. This kit has improved treatment decisions in over 1,500 patients globally till date, allowing more appropriate and effective treatment and provided cost savings of GBP600- GBP1,500 per patient.

King’s licensed the intellectual property relating to THP to Theragnostics Ltd, which commercialised the Galliprost kit. In October 2019, GE Healthcare and Theragnostics Limited announced a global commercial partnership for worldwide rollout of Galliprost based on a US market estimate of USD500,000,000 (10-2019).

2. Underpinning research

Prostate cancer kills over 10,000 men annually in the UK. Positron Emission Tomography (PET) imaging, central to managing prostate cancer, relies on radiotracers such as gallium-68 to identify cancer cells. However, traditional methods of synthesising gallium-68 radiotracers are complex, requiring time-consuming, costly preparation. This significantly limits the availability of PET imaging to patients.

The key to this problem lies in the engineering of the chelating agents, which bind the gallium-68 to a biomolecule vector. Previous chelators used in this area were not explicitly engineered for this purpose. These were macrocyclic to achieve long-term in vivo stability, which imposed barriers to synthesis that required complex synthesis steps that hospitals were ill-equipped to carry out. To overcome this, we reasoned that (i) because of the short half-life of ⁶⁸Ga, long-term in vivo stability (and hence macrocyclic structure) was unnecessary and (ii) the chemical similarities between iron and gallium provided a way forward by adapting known chelating agents for iron.

A suitable template for their design emerged from an earlier body of work by Hider and co-workers (also at King’s) on engineering hydroxypyridinone ligands which had been developed for treatment of diseases involving iron overload. A collaboration between Hider and Blower was begun to evaluate a tris-hydroxypyridinone (THP) ligand, and found it would complex gallium very rapidly, at room temperature, in quantitative yield, without extremes of pH, highly selectively so as not to be affected by contaminating trace metals, and free of isomerism. Thus, THP enabled fast and efficient gallium-68 radiolabelling using a simple, single-vial kit achieving a preparation time of just 5 minutes, instead of the several hours required for previous methods.

This formulation allows the tracer to be produced on site, in a manner suitable for frontline healthcare staff, without complex procedures or costly infrastructure.

We showed that it could be conjugated to targeting molecules without inducing new isomerism. We showed between 2007 and 2010 that THP uniquely fulfilled the criteria for a suitable bifunctional chelator to address the unmet need [R1, R2].

We then developed chemistry to incorporate the THP into targeting molecules including proteins [R3], small peptides [R4] and other molecules (unpublished) and demonstrated that they could be readily radiolabelled in a couple of minutes with minimal manipulation by operatives and no need for automated synthesis machinery.

All of these were successfully shown in animal models to be suitable for PET imaging. We developed a specific conjugate that would target prostate cancer by binding with high affinity and selectivity to the PSMA expressed by prostate cancer cells and validated it biologically in animals by PET imaging of human prostate cancers in mice [R5].

We then engineered a sterile kit (Galliprost) for producing the tracer quickly under clinical, good manufacturing practice (GMP) conditions, and validated it. The Galliprost tracer has been clinically evaluated at King’s and its partner NHS Trust in over 1,000 patients, showing that it meets both its key aims of impacting patient management (about one third of patients had treatment decision changed as a result of the scan) and being very easily synthesised in the hospital setting [R6].

3. References to the research

R1. Berry DJ, Ma Y, Ballinger JR, Tavaré R, Koers A, Sunassee K, Zhou T, Nawaz S, Mullen GED, Hider RC, Blower PJ (2011). Efficient bifunctional gallium-68 chelators for positron emission tomography: tripodal tris(hydroxypyridone) ligands. Chem Commun;47:7068 - 7070. PMC3929899. DOI: 10.1039/c1cc12123e

R2. Tsionou MI, Knapp CE, Foley CA, Munteanu CR, Cakebread A, Imberti C, Eykyn TR, Young JD, Paterson BM, Blower PJ, Ma MT (2017). Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling. *RSC Adv,*7:49586–49599. PMC5708347. DOI: 10.1039/C7RA09076E

R3. Nawaz S, Mullen GED, Sunassee K, Bordoloi J, Blower PJ, Ballinger JR (2017). Simple, mild, one-step labelling of proteins with gallium-68 using a tris(hydroxypyridinone) bifunctional chelator: a ⁶⁸Ga-THP-scFv targeting the prostate specific membrane antigen. Eur J Nucl Med Mol Imaging Res, 7:86. PMC5655379 DOI: 10.1186/s13550-017-0336-6

R4. Ma MT, Cullinane C, Waldeck K, Roselt P, Hicks RJ, Blower PJ (2015). Rapid kit-based ⁶⁸Ga labelling and PET imaging with THP-Tyr³-octreotate: a preliminary comparison with DOTA-Tyr³-octreotate. Eur J Nucl Med Mol Imaging Res, 5:52. PMC4600075. DOI: 10.1186/s13550-015-0131-1

