Impact case study database

The Cardiff team designed and implemented a new comprehensive care package for PPH. This was initially developed in Cardiff, then rolled out across Wales in a national quality improvement programme called the Obstetric Bleeding Strategy for Wales (OBS Cymru). It is now being integrated into clinical practice in Scotland and England. The research also changed international clinical guidelines on PPH.

The new Cardiff-designed PPH care package, developed at the University Hospital of Wales, Cardiff and Cardiff University between 2013 and 2015 [5.1], involves the following 4 stages:

1. risk assessment of all cases on arrival on delivery suite;

2. quantitative measurement of blood loss during childbirth using volumetric and gravimetric techniques [3.1];

3. escalation of care to senior clinicians at specified volumes of blood loss, with a senior midwife informed at 500mL, an obstetrician and anaesthetist required to attend at 1,000mL and a consultant obstetrician and anaesthetist informed at 1,500mL;

4. point-of-care FIBTEM testing and targeted, early replacement of fibrinogen and conservative use of FFP based on application of a standardised and validated algorithm [3.4, 3.6, 5.2].

4.1 All-Wales implementation: OBS Cymru

The implementation of the PPH care package in Cardiff resulted in an 83% reduction in massive PPH (bleeds ≥2,500mL). In addition, the number of mothers requiring a blood transfusion fell by 32%, and transfusion of ≥5 units of blood and FFP transfusion both fell by 86% [5.1]. Eighteen months after the end of the pilot, the overall incidence of massive PPH, blood transfusion ≥5 units or FFP transfusion was 2.8/1,000, compared to 6/1,000 elsewhere in the UK [5.1].

Following the positive health outcomes seen with the care package, it was rolled out across Wales (between January 2017-December 2018) in a national quality improvement programme (OBS Cymru) [5.2]. The programme included all maternity units in Wales, covering hospitals varying in size, complexity of cases, and staffing levels, and introduced point-of-care testing into every obstetric unit in Wales [5.2, 5.3]. The OBS Cymru care package led to major clinical health benefits in Wales as follows:

• By December 2017, the care package had been adopted by all maternity units with quantitative measurement of blood loss being used for 98% of deliveries [5.4].

• Incidence of massive haemorrhage fell by 23% with a 29% reduction in women progressing from early to massive bleeding. This equates to 46 fewer women a year experiencing massive haemorrhage after childbirth [5.4].

• The number of women requiring a blood transfusion fell by 23%; equating to 164 women avoiding transfusion each year, a reduction of 390 units in total blood transfused [5.4]. Further, massive blood transfusions (≥5 units) fell by 30% [5.4].

• 42% reduction in the number of women receiving FFP compared to standard guidelines, with no adverse effects on blood clotting [5.4].

• 29 senior clinicians noted that OBS Cymru had changed both individual and unit level management of PPH, including “awareness of ongoing blood loss” and “consistent management” [5.4].

• Feedback showed that 95% of women felt well supported during bleeding [5.4]

• Although hospital stays were sometimes marginally longer (1-2hrs on average), the care package itself was cost neutral across Wales [5.5].

Following the success of OBS Cymru, the Welsh Government issued a Health Circular in 2019 (WHC/2019/012) requiring all hospitals in Wales to embed the OBS Cymru care package into routine clinical practice [5.6].

The importance of OBS Cymru was recognised by the MediWales Innovation awards Efficiency through Technology Programme (December 2017), the NHS Wales Awards for Promoting Clinical Research and Application to Practice (September 2018), the NHS Wales Midwifery and Maternity awards for OBS Cymru champion midwives (2019) and the British Medical Journal Innovation in Quality Improvement Category awards (June 2019).

4.2 Implementation of OBS Cymru practice across the UK

Following the positive outcomes observed in Wales, the care package was implemented across Scotland as part of the Scottish Patient Safety Programme [5.7]. The OBS Cymru approach is also part of a larger package of changes being implemented by NHS England to “ improve the early recognition and management of deterioration of either mother or baby during or soon after birth”, via NHS Improvement in England [5.7, p.1 ], the quality improvement body for NHS England. The package document lists key aspects of the OBS Cymru programme, for example, targeting clinical training “to promote 4-stage PPH protocol” [5.7, p.4 ], and implementing “ the use of cumulative gravimetric measurement of blood loss” [5.7, p.6 ]. The package was implemented through the Maternity and Neonatal Safety Improvement Programme launched in July 2019. NHS England Trusts were split into three annual waves, with 44 trusts being supported to implement change in 2019, and a further 43 being supported in 2020; this schedule is currently under review as a result of COVID-19 [5.7].

