Impact case study database

It is widely reported that 85% of health research is wasted because ‘ it asks the wrong questions, is badly designed, not published or poorly reported’ ( The Lancet, 2009, 374(9683): 86-89). Research ethics committees (RECs) review research proposals and give an opinion about whether the research is ethical. Reviews by RECs normally occur after funding has been granted and protocols have been developed, but prior to study recruitment and data gathering. Failure to achieve a “favourable ethics opinion” can prevent a study progressing. This makes ethics committees a key gatekeeper of research, with the opportunity to influence research conduct so as to reduce research waste and enhance transparency. National Health Service (NHS) RECs consider and approve the ethical acceptability of research involving NHS staff and/or patients, as well as other health-related research. There are more than 60 NHS RECs across the UK and they review around 6,000 project applications each year. The Health Research Authority (HRA), an arm’s-length body situated in England’s Department of Health, takes a leading and coordinating role for managing RECs throughout the UK. The HRA’s mission is to promote and protect the interests of patients, harmonise and streamline regulation, and promote transparency in health and social care research.

4.1. Enhancing the transparency of research in the United Kingdom

Research transparency is central to ethical research practice. Health and social care research studies should be registered and the results made public, so that participants are protected from unnecessary studies, use of research funding is maximised and the greatest public benefit is delivered. Non-publication of research is the main cause of research waste (50%). Kolstoe’s research on reporting bias and non-registration of clinical trials has led to government policy change, specifically a significant extension of the mandate and role of the UK Health Research Authority in relation to monitoring clinical trials transparency. Following the primary publication ( R1), the topic of whether RECs should police reporting bias featured in a BMJ “Head to Head” debate ( https://www.bmj.com/content/356/bmj.j1501, 27/03/2017). Subsequently, Kolstoe submitted written ( S1) and oral evidence ( S2) to the 2017 House of Commons Science and Technology Select Committee (STSC) inquiry on research integrity. This evidence:

1. identified reporting bias as a research integrity issue;

2. highlighted a case where non publication of clinical trials results had led to significant wasted public expenditure (GBP424,000,000 spent on Tamiflu, based on incomplete evidence);

3. proposed that the Health Research Authority was best placed to support research ethics committees in monitoring publications arising from projects and ensuring clinical trials transparency.

In view of this evidence, the STSC considered the issue of clinical trials transparency to be so significant for public health that it recommended it be considered separately and an additional report, ‘ Research integrity: clinical trials transparency’ was published in October 2018 ( S3). This report repeatedly referenced Kolstoe’s research alongside recommendations that the HRA establish a national audit programme, modelled on Kolstoe’s work. The HRA was also instructed to publish information on trials that have received ethical approval but are not registered in a publicly accessible register, and introduce a system of sanctions to drive improvements in clinical trials transparency.

In February 2019 and coinciding with the publication of R2, the HRA established the Research Transparency Strategy Group, with Kolstoe as a member. Following drafting and public consultation, the HRA approved the HRA ‘ Make it Public’ Transparency Strategy, which was published in July 2020 ( S4). The HRA ‘ Make it Public’ Strategy extended the role of the HRA in relation to monitoring clinical trials transparency and directly addressed the Science and Technology Committee recommendations by committing the HRA to:

• assume responsibility for registering clinical trials on behalf of the sponsor, using data that provided for study approval;

• require the submission of a final report within 12 months of study completion; and

• use information in the final report to measure research transparency and take action in cases of non-compliance.

As such, the ‘Make it Public’ Strategy ‘ extends the role of the HRA in relation to monitoring clinical trials transparency and represents a significant advance in our ability to support high-quality health and social care research and to promote the interests of patients and the public’ ( S5).

The HRA also published their commitment to conduct ongoing audits of clinical trials registration, using the method developed by Kolstoe, to monitor legal and policy compliance ( S6). Additionally, in response to the results of R3, the HRA have incorporated data access arrangements into a revision of their ethics review form for Research Databases ( S5).

4.2. Improving the consistency and efficiency of NHS ethics committees

In response to the findings from R4, the Director of Approvals Service at the HRA halted the Shared Ethical Debate (ShED) consistency exercises in 2019, and reinstated them in a new format in 2020, with a new focus on using the exercise as a learning opportunity and encouraging members to explore decision-making ( S5), following suggestions published in R4.