R5. Young JD, Abbate V, Imberti C, Meszaros LK, Ma MT, Terry SYA, Hider RC, Mullen GE, Blower PJ (2017). ⁶⁸Ga-THP-PSMA: a PET imaging agent for prostate cancer offering rapid, room temperature, one-step kit-based radiolabeling. J Nucl Med, 58:1270-1277. DOI: 10.2967/jnumed.117.191882

R6. Kulkarni M, Hughes S, Mallia A, Gibson V, Young J, Aggarwal A, Morris S, Challacombe B, Popert R, Brown C, Cathcart P, Dasgupta P, Warby VS, Cook GJR (2020). The Management Impact of ⁶⁸Gallium-Tris(Hydroxypyridinone) Prostate Specific Membrane Antigen (⁶⁸Ga- THP-PSMA) PET-CT Imaging for High-Risk and Biochemically Recurrent Prostate Cancer. Eur. J. Nucl. Med. Mol. Imaging, 47:674-686. DOI: 10.1007/s00259-019-04643-7

4. Details of the impact

Galliprost addresses the unmet need for a generic radiolabelling technology that is quick, simple, and cost-effective to use, with minimal infrastructure or expertise. By providing an affordable and easily deployable technology it is democratising the access, availability, and usability of a vital radiolabelling technology. It has now been taken up by GE Healthcare which has primed it for a global rollout and impact.

Improved accessibility of prostate cancer screening:

The impact of this simplicity of production is illustrated by the screening service established in partnership with Guy’s and St Thomas’ Hospitals, beginning in 2017. This service was set up much more quickly (from typically 6 months to a few days in initial validation; and from typically 6 hours to a few minutes in daily production) than could be done previously [S1]. This has now benefited over 1,000 patients at Guy’s and St Thomas’ Hospitals alone, allowing the most appropriate primary treatment in patients with a new diagnosis and earlier and potentially more curative treatment in those with recurrence [S2], and provided significant cost savings of GBP600 to GBP1,500 per patient [S1]. In words of the Head of Radiopharmacy, Guy’s Hospital, “The development of Galliprost (THP-PSMA) kit formulation has had a massive impact on the clinical service at Guy's & St Thomas' NHS Foundation Trust” [S1].

Galliprost has been used routinely in >10 hospitals world-wide (including St Thomas’ Hospital London; Royal Marsden Hospital, London; University College Hospital, London; Addenbrookes Hospital, Cambridge; Medizinische Hochschule Hannover, Germany; Shanghai Cancer Centre, Shanghai, China; Peter MacCallum Cancer Centre, Melbourne, Australia; Moorabbin Hospital, Melbourne, Australia; and private hospitals in the London area) providing improved accessibility of prostate cancer screening, leading to reduced service implementation lead times (from 6 months to 3 days) and improved treatment decisions.

Better treatment plan for patients of prostate cancer:

By December 2020, an estimated 1,500 patients globally have benefited from the use of Galliprost, [S1, S2, S3, S4]. 34% of patients have their management or treatment changed from the adoption of this scan [S3]. Theragnostics has also reported data from a phase two clinical study which met its primary and secondary endpoints, demonstrating that one third of newly diagnosed prostate cancer patients - and over 50% of patients with biochemically recurrent disease - had their treatment plans modified as a result of a Galliprost scan. The change in patient management increased to 75% in a post-radical radiotherapy setting [S7]. In words of Dr Simon Hughes, Consultant Clinical Oncologist at Guy’s and St. Thomas’ NHS foundation Trusts, “As uro-oncologists we continue to see the benefit of the greater reliability and accuracy of ⁶⁸Ga-PSMA PET/CT in our patients, allowing the most appropriate primary treatment in patients with a new diagnosis and earlier and potentially more curative treatment in those with recurrence” [S2].

Galliprost has also created direct economic benefit:

We licensed our intellectual property to Theragnostics Ltd (formally Imaging Equipment Research Ltd.), who commercialised the kit formulation. Prof Blower is a Scientific Advisory Board Member of Theragnostics. Theragnostics has accrued GBP13,000,000 in investment capital [S4], ~90% directed towards Galliprost development.

Phase 2 trials were completed in 2020 with Phase 3 prostate cancer trials scheduled to start late 2020 with FDA/MHRA approval targeted for 2021. Theragnostics has recently launched a USD45,000,000 Series A financing round to take Galliprost to market [S4].

Since 2016, Theragnostics has appointed 6 staff in UK and 4 in USA as a result of Galliprost [S4]. The investment and progress through clinical trials has led to milestone payments and accrued royalties [S5], and to new research scientist and PhD student appointments funded by Theragnostics; totalling GBP500,000 with a future commitment of GBP530,000 [S4].

Further economic impact has also occurred via sub-licensing. Theragnostics commissioned ChemaTech to synthesise THP derivatives for sales to researchers for development of their own radiopharmaceuticals, and to supply the THP-PSMA conjugate for Galliprost kit production [S4, S6].