4.3 Changing national and international guidelines on PPH

Cardiff research additionally led to the following changes in guidelines and consensus statements:

• The British Society of Haematology guideline on point-of-care clotting tests, co-authored by Collins, recommends using the OBS Cymru blood product treatment algorithm for bleeding after childbirth [5.8]. This is the gold standard care recommendation in this area of medicine throughout the UK.

• Royal College of Obstetrics and Gynaecology (RCOG) guidelines on the Prevention and Management of Postpartum Haemorrhage (2016 update), which Collins assisted in developing, now state that “ A plasma fibrinogen level of greater than 2g/l should be maintained during ongoing PPH” [3.2, 5.9]. Previous RCOG guidelines had recommended maintaining fibrinogen >1g/L during major PPH.

• Citing the RCOG guidelines, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) 2017 guidelines on the Management of Postpartum Haemorrhage (PPH) recommend giving “ particular” attention to fibrinogen testing by using point-of-care tests and providing cryoprecipitate or fibrinogen concentrate where the fibrinogen is <1.5-2g/L [5.10a].

• The International Society on Thrombosis and Haemostasis (ISTH), a leading international organisation, recommended a more conservative use of FFP and platelets [3.2, 3.4] in its Guideline on Management of Coagulopathy Associated with Postpartum Haemorrhage, authored by Collins [5.10b].

• The 2017 German PPH guidelines, compiled by the German, Austrian and Swiss Societies of Gynaecology and Obstetrics, cite Cardiff research [3.2] in their recommendation that: " a fibrinogen concentration <2g/l may identify those at increased risk for severe bleeding {consensus of the committee}" [5.10c].

Through their research into measured blood loss and rapid point-of-care fibrinogen testing for PPH management, the Cardiff team created an integrated new care package which provided clearer, standardised methods for monitoring blood loss, aligned to the provision of more timely and effective treatment. This reduced the incidence of massive and life-threatening PPH and the need for blood transfusion whilst preventing infusion of unnecessary blood products. The new care package was implemented across Wales, and more recently Scotland and England. The research findings also underpinned changes to international guidelines used to inform clinical management of maternal bleeding globally.

The clinical trials outlined in Section 2 provided critical evidence for new clinical guidelines enabling more effective treatment of patients with prostate cancer, aligned to their stage of the disease.

4.1 Informing clinical guidelines for shared decision making and refined radiotherapy treatment in localised prostate cancer

Before the ProtecT study [3.1, 3.2], many specialists believed that immediate treatment was superior to surveillance, meaning patients were being treated unnecessarily. Yet, side effects of surgery include 46% of patients needing to use incontinence pads six months after a prostatectomy, compared to only 4% who opted for active surveillance. ProtecT trial findings (namely that patients’ risk of dying is very low; that aggressive intervention was not always necessary; and that surgery and radiotherapy are equivalent in effectiveness) changed multiple clinical guidelines focusing on clearer communication of options alongside risks to patients, as well as shared decision making. These included:

• NICE guideline NG131: This underwent rapid review and update in 2019 to include the recommendation (1.3.7) that clinicians should “Offer a choice between active surveillance, radical prostatectomy or radical radiotherapy to people with low-risk localised prostate cancer for whom radical treatment is suitable” [5.1, p.13 ]. The ProtecT trial was one of 3 studies cited in the evidence underpinning the recommendation. It was the largest in terms of participants and the only one to consider radiotherapy as an alternative treatment to surgery [5.2, p.7 ].

• European Association of Urology (EAU) prostate cancer guidelines (6.1.1.4): This states that “…the ProtecT study has reinforced the role of deferred active treatment (i.e. either AS [Active Surveillance] or some form of initial AM [Active Monitoring]) as a feasible alternative to active curative interventions for patients with low-grade and low-stage disease” [5.3, p.35 ].

• European Association of Urology Editorial: This emphasises the importance of the ProtecT trial, stating “we now have level 1 data to help patients navigate the choice between active monitoring [active surveillance] and treatment, and to balance the risks and benefits of each” [5.4, p.8 ].

By giving patients the option for their cancer to be actively monitored, as outlined in these guidelines, patients are now able to avoid unnecessary treatment with harsh side effects that could significantly affect their quality of life.

Where radiotherapy is identified as the appropriate treatment for localised prostate cancer, the CHHIP study [3.3] provided the evidence for updates to guidance which recommend hypofractionation of doses. This approach meant that instead of daily treatment for six to seven weeks, a patient receives a higher daily dose for four weeks only. NICE Guideline 131 (1.3.17) recommends hypofractionated radiotherapy “unless contraindicated” [5.1]. The CHHIP study is referred to in the evidence review as a “key trial” [5.5, p.6 ]. Radiotherapy given over a shorter duration is now standard practice for localised prostate cancer, recommended by NICE, EAU, and National Comprehensive Cancer Network (NCCN) guidelines in the UK, Europe and North America.