4.3. Enhancing the capability and efficiency of research in the UK Ministry of Defence

The Ministry of Defence Research Ethics Committee (MODREC) ensures that all research involving human participants undertaken, funded or sponsored by MOD meets nationally and internationally accepted ethical standards. It is recognised by the United Kingdom Ethics Committee Authority (UKECA) to review clinical trials of investigational medicinal products involving subjects who are UK Armed Forces personnel recruited in a military setting, as well as Phase 1 trials in healthy volunteers conducted by the MOD. It is also recognised as an Appropriate Body under the Mental Capacity Act 2005 for review of research involving UK Armed Forces personnel who are unable to consent for themselves (commonly research in emergency/battlefield situations).

On the basis of his research and experience of NHS RECs , Kolstoe was appointed chair of the MODREC in 2016, and was tasked by the Surgeon General with an evidence based modernisation of the committee, with the goal of streamlining research governance and approvals within the MOD ( G4). Kolstoe rapidly identified a gap in the MOD’s research governance arrangements in relation to the legal requirements for ethics review and, subsequently, represented the MOD in negotiations with the UKECA. These negotiations ensured that the MOD was able to continue to review and approve studies falling under the Clinical Trials Regulations 2004, Mental Capacity Act 2005 and Human Tissue Act 2004. Without this intervention, the MOD would have not been authorised to approve and conduct these types of research and the disruption to high profile and time-sensitive research would have been significant. For example, in 2014 the MOD directed GBP20,000,000 to a five-year, physiological research programme to understand the health effects of combat roles on men and women. This delivered significant changes within the British Army: data from the ‘Women in Ground Close Combat’ research team underpinned the Defence Secretary’s decision to open Ground Close Combat (GCC) roles to women in July 2016, and new role-related, rather than gender- or age-specific, Physical Employment Standards for GCC roles were introduced in April 2019. Any lapse in the ability of the MOD to conduct research with human participants would have jeopardised this, and other, research programmes of national significance.

The agreement brokered by Kolstoe required the subsequent harmonisation of the MOD human research governance policy (JSP536) with two national policies: the ‘UK Policy Framework on Health and Social Care Research’ and ‘Governance Arrangements for Research Ethics Committees’. A contract was awarded to the University of Portsmouth to complete this critical work ( G5, S7), and the new policy was published in December 2019 ( S8). The revised MOD policy was introduced in January 2020 and provided a Proportionate Review Service which allows for research proposals that present ‘no material ethical issues’ to be reviewed and approved via an executive sub-committee. ‘This revision has hugely improved and clarified the MODREC application process for researchers’ ( S7). As a result, the MODREC approval process has become more streamlined and the average time for MODREC project approval has reduced by 35%, from 32 days to 21 days. In addition, the capacity of the committee to review studies has increased by 40% ( S9) with no additional cost. As the annual governance budget is ~GBP350,000, this could be considered as a GBP140,000 efficiency saving for the department in 2020 alone, compared to the previous three years.

The four integrated, community-based programmes (MISSION Asthma; the Breathlessness Programme; MISSION COPD; MISSION ABC) provided an entirely new model for the assessment and care of individuals with chronic respiratory diseases. By bringing together specialist diagnosis and care teams into a single community-based setting, patients were assessed, and a programme of tailored care initiated in a single day. This approach was dramatically different to the traditional model of a series of appointments in secondary care, thus saving many months of delay before diagnosis and treatment. Furthermore, personalised plans, reinforced with education, enabled effective self-management of patients’ symptoms. Finally, the timely identification and intervention in cases of at-risk individuals significantly reduced unscheduled care from respiratory crises, reducing the, often significant, impact on individuals and on healthcare infrastructure.