In addition, King’s has received GBP157,360 in the REF reporting period between August 2013 to December 2020 as licensing fees, royalties on sales and reimbursement of patenting expenses [S5].

Uptake by Global Medical Technology leader GE Heathcare:

In 2019, Theragnostics entered a commercial partnership with GE Healthcare to provide global distribution, preparation and further development of Galliprost [S7]. “We are excited to partner with Theragnostics on Galliprost to give vital insights into prostate cancer” said Sanka Thiru, Global Product Leader, Molecular Imaging Oncology in GE Healthcare’s Pharmaceutical Diagnostics business. “We believe that this partnership enables both parties to leverage each other’s key areas of expertise in order to accelerate the development of Galliprost and ultimately improve patient care” [S7]. GE Healthcare is the healthcare division of GE and has operations in over 160 countries globally with a reported revenue of USD18,000,000,000 in 2020 [S8].

Improved diagnosis and treatment of patients with lymphoma globally using Positron ...

Submitting institution: King's College London
Unit of assessment: 12 - Engineering
Summary impact type: Health
Is this case study continued from a case study submitted in 2014?: No

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1. Summary of the impact

More than 100,000 people are diagnosed annually with lymphomas in the UK and US alone, and many more globally. Imaging technology research at King’s College London (King’s) using positron emission tomography (PET):

has led to new international guidelines using PET-CT scanning as the primary test for staging and for assessing response in lymphomas using a 5-point reporting scale developed at King’s;
has resulted in fewer side-effects and improved cure rates for patients with advanced disease globally;
has rendered bone marrow biopsy an unnecessary test in patients with Hodgkin lymphoma (HL) especially in UK, Europe, Australia and US;
has changed practice for the treatment of HL internationally, using an early PET-CT scan to guide treatment.

2. Underpinning research

Since the establishment of the King's PET Centre embedded in St. Thomas’ Hospital, King's has been at the forefront of the development of positron emission tomography (PET) technology, with a particular strength in multi-modality imaging, combining PET with computed tomography (PET-CT) and with magnetic resonance imaging (PET-MR). Since 2000, Marsden has led pioneering PET imaging technology development at King’s, notably in the areas of image registration, kinetic modelling, motion correction, multi-modality image acquisition, radiomics assessment and data-driven PET acquisition [R1-R3]. In 2016 Marsden was awarded the inaugural John Mallard Award from the International Organisation for Medical Physics (IOMP) for his contribution to the development of PET-MR.

A strong multidisciplinary approach, combining biomedical engineering research with clinical and scientific expertise, has formed the foundation of the PET imaging technology research carried out by the King's group. This approach, exemplified in the long-standing collaboration between Marsden and Barrington [R2,R4] has fostered a culture of continuous development, a rigorous approach to analysis of clinical trial data, and ongoing detailed assessment of all methodology in the complex PET imaging process.

King's research has adapted and comprehensively evaluated major aspects of the complex PET imaging technology for application in patient management, including production of short-lived radionuclides, tracer synthesis, data acquisition protocols and parameters, and subsequent image reconstruction and processing, facilitated by the synergy with hybrid imaging technology development, as outlined above. In 2008 Marsden was invited to be the technical lead for the National Cancer Research Institute (NCRI) PET Research Initiative, established to ensure a coordinated expansion of PET research in the UK [F1], which was followed by the establishment of a UK national PET Imaging Core Lab at St Thomas’ Hospital, co-led by Marsden and Barrington [F2]. Based on their combined expertise in performance assessment and quality control of PET-CT scanner systems [R5], the group at King’s devised detailed technical standards for scanner performance and quality control for the conduct of multicentre trials, which have then been implemented throughout the UK for cancer trial imaging. Barrington subsequently received the flagship award of Research Professorship from the National Institute for Health Research (NIHR) in 2017 [F3].

The multidisciplinary engineering and clinical research at King’s has led to significant advances in the role of PET imaging technology in the diagnosis, staging and treatment of lymphomas, which are cancers of the lymphatic system [R6]. Prior to the King’s-led research, lymphoma disease mapping at diagnosis and response assessment at the end of treatment were carried out using CT scans (which only serve to monitor the size of lymph nodes and tumour masses), as well as invasive, often painful bone marrow biopsies (which only show the presence or absence of lymphoma in a small sample acquired from the pelvic bone).

The underpinning PET imaging research at King’s led by Marsden, with Barrington as clinical imaging lead, has resulted in new international guidelines for imaging and management of patients with lymphoma. Specifically, King’s research has shown that PET scans using the tracer 18F-fluorodeoxyglucose (FDG) that images glucose metabolism, which is increased in lymphomas, can more reliably assess the majority of lymphoma subtypes in the body than CT scans, including in the bone marrow, and can predict treatment response much earlier than CT does.