4.2 Enhancing treatment in locally advanced prostate cancer

Prior to the MRC PR07 trial, locally advanced prostate cancer was frequently treated in the same way as metastatic disease, solely with hormone therapy. This was not based on clinical evidence. Following on from earlier recommendations cited in 2014 NICE guidelines (highlighted in the previous REF 2014 case study), PR07 findings were incorporated into NICE Guideline 131 entitled Prostate cancer: diagnosis and management which was published in May 2019 with recommendation 1.3.19 stating that clinicians should: “Offer people with intermediate and high-risk localised prostate cancer a combination of radical radiotherapy and androgen deprivation therapy, rather than radical radiotherapy or androgen deprivation therapy alone” [5.1 p.20 ]. This change to the NICE guideline and in clinical practice is underpinned by Cardiff research findings following the MRC PR07 trial, as detailed in section 2 [3.4, 3.5].

Following these changes to guidelines, an impact analysis estimated that alterations in UK patient treatment practice resulted in between 3,730 and 5,177 extra life-years at 15 years for a group of men diagnosed in a single year (7,930 men) [5.6]. As noted by Amini et al (2016) “The updated study results presented by Mason et al. […] confirms that local control of high-risk prostate cancer categorically improves survival at long term follow up” [5.7].

4.3 A change to the recommended therapy in advanced (metastatic) prostate cancer

STAMPEDE trial results [3.6] were translated into both the NCCN and EAU guidelines with approval for clinical use of agents, such as docetaxel and abiraterone, in this difficult to treat stage of the disease [5.2, 5.8a, 5.9]. As such, the worldwide standard of care is no longer conventional hormone therapy alone for patients with advanced prostate cancer. Two other randomized trials of docetaxel (GETUG 15 and CHAARTED) yielded conflicting results but the STAMPEDE trial convinced the medical community of docetaxel’s benefit due to its significant size, as well as evidence of an increase in median survival when patients were given docetaxel in addition to the standard treatment. This was underpinned by a non-Cardiff meta-analysis of all three trials [5.8b].

Tsao and Oh, Icahn School of Medicine at Mount Sinai, New York stated: “subsequent large randomized studies demonstrated a significant overall survival benefit with the addition of either docetaxel chemotherapy (CHAARTED, STAMPEDE) or abiraterone acetate plus prednisone (LATITUDE, STAMPEDE) to standard ADT in patients with metastatic, hormone-sensitive prostate cancer (mHSPC). On the basis of these data, a combination approach is now considered standard of care for mHSPC” [5.10].

In 2019, NICE guidelines were revised to reflect the STAMPEDE trial findings, recommending offering docetaxel to patients with mHSPC (Recommendation 1.5.6) [5.1, p.30. ], where previously it had only been recommended for hormone-insensitive metastatic prostate cancer. The implementation of these guidelines can also be seen in Scottish Government policy, where the STAMPEDE treatment recommendations were included in clinical quality performance indicators [5.11]. Over 87% of patients diagnosed annually (over 3,000 men per annum in Scotland) were treated according to the STAMPEDE standards between 2015 and 2018 [5.11].

In summary, Cardiff’s contribution to four robust clinical trials provided clear research evidence that changed clinical guidelines and practice for prostate cancer patients at all stages of the disease. These changes in clinical practice have led to better quality of life for patients and improved survival rates.

The Cardiff team’s research on the molecular mechanisms underlying tumour growth in TSC patients, and the effectiveness of mTOR inhibitors to reduce tumour growth, resulted in changes to international disease management guidelines. Their work also provided the basis for a successful lobbying campaign by the UK charity, the Tuberous Sclerosis Association, for the NHS to commission mTOR inhibitors for TSC patients.

4.1 International guidelines

Cardiff research contributed to the 2013 publication of Surveillance and Management Clinical Guidelines, developed from the 2012 International Tuberous Sclerosis Complex Consensus Conference. The new international guidelines recommended mTOR inhibitors as first line treatment for renal angiomyolipomas and are considered the international standard for clinical management of TSC [5.1]. Referring to the Cardiff research paper [3.5], the guidance states that: “For asymptomatic, growing angiomyolipoma measuring larger than 3 cm in diameter, treatment with an mTOR inhibitor is the recommended first-line therapy” [5.1, table 3, p.19 ].

The Tuberous Sclerosis Alliance (TS Alliance) is a US-based charity which commands a multi-million-dollar research budget and aims to improve treatment options, access to care and awareness of TSC both in the US and internationally. The TS Alliance sponsored the development and dissemination of these guidelines, and in describing Cardiff’s role, notes: “ The evidence provided by Cardiff University’s research was an essential factor in the process leading to the change in policy and clinical practice that has now become established globally” [5.2]. In 2017, the TS Alliance awarded Sampson their highest honour, the Manual R. Gomez Award, in recognition of Cardiff’s impactful research [5.2].