Improvements in the health of patients with chronic respiratory conditions

Each programme reported significant health benefits in the patients enrolled. In the six months following the Breathlessness, MISSION Asthma and MISSION COPD programmes, exacerbations were reduced by 89%, 37% and 50%, respectively ( S1). Unscheduled hospital admissions, often the result of respiratory crises, were eliminated in all but the MISSION COPD programme, where they were reduced by 55% ( S1). These marked reductions were achieved by identifying, diagnosing and treating at-risk patients and through the education of patients, carers and primary care staff. Education activities were wide-ranging, including the development of self-management plans and proper inhaler use. Prior to the programme, only 39% of patients attending MISSION COPD clinics recognised the need to improve their inhaler technique and 87% were judged to have inadequate technique that would reduce the efficacy of treatment ( S2). Personalised plans, reinforced with education, resulted in patients becoming significantly more confident in managing their condition ( S2, S3). One patient reported ‘ being taught how to use medications correctly ... for the first time’ ( S4). Healthcare practitioners also recognised these benefits. A member of the specialist clinical team commented: ‘ *I think by going out and doing the education side of things you hopefully have a knock-on effect for the rest of the practice, as well and for all the patients even if you haven’t seen them.*’ ( S3). Benefits extended beyond a reduction in exacerbations related to a patient’s primary condition. Following the MISSION Asthma programme, there was a 47% reduction in medicine use, including antibiotics, evidencing that this novel intervention also substantially reduced comorbidities in this population ( S5).

Improvements in quality of life

The benefits to patients’ quality of life and wellbeing have been significant. Patients have reported relief and reassurance in understanding their symptoms, and greater confidence in self-managing. One patient explained: ‘ [I have] wheezed...all my life. But [the programme] has enabled me, in my eighties, to be totally unwheezy. Whereas before, I never thought I could walk more than 250 yards without wheezing, with the medication and… exercising, I’m now more than happy to walk for 12 minutes.’ ( S6). This improvement in quality of life was long-lasting, seen in 75% patients six months after the MISSION Asthma clinics ( S5). Improvements to quality of life were recognised by healthcare practitioners, with one Respiratory Nurse Lead commenting: ‘ ...within the month, his [the patient’s] whole life had completely changed. It’s a transformation from someone who was housebound. The impact is clear. He is now mentally and physically well. I had these types of stories throughout the day.’ ( S3).

Identifying undiagnosed disease and at-risk patients

By providing screening questionnaires, physiological assessment and medical review, each programme identified patients with undiagnosed or uncontrolled respiratory disease. For example, of the COPD patients recruited in MISSION COPD, 24% were subsequently diagnosed with asthma, asthma-COPD overlap and even heart failure ( S7). Accurate diagnosis is key to management of symptoms and in preventing exacerbations. This is particularly important given the 3,700,000 people in the UK with undiagnosed COPD. Identifying those at high risk of having undiagnosed COPD enables earlier diagnosis and evidence-based chronic disease management. If this results in a 25% reduction in mortality in people who would otherwise have been admitted with undiagnosed COPD, it would save approximately 400 lives per year ( S4). All four programmes referred patients to hospital because of the severity of their condition, in some cases, patients had very serious diseases that may not have been detected otherwise ( S3).

Cost savings associated with reduced health services utilisation and benefits to national productivity

Breathlessness, MISSION Asthma and MISSION COPD programmes delivered significant reductions in health service utilisation, including reductions in unscheduled GP (84, 39, 48%), out-of-hours GP (100, 80, 98%) visits and visits to Emergency Departments (100, 67, 97%) ( S1). This reduction in health services utilisation, and requirement for medicines, results in cost savings of between GBP90 and GBP490 per patient ( S5, S7). This equates to projected savings in Wessex of GBP12,000,000 for asthma, and GBP1,200,000 - GBP5,900,000 for COPD. If the programmes were to be adopted nationally, projected savings would be GBP450,000,000 for asthma and GBP100,000,000 - GBP500,000,000 for COPD. Indirect cost savings are also significant. Most people with chronic respiratory diseases report breathlessness as being the major disabling symptom that interferes with everyday activities. A survey by the British Lung Foundation found that around 40% of people with lung disease are below retirement age and a quarter of these are unable to work, costing business an estimated 24 million working days in sick leave each year ( S3).