3. References to the research

R1. Marsden PK, Strul D, Keevil SF, Williams SC, Cash D (2002). Simultaneous PET and NMR. British Journal of Radiology 75(suppl_9):S53 - S59. DOI: 10.1259/bjr.75.suppl_9.750053

R2. Schleyer PJ, O'Doherty MJ, Barrington SF, Marsden, PK (2009). Retrospective data-driven respiratory gating for PET/CT. Physics in Medicine and Biology 54(7):1935-1950 DOI: 10.1088/0031-9155/54/7/005

R3. Chicklore S, Goh V, Siddique M, Roy A, Marsden PK, Cook GJR (2013). Quantifying tumour heterogeneity in 18F-FDG PET/CT imaging by texture analysis. European Journal of Nuclear Medicine and Molecular Imaging 40(1):133-140. DOI: 10.1007/s00259-012-2247-0

R4. Barrington SF, MacKewn JE, Schleyer P, Marsden PK, Mikhaeel NG, Qian W, Mouncey P, Patrick P, Popova B, Johnson P, Radford J, O'Doherty MJ (2011). Establishment of a UK-wide network to facilitate the acquisition of quality assured FDG-PET data for clinical trials in lymphoma. Annals of Oncology 22(3):739-745. DOI: 10.1093/annonc/mdq428

R5. Pike L, Julyan P, Marsden PK, Waddington W (2013). Quality Assurance of PET and PET/CT Systems. IPEM Report 108, ISBN: 978 1 903613 54 2.

R6. Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M, Müeller S, Schwartz LH, Zucca E, Fisher RI, Trotman J, Hoekstra OS, Hicks RJ, O’Doherty MJ, Hustinx R, Biggi A, Cheson BD (2014). Role of imaging in the staging and response assessment of lymphoma: consensus of the ICML Imaging Working Group. J Clin Oncol, 32:3048–58. DOI: 10.1200/JCO.2013.53.5229

Research funding:

F1. Marsden, PK, NCRI: PET research network, Cancer Research UK. GBP318,726, 1/05/2009-31/07/2012

F2. Barrington S, Marsden, PK, NCRI: PET Core Lab, Cancer Research UK. GBP401,176, 1/08/2012-31/03/2017

F3. Barrington S. Using PET Imaging to improve survival and reduce side-effects of treatment for patients with cancer, NIHR (RP-2016-07-001). GBP1,567,064, 1/12/2017-30/11/2022

4. Details of the impact

Research at King’s on the standardised use of FDG-PET scans to inform lymphoma treatment has led to the development of new international guidelines, shaped professional practice and treatment and helped improve patient diagnosis, management and outcomes internationally. Over 100,000 people are diagnosed annually with lymphomas in the UK and US alone, and many more globally.

Background: PET-Directed Therapy for Lymphoma

Hodgkin lymphoma (HL) is the commonest cancer in teenagers and young adults, but also affects older patients, with 2,000 new diagnoses in the UK and over 8,000 new diagnoses in the US annually. Non-Hodgkin lymphomas mainly affect patients over 60, with 14,000 patients diagnosed annually in the UK and 77,240 in the US with many more affected globally.

The PET imaging quality assurance and standardisation procedures established by the UK PET Core Lab (http://www.ncri\-pet.org.uk\) co-led by Marsden and Barrington [F2], and the preceding work on which they are based [R1-R4], ensure that accurate radiotracer uptake values are obtained, which is critical for conducting multicentre trials where quantitative data from all sites need to be pooled in combined analysis to maximise the statistical power of the study. Barrington led the clinical imaging working group that developed the international guidance on imaging stage and response assessment for patient management [R6] and led the use of quality-assured PET imaging scans to guide treatment in the clinical trials RAPID [S1] and RATHL [S2,S3]. The quality assurance and standardisation procedures developed at King’s and documented [R5] contributed to obtaining statistically significant results of these studies, and their high clinical impact.

The ‘RAPID’ trial, funded by Blood Cancer UK, recruited patients from 2003 to 2010, involved 602 patients from the UK and the ‘RATHL’ trial, funded by Cancer Research UK (Grant reference: CRUK/07/033), which recruited from 2008 to 2012, involved 1,204 international patients. These trials demonstrated that it was safe to reduce treatment when patients have a satisfactory (complete metabolic) response on PET after two or three months of planned 4-6 months treatment, with fewer side-effects for patients with advanced disease, while patients with inadequate early response lived longer if more intensive chemotherapy was given. This approach also reduces the need for high-dose chemotherapy and bone marrow transplant in non-responding patients [S1,S2,S3].

Changes to international guidelines and influence on professional practice

The methods developed in the King’s-led trials for performing and reporting quality-assured, standardised PET imaging [S1,S2,S3] have contributed to harmonisation of practices across PET imaging centres worldwide. Specifically, King's research led to changes to international guidelines for management of lymphoma [S4,S5] and contributed to European guidelines for performing quality-assured PET imaging [S6]. The 5-point scale developed at King’s has become the international standard also known as the ‘Deauville criteria’ and was adopted on 20 September 2014 [R6]. Previously, there was no agreed common method to perform and report PET scans in lymphoma. Barrington has continued to influence professional practice amongst haematologists and radiologists as a member of the European Lymphoma Institute’s scientific committee for international workshops on PET and lymphoma (September 2014 till October 2018) [S7].