4.2 NHS clinical commissioning policy statements on everolimus

Prof Bissler summarised the importance of Cardiff research in the approval of mTOR inhibitors, including everolimus, as a treatment strategy for TSC: *“Following [Cardiff] work identifying and characterizing the TSC2 gene my group in Cincinnati and yours in Cardiff undertook phase IIb studies to establish initial evidence for safety and efficacy of sirolimus treatment for this important manifestation of TSC **[3.5]*…These foundational studies lead to our registration trial using everolimus, and finally the approval of such mTORC1 inhibitor therapy” [5.3, 5.4].

In 2015, NHS Wales was the first UK health service to commission mTOR inhibitors for the treatment of angiomyolipomas in TSC, prior to appraisal of everolimus by NICE [5.5]. This included a 2-year deal with Novartis, who agreed to invest £1.3M to run an observational study of patients being treated with everolimus, as part of plans for future appraisal of the treatment [5.5].

Despite the commissioning of mTOR inhibitors for Welsh patients, access to treatment in England required individual patient funding requests (IPFR) to access the drug. The Tuberous Sclerosis Association, a UK charity representing TSC patients, discovered that IPFRs for mTOR inhibitor treatment were rarely successful, with fewer than 5 approved in 2014-2015 [5.6]. Following the success of trials, including Cardiff’s TESSTAL trial, the Tuberous Sclerosis Association lobbied and campaigned for mTOR inhibitors to be commissioned by NHS England for the treatment of TSC patients in England [5.6]. As a result, in 2016 NHS England: “reviewed the evidence and concluded that it is sufficient to enable everolimus (Votubia®) to be routinely commissioned and therefore available to children from three years of age and adults with TSC-associated AMLs” [5.7]. The evidence described in the commissioning statement included the Cardiff-led TESSTAL trial [3.5, 5.7].

4.3 UK guidelines for management and surveillance of TSC

Sampson was an author of new 2019 UK Guidelines for Management and Surveillance of TSC, which were developed through repeated online surveys of 86 UK clinicians and researchers, as well as consultation with the Tuberous Sclerosis Association. The two surveys constituted a Delphi process, by which a consensus was reached [5.8]. Cardiff research [3.4, 3.5] underpins these UK guidelines, which state that “ There was a consensus that growing AMLs measuring ≥3cm in diameter should be treated with mTOR inhibitors”. These were the first UK guidelines to be produced on management of TSC, with the importance of these guidelines noted by the Tuberous Sclerosis Association on their website: “ Publication of the UK TSC clinical guidelines was a defining moment in the diagnosis, treatment and management of people living with TSC, with the guidelines helping to drive improvements in the consistency and quality of care that people with TSC receive from the NHS” [5.9].

4.4 Improved patient outcomes

In addition to Cardiff’s trials into mTOR inhibitors for treatment of TSC, retrospective and prospective studies conducted by other centres showed that TSC patients treated with mTOR inhibitors showed shrinkage of renal tumours and a greatly reduced risk of bleeding, confirming significant patient benefits from the research [5.4].

As further evidence, the Tuberous Sclerosis Association estimated that up to 11,000 people in the UK live with this challenging condition, and describe the improvements to patients’ quality of life: “The impact of successful treatment of renal angiomyolipoma with mTOR inhibitors on patient quality of life has been immense as the treatment can be taken by patients orally within the comfort of their home, while previous surgical and embolization approaches required hospital admission and caused permanent damage to renal function. As it is directed to the underlying disease mechanism, the treatment also benefits patient’s skin lesions and epilepsy, further contributing to improvement in quality of life” [5.10].

Prior to Cardiff’s development of the DLQI, including the generation of validated score bands for enhanced clinical use [3.1], there was no simple, and standardised quality-of-life measure for the clinical assessment of dermatological conditions. Highlighting the vital importance of the DLQI, the World Health Organisation notes that the questionnaire “ is currently the most frequently used method of evaluating quality of life for patients with different skin conditions” [5.1, p.18 ]. Further systematic review validated the DLQI as the most commonly used instrument for quality-of-life assessment in psoriasis [5.2].

The 2005 publication of new, simple, quality-of-life assessment bandings accelerated DLQI’s use in clinical settings, including increased use of the DLQI by the pharmaceutical industry as part of drug development studies. Inclusion of the DLQI in critical national and international guidelines, as well as the successful move towards a digital format (see section 4.2), further extended the reach of the tool, across multiple countries, generating new income for Cardiff University.