Changes to practice: management of chronic respiratory conditions in primary care

In addition to the education provided to patients, the programmes provided education to healthcare practitioners working in primary care through the provision of diagnosis and therapeutic guidelines, a guided consultation template and videos on respiratory consultation, breathing control and mucus clearance. Across the four programmes, healthcare practitioners at 17 GP surgeries in Hampshire received these resources and training. Testimonials reflect that this upskilling led to an increased confidence and satisfaction: ‘In the GP surgery – there’s been lots of learning. You’re just more aware of approaches to take to breathlessness symptoms. We’ve been taught better procedures, like inhaler techniques. That’s something quite big really because if patients aren’t taking their inhaler properly, they aren’t getting their medication.’ ( S3)

Developments since MISSION: community-based education for respiratory conditions and other chronic conditions

Recognising the value of education in improving symptom management and reducing healthcare utilisation, an ongoing clinical trial, ESMENA (Education, Self-Management and Empowerment in exacerbatioN prone Asthma, April 2018 to December 2021; ISRCTN17338269) is evaluating an education programme aimed to reduce asthma exacerbations. As with MISSION programmes, ENSEMA utilises a multi-disciplinary team to deliver community-based education in order to improve asthma control, improve patients’ quality of life and reduce the incidence of respiratory crises and associated hospitalisations.

The team has also developed the Wessex Asthma Toolbox that contains clinical equipment, demonstration models, information and guidance to aid healthcare professionals to educate people with asthma. Distributed at educational events, the toolbox is in use in 107 of 120 GP surgeries in the Wessex region, benefitting approximately 120,000 asthmatics. In a survey to capture feedback following initial uptake, all 61 healthcare providers that responded said that they use the Toolbox for asthma reviews as a visual aid, educating colleagues and to assist in prescribing the correct inhalers (Primary Care Respiratory Update 2020). MISSION ABC offers a toolkit via their website ( missionabc.uk) that allows healthcare practitioners to implement MISSION-style assessment and care via specialist multidisciplinary clinics. The toolkit is recommended by NICE ( S4). Since 2017, at least ten Clinical Commissioning Groups in England have implemented the MISSION approach for the management of chronic respiratory conditions, benefitting around 860,000 sufferers of asthma and COPD.

The MISSION model has been translated for the assessment and care of patients with other long-term conditions, including dementia and diabetes. MISSION Diabetes is being piloted in 2 GP practices. Its carousel model incorporates a single day of appointments with a GP, podiatrist, a dietician, diabetologist, diabetes specialist nurse, ophthalmologist and psychologist. The multidisciplinary team provides each patient with a personalised plan to manage his or her condition. MISSION Dementia, being piloted in a single GP surgery, integrates the GP, carer(s), secondary care and specialist support services to support patients and families following dementia diagnosis. 92% of participants agreed that they had a positive experience in the ease of access to the service, with one carer commenting: ‘ I feel the practice [has] been our main source of support since my mother’s diagnosis. The team has provided a great deal of knowledge, understanding and guidance that no other mental health service has offered.’ ( S8).

Recognition for MISSION programmes

The MISSION programmes have been shortlisted for numerous national healthcare awards. MISSION Asthma won HSJ awards for Value in Diagnostics (2015) and for Innovation in Primary Care (2016). MISSION COPD won a Patient Safety Award in 2016. The judging panel said: ‘If patients with severe COPD can be recognised before they arrive in hospital in a crisis, there is a lot that can be done to improve their lives, their health and the cost to the NHS of looking after these individuals. Portsmouth’s MISSION COPD does just that’. The Wessex Asthma Toolbox was nominated in two categories, ‘Respiratory Nursing’ and ‘Managing Long Term Conditions’, at the Nursing Times Awards 2019.

In summary, a one-stop assessment-and-care clinic delivers significantly improved symptom management and associated quality of life. In providing patients the means to effectively self-manage their conditions, the incidence of unscheduled admissions from crises is greatly reduced, massively reducing the impact on patients and healthcare infrastructure. This approach is now in use nationally and has been successfully applied in other long-term health conditions.