Impact on diagnosis, patient management and outcome

Research from the PET Core lab, applied to the RATHL trial [S2], directly contributed to PET-CT imaging effectively replacing CT and bone marrow biopsy as the standard-of-care for diagnosis and staging of HL [S3]. Guidelines resulting from King's research indicate PET-CT is now the standard imaging test at diagnosis of HL since 2017 [S4,S5], allowing patients to avoid painful and invasive bone marrow biopsies, as documented in patient material [S8].

The research and associated trials effected a change of practice for the treatment of HL since 2017 using early PET scans to guide current treatment, with fewer side-effects and improved survival for patients with advanced disease. In the RATHL trial [S2], early PET scans were used for treatment adjustments. Furthermore, PET-CT has also become the standard-of-care for monitoring response in patients with follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma, receiving chemoimmunotherapy after research conducted in the international collaborative study ‘GALLIUM’ [S9,S10]. In this study (funded by Hofman la Roche Pharmaceuticals) involving 533 patients, Barrington and colleagues in Europe and Australia showed PET to be superior to CT for response adopting the 5-point scale previously developed for HL, and, importantly, a surrogate for overall survival (which is typically more than 10 years) for testing of novel agents in this disease [S10].

Patient outcome has been positively impacted since 2016.

Quality assured PET reporting led to improved outcomes for HL patients with inadequate early response in the RATHL trial. These patients received more intensive treatment and 67% of them were alive and free of lymphoma 3 years after treatment [S2,S3]. This is in contrast to previous reports where only 20% of patients with adverse early PET scan findings survived using the then standard-of-care. More than 85% of patients in the RAPID and RATHL [S1, S2, S3] trials who received less toxic treatment as a consequence of the quality-assured PET reporting were alive without lymphoma three years after treatment. The approaches tested in these trials using PET have become a new standard-of-care amongst the haematology and oncology community and are widely used in the UK, USA, and parts of Europe and Australia. This is evidenced by inclusion in international guidance [S4,S5], professional material [S11], and patient booklets [S7,S12]. Bleomycin is a drug that was previously given to patients for six months with advanced HL. Since RATHL, over 80% of patients with advanced HL need only take this drug for two months [S4,S5,S11].

As Dr. Graham Collins, Chair of the UK National Cancer Research Institute’s Hodgkin Lymphoma Research Group, says, “Professor Barrington has led the core PET laboratory at King’s which has resulted in practice changing research that has directly improved the care for patients with lymphoma. PET adapted therapy is [now] routinely practised worldwide for Hodgkin lymphoma and Professor Barrington pioneered this approach by leading the PET component of the RAPID and RATHL international studies. The resulting practice change has limited acute and late toxicities of treatments for patients and improved the cure rate for advanced stage disease” [S13].

In the words of Professor Judith Trotman, Head of Department of Haematology at Concord Hospital, the University of Sydney ( Australia) and as past Lymphoma Chair of the Australian Lymphoma and Leukaemia Group, "The PET guided approaches tested in RATHL and RAPID have shaped the management of patients treated in Australia, which is reflected in guidelines that will be published in Feb 2021” [S14].

As Professor Bruce Cheson, Scientific Advisor at Lymphoma Research Foundation ( USA), says, “Dr. Barrington’s practice changing research now allows physicians to alter treatment in high risk patients resulting in improved outcomes, and reduce the amount of therapy for those at low risk, with a reduction in toxicities” [S15].

Informing the work of Lymphoma Action and Blood Cancer UK

Lymphoma Action is the UK's only charity dedicated to lymphoma (5th most common cancer) and have been providing in-depth, expert information for over 30 years, helping thousands of people affected by lymphoma. In 2016, their website reported on the RATHL trial conducted on HL at King’s [S16], and in 2018, in a Lymphoma Action Meeting at their National patient and carer conference, the benefits of using PET to guide treatment demonstrated in RAPID and RATHL was highlighted [S17, p.17-23]. Blood Cancer UK, a charity dedicated to beating blood cancer since 1960 reported how findings from the RAPID trial conducted on HL at King’s were changing practice worldwide “making Hodgkin lymphoma treatment kinder” by offering less intensive treatment to patients with fewer side-effects which can include secondary cancer and heart disease [S18].

5. Sources to corroborate the impact

S1. Radford et al., (2015). Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med, 372(17):1598–607. DOI: 10.1056/NEJMoa1408648

S2. Johnson PWM et al., (2016). Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med, 374:2419–29. DOI : 10.1056/NEJMoa1510093 (RATHL trial) editorial: NEJM 2016 June 23; 374(25): 2490–1

S3. Barrington SF et al., (2016). PET-CT for staging & early response: Results from ‘Response Adapted Therapy in Advanced Hodgkin Lymphoma’. Blood, 127(12):1531–8. DOI: 10.1182/blood-2015-11-679407.