4.1 Increased use of the DLQI in drug development and clinical trials

During this REF period, 1601 licences for the DLQI were issued, of which 826 were for commercial use, generating revenue of over £3.5 million (with annual revenue increasing year on year) [5.3]. Since Cardiff’s validation of the e-format DLQI in 2017 [3.4], 314 requests were granted for use of an e-format DLQI between 2018 and 2020, compared to 82 requests between 2013 and 2016 prior to validation [5.4]. Licenses purchased by pharmaceutical companies are typically used for clinical trials, contributing to the successful development approval of novel biologics for dermatological conditions. For example, the DLQI was a key patient reported outcome measure in the Sanofi funded Phase III trials SOLO 1 and 2, CHRONOS and CAFÉ, which tested the effectiveness of dupilumab in patients with moderate to severe atopic dermatitis [5.5]. Based on successful trial outcomes, dupilumab was approved for use by NICE with the DLQI recommended as the sole quality of life measure for treatment efficacy [5.6]. Furthermore, the trials made use of the new Cardiff-led MCID score of 4 rather than 5 [3.3], ensuring patient benefit from dupilumab intervention was accurately recorded.

The Cardiff team’s new validated method to calculate EuroQol (EQ-5D) data and utility values from DLQI scores [3.5], which then feed into health economics analyses, has been requested 15 times by pharmaceutical companies and researchers undertaking clinical trials in this REF period (detailed information cannot be provided due to confidentiality agreements) [5.4].

4.2 Inclusion of the DLQI in national and professional guidelines

The DLQI is utilised worldwide and forms part of national guidelines and treatment registries for a diversity of dermatological conditions in 45 countries. Thirty-one of these country guidelines/registries are new recommendations added between 2014 and 2019, a more than 100% increase from the last REF period. Additional countries since the prior REF 2014 case, with national guidelines that recommend use of DLQI for skin diseases, include the USA, New Zealand, China, Germany, France, as well Brazil, Chile, and Venezuela [5.7].

As noted in the REF 2014 case, NICE recommended the use of the DLQI for clinical monitoring and informing clinical decisions of patients with severe psoriasis and hand eczema in England and Wales. Within the current REF period, the DLQI score was additionally included as part of recommendations in 15 further NICE Technology Appraisals and Evidence Summaries, as a clinical threshold for treatment decisions or sensitive indicator of response for other dermatological conditions (e.g., atopic dermatitis, hidradenitis suppurativa, psoriatic arthritis, hyperhidrosis and rosacea) [5.6]. Additionally, the NICE clinical guideline for psoriasis (CG153) was reviewed in late 2017, with the DLQI the single assessment measure noted for use in the condition, specifically as a “ validated tool to assess the impact of any type of psoriasis on physical, psychological and social wellbeing” [5.6].

4.3 Establishing global use of the DLQI

Over the REF period, there have been a further 34 validated translations of the DLQI, and it is now available in 125 languages [5.8]. As a result, the DLQI has now been used in research studies and clinical trials in 62 countries, covering over 70 diseases.

The DLQI was recommended as a core outcome measure for all clinical research studies and in the assessment and management of atopic eczema by the Harmonizing Outcome Measures for Eczema (HOME) group [5.9]. HOME includes over 300 members across the world (e.g., patients, healthcare professionals, journal editors, regulatory authorities and pharmaceutical companies) and focuses on identifying the best consensus-based outcome measures for clinical research and management of atopic eczema [5.9].

The critical importance of the DLQI is further illustrated by its wide use as the “gold standard” with which to cross validate new measures, with 44 published new measures validated against the DLQI within the 2014-2019 period [5.10]. These measures include both patient-reported outcome measures and other disease activity measures, and cover conditions such as alopecia, atopic dermatitis, albinism, and non-melanoma skin cancer.

Since REF2014, the DLQI has become a widely used international assessment tool, benefiting a wide range of stakeholders, including patients, clinicians and pharmaceutical companies. This is reflected in its inclusion in a large number of guidelines worldwide. As a critical outcome measure for drug development and clinical trials, licensing revenue increased over the REF period. The critical role DLQI plays in routine clinical practice is well-evidenced, with an editorial from the Journal of the European Academy of Dermatology and Venereology stating: “Andrew Finlay and his team have given a voice to all our patients in everyday consultation. This contributes to a new way of practicing medicine and dermatology, putting the patient in the centre, making a person-centred consultation” [5.11].

Cardiff research on hidradenitis suppurativa (HS) informed National Institute for Health and Care Excellence (NICE) guidance, establishing adalimumab as a treatment of choice for HS. It also led to new British Association of Dermatologists’ guidelines, with new HS screening protocols and recommended treatment (adalimumab) for HS patients, whilst additionally setting the direction of a new research programme addressing clinical gaps in knowledge around HS.