Having demonstrated the improved accuracy of AAC for detection of precancer and cancer compared to existing methods through the ABBA trial ( R6), the next step was to communicate benefits to other endoscopists. Key to this was the design of ABBA as a multicentre trial. Senior endoscopists working at the UK’s major centres for gastrointestinal medicine were able to evaluate its efficacy first-hand ( R6). Their junior colleagues were the naïve endoscopists that received training from Bhandari and his team ( R4). Observing both the benefits of the technique, and the ease by which a naïve endoscopist could achieve professional standards of competency in just one day of training, were persuasive arguments. AAC for BO quickly became routine practice in the UK’s major centres for gastrointestinal medicine, with trained Fellows now working at other UK sites and using AAC routinely. Outside of the UK, uptake was driven by the international endoscopists who assessed the PREDICT protocol ( R5) and by significant efforts of Bhandari and colleagues to disseminate at major international conferences (ESGE Days Congresses; British Society of Gastroenterology Annual Meetings; International Digestive Disease Forum; Congreso de la Sociedad Española de Endoscopia Digestiva) and train virtually, with live streaming of cases (Endoport.org, Jan. 2020).

With improved accuracy of detection of oesophageal cancer compared to existing methods, the US and European professional bodies went on to recommend that AAC be used in BO surveillance, replacing the use of random surveillance biopsies ( S1, S2). The American Society of Gastrointestinal Endoscopists has more than 15,000 members worldwide, provides the highest standards for endoscopic training and practice and is the foremost resource for endoscopic education. They endorse the method ( S1), concluding: ‘ Our meta-analysis indicates that targeted biopsies with acetic acid chromoendoscopy... meet the thresholds set by the ASGE PIVI (Preservation and Incorporation of Valuable endoscopic Innovations), at least when performed by endoscopists with expertise in advanced imaging techniques. The ASGE Technology Committee therefore endorses using these advanced imaging modalities to guide targeted biopsies for the detection of dysplasia during surveillance of patients with previously nondysplastic BE [Barrett’s oesophagus], thereby replacing the currently used random biopsy protocols’.

Dr Cesare Hassan, Head of the Guidelines’ Committee for the European professional body (2013 – 2017), confirms that ‘All major European centres providing specialist Barrett’s service are now using acetic acid [AAC] as an adjunct to help detect and delineate Barrett’s neoplasia.’ ( S3)

By providing earlier detection, at the precancer stage, achieving more accurate detection than previous methods, being easy to learn to professional standards and applicable to any endoscope, AAC has achieved the following impacts:

1. Patient Benefit

More accurate detection means fewer advanced cases of oesophageal cancer. The means to identify precancerous and cancerous cells based on the time it takes for acetowhitening to fade was a significant discovery ( R3) by the team, benefiting patients through ‘highlighting [precancerous or cancerous] areas that otherwise would be missed’ using standard endoscopy ( S4) and significantly improving prognosis by early interventional surgery to remove the abnormal tissue. The consequences of failing to detect precancerous cells are catastrophic for the patient, with the annual progression from precancer to oesophageal adenocarcinoma up to 40% and, from diagnosis, there is a <15% five-year survival rate.

Early identification of precancerous cells allows removal by a minimally-invasive procedure, significantly reducing risks. Precancerous cells detected by AAC can be removed by a surgical intervention which is, in most cases, minimally-invasive and endoscopic-led. Previously, in the absence of a reliable means for the early detection of abnormal tissue, oesophageal adenocarcinoma was detected at a later stage in development and oesophagectomy was the only means to remove cancerous tissue. Oesophagectomy is significantly riskier, with up to 20% mortality and 30-50% of patients developing at least one serious postoperative complication such as pneumonia, arrhythmia, myocardial infarction or heart failure. In stark contrast, minimally-invasive endoscopic-led procedures have no mortality or major complications. Unlike oesophagectomy, which has an average hospital stay of 2 weeks, the majority of patients undergoing endoscopic-led procedures can return home the same day.

Treatment where it was not previously possible in older adults and those with underlying disease. A third of BO patients are 70 years old and above. As age increases above 70 years, oesophagectomy-associated risks of mortality and major complications rise steeply - a trend not observed for minimally-invasive, endoscopic-led procedures. A third patient benefit is therefore treatment where this was previously not possible, as the highly significant reduction in risk of an endoscopic-led procedure permits intervention in older adults with comorbidities where oesophagectomy would previously have been contraindicated.

Regular surveillance is painless and ensures patients can live their lives unaffected. Patients with BO have periodic surveillance, comprising endoscopic inspection of the oesophagus with AAC. Knowing that AAC is highly accurate in identifying precancerous and cancerous cells gives patients peace of mind. One patient described AAC as ‘ completely painless… [allowing] the clinician to correctly diagnose my condition at the time and remove the nodule via endoscope. Since that day and all the follow-up procedures, I always swallow this mixture just prior to having the scope. This is one of the main reasons I still have my oesophagus and have not had to have an esophagectomy, due to early diagnosis and of course the treatment I received via endoscope.’ ( S5).