S4. Eichenauer DA et al. (on behalf of the ESMO Guidelines Committee), (2018). European Society of Medical Oncology of Medical Oncology Guidelines for Hodgkin lymphoma. Hodgkin Lymphoma: ESMO Clinical Practice Guidelines. Ann Oncol., 29 (Suppl 4): iv19–iv29. DOI: 10.1093/annonc/mdy080

S5. Hoppe RT et al., (2017). US National Comprehensive Cancer Network Guidelines for Hodgkin Lymphoma, Hodgkin Lymphoma Version 1, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw., 15(5):608–38 DOI: 10.6004/jnccn.2017.0064

S6. Boellaard R et al., (2015). European Association of Nuclear Medicine guidelines for performing PET-CT tumour imaging, FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0., Eur J Nucl Med Mol Imaging, 42(2):328–54, DOI: 10.1007/s00259-014-2961-x

S7. International workshops on PET in Lymphoma

S8. Lymphoma Action - A Young person’s guide to Hodgkin Lymphoma Booklet. 6th edition: January 2017 ISBN: 978-0-9929362-9-7

S9. Website of Medpage Today, a medical online media company for health professionals

S10. GALLIUM trial: Trotman et al., (2018) Lancet Oncol, 19:1530–42 doi: 10.1016/S1470-2045(18)30618-1

S11. You tube video from New England Journal of Medicine describing outcomes from the RATHL trial with 27,401 views last accessed 18/01/2021 -Patient booklets published by Lymphoma Action a UK charity dedicated to lymphoma:

S12. Hodgkin Lymphoma: - Pages 50,53 refer to treatment approach tested in RAPID trial and pages 53,55; page 52 refers to RATHL trial now in routine clinical practice. Last accessed 18/01/2021.

S13. Testimonial email from Graham Collins, Chair of the National Cancer Research Institute’s Hodgkin Lymphoma Research Group, 17^th June 2020

S14. Testimonial quote from Judith Trotman, Head of Department of Haematology at Concord Hospital, University of Sydney 27^th January 2021

S15. Testimonial email from Bruce Cheson, Scientific Advisor at Lymphoma Research Foundation (USA), 17^th June 2020

S16. Lymphoma Action website (charity and patient support group dedicated to supporting people with lymphoma) comments on RATHL trial ‘Reducing serious side effects and improving outcomes’

S17. Lymphoma Action Patient Conference presentation by Dr MacKay from University of Glasgow discussing RAPID and RATHL and how they are used in clinical practice slides, 15-23 September 2018. Last accessed 18/01/2021

S18. Blood Cancer UK website (charity and community dedicated to beating blood cancer) comments on RAPID trial ‘Making Hodgkin lymphoma treatment kinder’

IXICO, a King's spin out leveraging medical image data curation and analysis for ...

Submitting institution: King's College London
Unit of assessment: 12 - Engineering
Summary impact type: Technological
Is this case study continued from a case study submitted in 2014?: Yes

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1. Summary of the impact

Research into medical imaging at the School of Biomedical Engineering and Imaging Sciences of King’s College London (King’s) led to the formation of a spinout company, IXICO, which was listed on the Alternative Investment Market (AIM) of the London Stock Exchange in October 2013. In 2020, the company which employed 78 full time staff members, reported a full year revenue of GBP9,500,000, an order book of GBP21,700,000, and a four-year compound annual growth rate of 33%.

IXICO provides medical imaging solutions for clinical trials and healthcare products that support diagnosis of dementia. Since 2013, IXICO has commercial partnerships with 9 of the top 15 pharmaceutical companies, including Pfizer, Bristol-Myers Squibb, Biogen and Eli Lilly. The company has qualified sites in over 50 countries across the Americas, Europe, and Asia-Pacific, and has analysed over 100,000 brain scans from more than 27,000 patients, by the end of 2020. IXICO’s work has provided pivotal imaging results that have impacted trial outcomes, providing more definitive results requiring smaller patient cohorts than other outcome measures.