4.1 New treatment approaches for HS

a. NICE approval for use of adalimumab in treatment of HS

Cardiff’s 2015 Cochrane review [3.2], which evidenced adalimumab’s efficacy for treatment of moderate and severe HS patients, informed the work of a NICE team as they undertook a Single Technology Appraisal (TA392) for the use of adalimumab as a treatment of HS. Ingram represented the British Association of Dermatologists (BAD), with Ingram’s evidence and research being cited over 25 times in the NICE Committee Papers [5.1]. Ingram was also a member of the Evidence Review Group commissioned by NICE which determined that adalimumab was cost effective for HS [5.2].

In 2016, NICE approved the use of adalimumab as the first biological drug intervention for HS in the UK [5.3]. A patient representative from the Hidradenitis Suppurativa Trust commented on NICE’s decision: “ When we were told last July that Adalimumab was licensed for HS, it was like a ray of sunlight. It means that those who were stage 2 and 3 could go to their GP and name a medication that could help” [5.1]. Prior to the NICE Technology Appraisal, clinicians were required to submit a funding request for each patient they wished to treat with adalimumab. This was a complex process with low rates of take-up by clinicians, resulting in few patients benefiting from the treatment. As Philip Hampton, Joint Lead for the Newcastle HS service, confirms: “ The NICE approval of adalimumab for the treatment of HS was a pivotal moment in the care of HS patients” [5.4]. This change led to a 3-fold increase in prescribing of adalimumab for HS (see section 4.2 for details of change on clinical practice).

b. Recognition of HS as a prevalent and serious condition by UK Department of Work and Pensions

Following the NICE approval, the UK Department of Work and Pensions formally recognised HS as a disability, enabling those affected by HS to apply for Personal Independence Payments and other benefits based on their diagnosis. To ensure translation of this change into practice, in 2015 the Department of Work and Pensions produced a training module to guide occupational physicians in their assessment of HS patients. This training was further updated in 2019 [5.5]. The training module cites Ingram and Piguet’s study on HS prevalence [3.2] and British Association of Dermatologist’s guidelines, which were developed by the Cardiff team (see section 4.1c) [5.6], the latter being named as a key resource for physicians in the training package.

c. British Association of Dermatologists (BAD) Guidelines

While the NICE appraisal was ongoing, Ingram chaired (with Piguet a key contributor) the British Association of Dermatologists’ (BAD) Guideline Development Group on HS. This group produced the first UK clinical guidelines for HS in 2018 [5.6].

The guidelines adhere to GRADE methodological standards, with BAD’s guidelines development process accredited by NICE. Based on Cardiff’s research demonstrating increased risk of depression and death from cardiovascular disease [3.2], a core recommendation in the guidelines was that HS patients be screened for depression and cardiovascular disease risk factors: [Recommendation 4] *: “Screen people with HS for associated comorbidities including depression, anxiety and cardiovascular risk factors (diabetes, hypertension, hyperlipidaemia and central obesity)*” [5.6, p.3 ].

Aligned to Cardiff’s research, in patients with moderate to severe HS, who were found to be “ unresponsive to conventional systemic therapy”, adalimumab was recommended as the frontline biological drug therapy for this patient group [Recommendation 13] [5.6, p.3 ].

In January 2016 Ingram was also asked by BAD to update their Patient Information Leaflet (PIL), taking into account new research outcomes. The updated PIL includes Cardiff research, for example, the recommendation to provide adalimumab as a treatment option. The leaflet also focuses on mental health ‘self-care’ options (e.g., stress management and joining a support group), as recommended by the research [5.7]. Provision of the new PIL to all diagnosed patients is recommended in the BAD HS guidelines [5.6].

Ingram was also author of two chapters on HS in UpToDate, a medical information repository. UpToDate is used by more than 1.3 million clinicians in 187 countries, including 90% of academic medical centres in USA. In 2018 alone, his Medical Treatment of HS chapter was viewed 214,000 times, with his HS Aetiopathogenesis chapter viewed 86,000 times [5.8].

4.2 Driving clinical practice change

The Cardiff team conducted baseline and follow-up surveys of dermatological practice (2014 [5.9] and 2019 [5.10] respectively). These were designed to assess the effects of NICE’s approval of adalimumab and the introduction of the BAD HS guidelines on frontline patient care. The survey found that dermatologists had positively amended their practice as follows [5.10]:

• For moderate to severe HS cases, 83% of dermatologists were now prescribing adalimumab compared to only 27% in 2014;

• Use of the vitamin A derivative isotretinoin (not recommended by the Cochrane review **[3.2]**) fell by nearly a half from 62% to 35%;

The impact of the NICE approval on clinical practice is described by Philip Hampton (Newcastle): “ as we identify patients at an earlier stage in their disease, we are seeing better responses with more patients going into remission and managing to resume a normal life. With previous limited treatment options, this was an extremely rare outcome” [5.4].