2. Cost savings to the healthcare system

As a more efficacious means of diagnosis, AAC has a number of benefits to the healthcare system:

• When compared to periodic monitoring of BO patients with endoscopic inspection and spaced biopsies for histological assessment, there are significant financial savings (of up to 97% or >GBP1,000 per patient) with an approach that biopsies only the abnormal regions identified by AAC ( S6). Based on approximately 1,500 AAC procedures for BO from 2013 to 31 July 2020 at the Royal Bournemouth Hospital ( S4), this equates to a GBP1,600,000 saving compared to spaced biopsies with histological assessment.

• The greater use of minimally-invasive, endoscopic-led procedures to remove precancerous cells - replacing more complex and risky oesophagectomy to remove cancer developed at a later stage in its development - was identified to save >GBP90,000 and 170 bed days a year at the Queen Alexandra Hospital, Portsmouth ( S7).

3. The simplicity of AAC means that naïve endoscopists can be trained to professional standards in single day

Naïve endoscopists with experience of endoscopy of BO patients but with no formal training in AAC are able to develop professional standards of competency following online training and a one-day interactive seminar ( S8). Once trained, endoscopists miss just 2% of cancer using AAC, compared to a 41-66% miss rate with the standard practice of random sampling. For a medium-sized hospital such as Leicester General Hospital which performs around 150 AAC procedures on BO patients a year, this equates to up to 96 patients a year in which early stage oesophageal cancer would simply have been missed. An endoscopist based in Hungary commented ‘It can help clinicians to identify precancerous lesions and early cancer with great confidence.’ ( S9)

4. AAC for detection of precancer and cancer in BO has changed endoscopy practice and policy

The final impact comes from the ease with which this technique can be integrated into standard endoscopic practice in gastroenterology. Acetic acid is inexpensive and, at a concentration of <3%, safe to patients and practitioners. It is non-proprietary and compatible for use with any endoscopy system. Given evidenced benefits - to the health of patients, in cost savings to healthcare systems, in ease of use and ease of integration into healthcare systems - AAC is recommended in BO by American ( S1) and European ( S2) professional bodies.

In summary, AAC allows earlier detection, at the precancer stage; it allows more accurate detection, compared to previous methods; it is easy to learn to professional standards and applicable to any endoscope. These characteristics produce significant benefits to the health of patients, in cost savings to healthcare systems, in ease of use and ease of integration into healthcare systems; and have resulted in changes in practice and policy.

The EXRC is the largest of three centres worldwide that provide biological and bioinformatic resources for studying Xenopus. All centres breed, hold and distribute wild type, transgenic and mutant animal lines but the EXRC supports the needs of the international Xenopus community in three unique ways:

(i) it is the world’s sole centre for the collection, characterization and distribution of quality- assured molecular resources relating to Xenopus research;(ii) it provides on-site service and training for one-off projects to non- Xenopus researchers;(iii) it offers a ‘research hotel’ facility where visiting scientists can access the EXRC infrastructure and expertise and perform experiments.

Since 2014, and in response to priorities set by the Xenopus community (Xenopus White papers 2011, 2014), the EXRC has expanded its suite of molecular resources and services to include: testing, curation and distribution of Xenopus-specific antibodies; curation of a library of large sequences of frog genome; generation of novel transgenic Xenopus lines; and combination of gene editing and protein-tagging techniques to improve the detection of specific proteins ( G4, G5). All EXRC resources are globally accessible via the EXRC website and Xenbase, the Xenopus bioinformatic knowledge base. Over the last three years, the EXRC has supplied resources to over 180 laboratories in 25 different countries in the UK, Europe, North and South America and Asia. Measured by growth in annual income from sales of frogs/products supplied at cost, demand has doubled over the last two years and continues to increase, indicating its significance within the research community.