2. Underpinning research

In 2002 a team led by Derek Hill from the School of Biomedical Engineering and Imaging Sciences at King’s, together with collaborators at Imperial College London, designed and engineered a technology demonstrator that explored how to deploy image registration algorithms securely and at scale using an emerging distributed computing infrastructure known as a computational grid [R1], a forerunner for cloud-based computing and secure web services. The demonstrator allowed a user to securely upload a 3D magnetic resonance image (MRI) of a human head to a remote computer server, where the brain was automatically labelled by tissue type (grey matter, white matter and cerebrospinal fluid) and the result returned to the user. This anticipated the distributed computing methods that are commonplace today for analysis of medical images at scale using secure cloud-based services. The modern equivalent can deliver high performance using computationally intensive algorithms yet remain compliant with data protection requirements such as the General Data Protection Regulations (GDPR). In 2002 such a capability did not exist, and this was recognised as a limiting factor for deployment of advanced image analysis algorithms, stopping them from effective deployment at scale for both Neuroscience and medical purposes. On the strength of this novel engineering, the team won funding from the UK e-Science initiative to explore the potential of grid computing in medical imaging applications (GR/S21533/02). The aim of the project, which was called ‘Information extraction from Images (IXI)’, was to work out how to use the then emerging grid technology, with its secure protocols, for medical imaging applications with particular emphasis on ensuring full clinical governance standards were maintained at all times. An integrated team working across institutional boundaries, but led by Derek Hill from King’s, set about systematically developing the processes and infrastructure needed, first building an image database designed specifically to interface with grid services [R2] and then developing the workflow protocols needed to flexibly perform advanced image analysis using distributed but secure grid services [R3]. The project delivered on all these component parts, achieving a full system capable of protecting personal data while allowing flexible deployment of powerful computer resources in a scalable way. The framework also provided complete provenance information for all outputs, such that any image resulting from IXI grid system processes would be accompanied by a digitally signed record specifying all its antecedent input images, all processes performed including all parameter values used and the software versions of all algorithms deployed. Thus, the system was designed to provide a secure and verifiable data framework for processing of sensitive medical data at scale.

The core technology that has powered the company’s business is medical image registration, the spatial alignment of images with one another, to compare images from the same subject or to place information from one subject in the context of others. The team at King’s led by Hawkes and Hill pioneered this technology. A particularly challenging problem is aligning images when non-rigid transformations are required, such as when there has been tissue deformation or to align one subject with another. In 2001 they engineered a solution to the problem of non-rigid alignment using a flexible and versatile deformation model built on B-splines [R4]. Achieving accurate results is particularly challenging when corresponding tissues have very different signal properties in the images to be matched. Calculating the change in mutual information between images as one is warped to match the other is a powerful approach but is technically challenging because it relies on analysis of histograms of image intensities that themselves change as the applied deformations change. In 2003 the team presented an elegant means to address this problem [R5]. Jo Hajnal, during his period of engagement with IXICO while at King’s (2012-13), continued to work in the area of hippocampal labelling in MRI of the brain for subjects with Alzheimer’s Disease, addressing a pivotal need for methods that can form sensitive markers of disease progression [R6].

4. Details of the impact

Directly following the successful completion of the IXI project, a university spinout called IXICO Ltd. (literally the Company that came from IXI) was formed in 2004 by Derek Hill and David Hawkes from the School of Biomedical Engineering and Imaging Sciences at King’s together with partners at Imperial College [S1]. IXICO’s first employee, Thomas Hartkens, transitioned from being a postdoctoral researcher on the IXI project at King’s, bringing expertise and software know-how. He was instrumental in importing key elements of the project software, which were rapidly implemented within a bespoke ISO certified quality management system. A critical feature was companywide compliance by construction (i.e. from the ground upwards), with the relevant regulations in place for electronic record-keeping in clinical trials, most notably the USA Food and Drug Administration (FDA) title 21 of the Code of Federal Regulations; Electronic Records (21 CFR, Part 11) [S11]. This technological edge helped launch the company on its path to developing a thriving business offering medical image analysis for clinical trials and healthcare products for diagnosis of dementia. Jo Hajnal, who has been at King’s since April 2012, was on IXICO’s board, acting as a scientific advisor working with the company 1 day/week until October 2013. He provided expertise on medical image protocol design, data acquisition and image analysis, sustained by his ongoing research activities [R6, S1, S2 p.38].

The table below summarises the key impact metrics for the REF2021 reporting period [S1, S3, S8, S10].

### Key impact metrics	### 2012/13	### 2020
Turnover	GBP2,500,000	GBP9,500,000
Employees	36	78
Imaging centres	400	2,000+
Brain scans analysed	10,000	100,000+
Safety and eligibility reports	n/a	20,000+

Economic impact

In October 2013, IXICO was listed on AIM, London Stock Exchange's market for small and medium size growth companies, becoming IXICO Plc [S2]. In 2020, the company which employed 78 FTE staff members reported a full year revenue of GBP9,500,000, an order book of GBP21,700,000, and a four-year compound annual growth rate of 33% [S1].

“IXICO Technologies Limited was incorporated in 2004 and spun out of King’s (which remains a shareholder), building on the ‘IXI’ project. … We are very pleased to have achieved [in 2020] GBP1,300,000 [earnings before interest, tax, depreciation, and amortisation] EBITDA profitability, more than doubling our profitability in 2019 (which was GBP500,000) and outperforming the market expectations. GBP1,300,000 EBITDA represents 14% EBITDA margin and further reflects the strengthening of IXICO as a growth medical imaging technology company.” – CEO of IXICO [S1]

Impact on the neurological drug development industry and healthcare

A key benefit of IXICO’s medical image analysis products is that they provide more definitive results requiring smaller patient cohorts than other outcome measures [S1]. IXICO has worked with 9 of the top 15 pharmaceutical companies (including Pfizer, Bristol-Myers Squibb, Biogen and Eli Lilly) as well as with many speciality biotechnology companies [S1, S7b]. It has completed multiple clinical trials (phases 1–4) and is currently responsible for data acquisition and analysis of primary endpoints on 4 late-phase pivotal clinical trials [S1, see also patient numbers quoted above]. During the reporting period, the company has expanded both the neurological conditions that its technology can be applied to and has moved into healthcare, supporting both early diagnosis and disease monitoring.