He further confirms that the NICE approval and the BAD guidelines led to a transformation of care for HS patients: “ Together, the approval of adalimumab and the BAD guidelines have hugely improved how clinicians approach managing and treating HS in their patients. I have also had the opportunity to see the improvements these changes have led to for HS patients. Improvements in diagnosis and a clear framework for treatment give patients greater confidence that the debilitating effects of their condition are recognised and can be managed. For many patients that I see, treatment with adalimumab brings alleviation of painful and distressing symptoms that have an extremely detrimental effect on quality of life” [5.4].

4.3 Setting a new research agenda and evaluating new treatments for HS

Through leadership of the HS Priority Setting Partnership the Cardiff researchers were instrumental in influencing allocation of public funds to HS research for the first time in the UK. The new funding was made available by the commissioning of a Health Technology Assessment (HTA) funding call, by the National Institute of Health Research, in 2018. HTA supports research and innovations of direct benefit to patients, clinical practice and policy makers, which must be immediately effective within the existing NHS care pathway. The research priorities identified by the HS PSP (chaired by Ingram) [3.3], and the research outcomes from Ingram’s 2015 Cochrane Review [3.2], were directly cited in the HTA briefing document [5.11] and provided the basis for the new £600K funding call.

4.4 Summary

Cardiff research resulted in NICE approval for adalimumab as a critical, and highly effective treatment for HS. New guidelines and recommendations altered clinical practice, evidenced by clear changes in dermatological treatment over the REF period, as well as improved patient access to disability payments and monitoring for associated health conditions. The research also supported establishment of a new funding scheme for health innovations for HS.

Cardiff researchers’ leadership of AML trials, and their robust meta-analysis of clinical trials involving Mylotarg®, provided the comprehensive evidence-base for the re-approval of Mylotarg® in the US, as well as its approval in Europe. The research also resulted in changes to international standards of care through NICE and the European Society for Medical Oncology. These impact outcomes delivered financial benefits for the NHS and Pfizer, and improved treatment options for AML patients globally.

4.1 Licensing of Mylotarg® in the United States and Europe

a. Re-approval for use in the USA

In 2017, Cardiff research was used in Pfizer’s submission to the FDA for the re-evaluation of Mylotarg®, aligned to changing the previous FDA license which limited the drug to relapsed patients over 60 years. The submission cites outcomes from AML15 and AML16 [3.1, 3.2], as well as a confidential Individual Patient Database (IPD) meta-analysis undertaken by Cardiff’s Hills at the invitation of Pfizer, specifically to inform the company’s FDA submission. This analysis, itemised in the FDA license, looked at overall survival and event-free survival from all randomised trials of Mylotarg® [5.1, p.37 ]. In the submission, it is acknowledged that “the Applicant [Pfizer] submitted an IPD Meta-Analysis to support the pivotal trial” and that the primary comparison came from “data [from the five trials, which] were provided to Dr. Robert K. Hills (Cardiff University) to perform the meta-analysis” [5.1, p.37 ].

Based on Pfizer’s submission, including Cardiff’s AML15 and AML16 trials showing positive outcomes in newly diagnosed and untreated patients [5.1], the FDA approved Mylotarg® “for the treatment of adults with newly diagnosed acute myeloid leukemia whose tumors express the CD33 antigen (CD33-positive AML)” [5.1, p.290 ]. The approval also covered treatment of patients aged 2 years and older with CD33-positive AML, where they experienced a relapse or were not responding to initial treatment [5.1, p.291 ]. The expansion of the patient criteria made Mylotarg® more widely available, effectively accessible to almost all the 21,380 new cases of AML diagnosed in the US in 2017.

b. Approval for use in Europe

Cardiff research further influenced licensing of Mylotarg® in the EU, as well as the European Society for Medical Oncology’s clinical practice guidelines on treatment algorithms. The research also delivered financial benefits for Pfizer and the NHS.

In April 2018, Mylotarg® was licensed by the European Medicines Agency (EMA) for use in the EU, specifically “for combination therapy with DNR and AraC for the treatment of patients age 15 years and above with previously untreated, de novo CD33‐positive AML, except APL” [5.2]. Cardiff’s trial data and meta-analysis formed a key part of the evidence base for this decision [5.2]. Specifically, the EMA’s analysis cited [3.4] as evidence that the benefits of Mylotarg® were not limited to the favourable cytogenetic risk group and could be extended to the intermediate risk group [5.2].