Refinement and reduction of numbers of Xenopus used in research

The concentration of frogs at a single, central and closely monitored site has impacted positively on Xenopus welfare and has reduced the numbers of adult animals held globally. The [text removed for publication] confirms that ‘ the EXRC has made significant contributions to improvements in Xenopus welfare through reduction in animals used, refinement of research techniques and training for research personnel’ ( S1). Over the last 3 years, EXRC staff have spent a total of 150 days visiting research laboratories in the UK, Europe and the US to provide training and expert advice on animal husbandry. The Executive Director, Institute of Molecular Biology, Mainz, Germany confirms that EXRC resources and frog husbandry advice ‘…. constitute an irreplaceable platform for the international Xenopus community at large’ ( S2). Sperm freezing and streamlined oocyte preparation procedures developed at the EXRC have reduced the number of animals needed to provide the same volume of bioresources. Additionally, transport as sperm or eggs eliminates stress on live animals and offers cost savings to researchers and funding bodies. Since the beginning of 2014, the EXRC has supplied 1,400 batches of oocytes and, since 2018, shipped 200 testes and 1,500 batches of frozen sperm to laboratories around the world. As a result, several laboratories have discontinued hosting local colonies of adult frogs and now obtain all of their Xenopus bioresources from the EXRC, thus reducing the total number of adult animals in captivity ( S3). The EXRC actively promotes the uptake of 3Rs techniques. For example, the EXRC sperm freezing protocol ( R3) was presented to UK and international audiences at the European Amphibian Club, Rennes (June 2017), the NC3Rs/Zoological Society of London Workshop on Amphibian Welfare (October 2017) and the Xenopus Genome Editing Workshop, Woods Hole (October 2019). A video on ‘Using Frozen Sperm’ is available on the EXRC website: https://xenopusresource.org. Between April and December 2019, EXRC staff visited key research centres in the UK (Universities of York, Cambridge, Aberdeen and UCL) and Europe (CNRS Paris, NHM Paris, DKFZ- Heidelberg, Munich Medical School, Barcelona Medical School, University of Ghent) to train researchers in the use of frozen sperm. Further visits and a workshop in Portsmouth planned for 2020 were curtailed by COVID-19.

The EXRC has driven the incorporation of ‘3Rs’ into policy and practice

The EXRC has led on community initiatives to extend and embed the ‘3Rs’ into national and international guidelines on the use of Xenopus in research. In 2019, and based on expert advice from the EXRC, the NC3Rs published a new checklist to assess the welfare standards in research proposals involving the use of X. laevis or X. tropicalis ( S4). Adherence to this checklist is required to meet the expectations of all major UK public funders of Xenopus research conducted in the UK and overseas, in accordance with UK legislation, ‘Responsibility in the Use of Animals in Bioscience Research’. The EXRC also acts as a "hub" for the Xenopus research community in the UK and Europe and lobbies to influence international policies on its behalf. Currently, the European Commission is undertaking a risk assessment to designate Xenopus as an Invasive Alien Species, based in part on concerns about transmission of amphibian diseases to native species. Such a designation would significantly restrict the use of Xenopus in research. In April 2019, Guille submitted a community response that confirmed the implementation of improved biosecurity measures at laboratory and breeding facilities in the UK and Europe (based on R2 and led by the EXRC), and provided a robust evidence base for Xenopus as a key model for biomedical and environmental research, with significant socio-economic benefits ( S5). A revised Commission proposal has been delayed by COVID-19 but is expected in summer 2021.

Improvements in the efficiency and competitiveness of the national and international Xenopus research base

National investment in Xenopus research resources has yielded an outstanding return in published new discoveries benefitting science, medicine and society. A PubMed search using the term “ Xenopus” retrieves over 4,500 papers in the last five years: UKRI Gateway to Research identifies 17 active Xenopus projects totalling GBP3,900,000 (09/11/2020). The EXRC enhances the efficiency of research by Xenopus users' laboratories through:

(i) acting as a centralised curator of frog lines and reagents. The EXRC curates a full collection of reagents and animals from laboratories around the world: together with an efficient website and good administration, this enables the global science base to access Xenopus resources more efficiently, as well as reducing the time and effort spent by producer laboratories on sending out reagents. Since 2014, the EXRC has also ‘rescued’ valuable and expensive reagents generated by laboratories that are downsizing or when research leaders retire, including antibodies, large collections of plasmids, fosmid libraries and key Xenopus lines. Without these efforts, these reagents would be lost to the research community and their replacement would require significant time and resource.