The company now has active contracts focusing on Huntington’s Disease (HD) [S6c, S7a], Parkinson’s Disease (PD), Multiple Sclerosis and rare neurological disorders, as well as its historic strength in Alzheimer’s Disease (AD) [S6a, S6b]. For example, IXICO has won 11 clinical trial contracts in HD, including a GBP10,500,000 contract for a late-phase open label study in Huntington's disease with an estimated 1000 subjects in Europe, North America and Asia enrolled during the summer of 2020 [S6d]. An important function that IXICO has provided focuses on the need to enrich clinical trials with carefully profiled subjects. Since 2013, IXICO has provided safety and eligibility reports on over 20,000 subjects [S10].

Impact on health regulatory policy

IXICO’s image analysis and data management/curation technologies are playing a key role in a number of public-private consortia, that are gathering the evidence base needed for policy changes in relation to the assessment of key neurological diseases and development of new treatments for them [S9]. For example, IXICO played a leading role in the submission to European regulators to qualify low hippocampal volume as a biomarker that can provide more precise and effective assessment of patients to enrich trials of treatments for AD [S4]. This submission, which was supported by the US Food and Drug Administration (US FDA) [S5], incorporates key data obtained using a core IXICO image analysis technology.

IXICO’s role in some of the key consortia is as follows:

The European Prevention of Alzheimer’s Dementia (EPAD) – “the largest ever public-private partnership in Alzheimer’s Disease research”, which has built an adaptive clinical trials platform to enable pharma companies to efficiently evaluate the safety and effectiveness of their medicines in patients prior to onset of symptoms by utilising adaptive clinical trial approaches. IXICO provided the technology to collect, manage, and analyse magnetic resonance imaging (MRI) scans (pan European register of 0.5m subjects, >1,500 subjects in database in 2020) [S7c].

“IXICO were a pivotal partner in the EPAD programme providing excellent service throughout the 6 years to our sites and central team. Not only did they provide valued operational support they also contributed in a crucial way to design aspects of EPAD in terms of data flows and imaging science. The data from EPAD will make a huge difference to our understanding of Alzheimer’s Disease in its early stages and IXICO has been pivotal in providing the best quality and relevant imaging data to that effort.” – Professor Craig Ritchie, EPAD Principal Investigator, Chair of the Psychiatry of Ageing and Director of the Centre for Dementia Prevention at the University of Edinburgh [S8 p. 16]

Critical Path Institute initiatives: Huntington’s Disease Regulatory Science Consortium (HD-RSC), a global initiative aiming to improve the regulatory path for new HD therapies, and Critical Path for Parkinson’s (CPP) Disease, which brings together the world’s largest pharmaceutical companies advancing novel promising treatments for people living with Parkinson’s. IXICO is contributing towards FDA clearance of imaging biomarkers to support the development and approval of new medicines to treat HD and PD. Achieving regulatory approval for imaging biomarkers for these diseases is a critical step for conducting more efficient clinical trials using smaller cohorts and is therefore a gatekeeper for maximising societal impact.

In words of Diane Stephenson, Executive Director, Critical Path for Parkinson’s Consortium (‘CPP’), Critical Path Institute: “We are delighted to continue our collaboration with the IXICO team in two further Critical Path consortia, the Critical Path for Parkinson’s (‘CPP’) consortium and the HD Regulatory Science Consortium (‘HD-RSC’). In these consortia, our aims are to develop new, regulatory-endorsed drug development tools that will improve the clinical trial process and regulatory path for emerging therapies for HD and PD and ultimately de-risk the development of new treatments that are urgently needed. IXICO’s expertise in data analysis and regulatory qualification is supporting our efforts to develop the regulatory path to qualify new imaging and digital biomarkers for use in clinical trials.” [S10]

Amyloid Imaging for Prevention of Alzheimer’s Dementia (AMYPAD) – IXICO provided the technology to collect, manage, and analyse MRI and positron emission tomography (PET) scans for evaluating the diagnostic value of amyloid imaging in Alzheimer’s Disease [S6e]. The project succeeded in recruiting 844 out of the planned 900 participants despite the negative impact of COVID-19. These studies are ongoing, but large cohort data is already available, providing a massive community resource [S7d).

The societal impact of IXICO’s work is significant. Its technology has been, and continues to be, helping large pharmaceutical companies develop treatments for neurological diseases with major unmet medical needs. IXICO has provided automated analysis of over 100,000 images as part of clinical trials, its technology is now enabling a new generation of clinical trials for neurodegenerative diseases such as Alzheimer’s Disease where patients early in their disease pathway can be identified and recruited for better understanding of pharmacological interventions and this has contributed to health policy and regulation.

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