(ii) saving costs associated with keeping local Xenopus colonies. The cost of keeping a Xenopus colony of 20 animals, with suitable technical support, is in the region of GBP25,000 p.a. compared to GBP4,500 to obtain equivalent bioresources from the EXRC. Dr Ian Mellor, whose research develops leads for new drugs for Alzheimer's disease, confirms ‘ when the EXRC made quality-assured oocytes available, we stopped keeping our own Xenopus colonies altogether. (This) …was not only more cost effective than housing our own animals, but also provided greater experimental efficiency by removing a step in the protocol’ ( S3).

(iii) providing quality assured frog lines and molecular reagents. This saves both time and money for research laboratories and for funders of research. Prof Jeremy Green at the Centre for Craniofacial & Regenerative Biology, KCL, sources wild type frogs, frozen sperm and shipped testes from the EXRC for a project, funded by the NC3Rs, that promises to halve the number of Xenopus used for fertilisation and embryological study worldwide. He confirms ‘ The validity of our results depends absolutely on the consistency of the animals and of the sperm or testes… ‘ and ‘having the frozen sperm protocol and shipped testes (not available elsewhere) has had a huge impact on my ability to deliver worthwhile results' ( S6).

(iv) offering facilities, expertise and training to visiting researchers: between 2018 and 2020, over 60 scientists attended the EXRC research hotel for a total of 190 days. In this way, the EXRC delivers highly skilled scientists who are knowledgeable about the 3Rs and, for researchers who lack the facilities or knowledge at their home institution, the ability to access high-quality, specialised resources and to generate pilot data that is vital to their research careers. Data generated at the EXRC by Dr James Cobley, an early career researcher, has underpinned key publications and successful grant applications. He says ‘my work is only possible because the EXRC exists. It is, therefore, difficult to overstate the profound impact EXRC has had on my

research programme’ ( S7).

Enhancing the capability and competitiveness of international CROs

Xenopus development is highly sensitive to environmental changes. In June 2018, concerns over the safety of chemicals with endocrine-disrupting properties, found in pesticides, pharmaceuticals and household products, prompted relevant European authorities to issue new regulatory guidance. This included two Xenopus-based tests as mandatory components for registration of pesticides and biocides in Europe. Consequently, contract research organisations (CROs), which regularly undertake regulatory testing, had to rapidly extend their testing capacity and capabilities in order to continue to provide a full-service portfolio in environmental toxicology. Since July 2019, the EXRC has supplied Xenopus embryos to three globally-significant CROs: Covance, Charles River Laboratories (CRL) and ibacon. The Study Director Environmental Sciences, CRL, confirms ‘ This high quality supply is essential for us and our clients. Alternative quality sources of Xenopus are not available and to keep our own frogs would be too time consuming and costly. Our ability to source embryos from the EXRC has enabled CRL to meet demand from the market, increase our testing capacity and helps to create a safe environment’ ( S8).

Transforming the speed and accuracy of diagnosis of rare genetic diseases (RGDs)

There are over 6,000 known RGDs and 7% of the UK population is affected by an RGD, mainly as children. Despite transformational advances in mapping genome sequences, there are critical difficulties in linking a genetic change observed in a patient to their disease with sufficient certainty to allow clinical intervention. Delays in diagnosis are critical: more than half of children with an RGD will die before their 5th birthday (Blencowe et al, 2018), whilst 5-year survival rates rise to 80% upon diagnosis, and the patient’s family suffers, with 83% needing support for their mental health. ‘ Research by the team at the EXRC using the Xenopus model has clarified variants of unknown significance found in genomic clinical testing and has enabled clinicians to describe two new syndromes by proving that variants found in two genes that were never associated with a human disorder were, in fact, causal. This insight is critical for clinicians to be able to develop targeted interventions for treatment or management’ ( S9). Additionally, the speed with which results from the Xenopus studies are available has significant impacts on the speed of diagnosis and offers the potential for screening and prenatal diagnosis. ‘ This impacts patients through changes in clinical management, facilitating prenatal diagnosis, allowing relevant health screening and family cascade testing, as well as ending the diagnostic odyssey that many families go through’ ( S9).