The current European license now includes patients with both intermediate and favourable cytogenetic risk who are commencing intensive chemotherapy [5.2]. This significantly expanded the proportion of newly diagnosed AML patients able to receive Mylotarg®. For example, in patients aged 66-75 years, while only 5% have favourable risk cytogenetics, 56% have intermediate risk cytogenetics.

Cardiff research on Mylotarg® efficacy also led to cost benefits for drug manufacturers and the NHS. For example, following the approval of Mylotarg® in the EU, Pfizer stated in their 2019 financial report that arrangements surrounding the licensing of the drug led to “a non-cash $17 million pre-tax gain…in the second quarter of 2018” [5.3, p.100 ]. Additionally, the AML18 and AML19 trials, which commenced in 2014, generated an overall cost-benefit to the NHS (e.g., estimated in an NHS 2014 Specialized Services Circular to be greater than £7.5M between 2014 and 2020 **[5.4]**). The cost-benefit arises from the Cardiff-led trials’ eligibility for Blueteq Approval funding in England [5.5 p.88 ].

4.2 New standards of treatment in international clinical guidelines

a. European Society for Medical Oncology

Cardiff research influenced both the August 2013, and 2020, versions of the European Society for Medical Oncology’s clinical practice guidelines for AML. In the 2020 guidelines, [3.1] is cited as evidence to support recommendations for treatment algorithms involving Mylotarg® as a first-line therapy for newly diagnosed adult AML patients [5.6 p.700 ]. The 2020 guidelines stated: “Our recommendation is based primarily on the meta-analysis [3.4] of five studies with GO (Mylotarg®), in which patients with CBF-AML …benefit most from the addition of GO [GO improved 6-year overall survival (OS) by 20.7% to an OS of 75.5% in this meta-analysis]” [5.6 p.702 ]. The 2020 clinical practice guidelines also cite AML17 [3.3] in recommendations for treating APL with all-trans retinoic acid (ATRA) and arsenic trioxide [5.6 p.706 ].

b. NICE Technical Appraisals

The Cardiff trial data was used by NICE as part of ‘Technical Appraisal TA545 Gemtuzumab ozogamicin [Mylotarg®] untreated acute myeloid leukaemia’ [3.4, 5.7]. Cardiff’s Knapper advised the TA545 Appraisal Committee that approved Mylotarg® for treatment of AML. In their submission to the NICE committee, Pfizer used pooled survival data from the Cardiff trials including AML15 and AML16 [3.1, 3.2] as well as the Cardiff meta-analysis [3.4]. The cost-benefit analysis in the NICE Appraisal uses the Cardiff research survival rate of 5% after five years (i.e., at five years, one extra patient in 20 is alive) [3.4, 5.7, p.112 ]. The Appraisal further notes the importance of Cardiff’s trial data, stating that the cost benefit was “derived using an analysis of pooled survival data from UK AML trials 10 to 16…performed by Professor Robert Hills (see Appendix M.4) which is ideally suited for calculating an excess mortality HR to better inform the economic evaluation of this submission compared to published literature” [5.7, p.112 ].

The findings of AML17 [3.3], with respect to beneficial treatment with ATRA plus arsenic trioxide, were also included as supporting evidence for NICE ‘Technical Appraisal TA526 Arsenic trioxide for treating acute promyelocytic leukaemia’ [5.8 p.9 ]. Outcomes from AML17 were further used as evidence to support the EMA’s 2020 decision to license arsenic trioxide for low-to-intermediate risk APL patients across Europe [5.9].

These decisions had far-reaching benefits on clinical practice. For example, Spearing, Haematologist at Christchurch Hospital in New Zealand noted: “As a result of the findings of Cardiff University-led research, we have implemented new standards in the treatment of AML in New Zealand patients” [5.10]. Specific changes to treatment from AML17 [3.3] “included … the use of arsenic trioxide and all-trans retinoic acid for low and standard risk acute promyelocytic leukaemia patients rather than the chemotherapy-centred Idarubucin and all-trans retinoic acid, which had been the previous standard” [5.10].

AML trials are now standard of care for patients in New Zealand [5.10], and Spearing noted that the new chemo-free regimen implemented in AML17 [3.4] “ resulted in a high cure rate with less relapse, and a lower requirement for ongoing supportive care of patients” [5.10]. She also highlighted positive outcomes for patients from the ongoing AML19 trial: “The minimal residual disease monitoring of AML19 has saved a significant number of patients undergoing allogeneic transplantation” [5.10], which is the most invasive and high-risk treatment for AML.

In summary, Cardiff’s leadership of AML clinical trials on Mylotarg®, and meta-analysis of different clinical trial outcomes, provided robust data used to inform expansion of licensing for Mylotarg® in the US and EU, and changes to treatment standards in clinical guidelines (e.g., NICE and the European Society for Medical Oncology). Ongoing trials informed by this research continue to save lives, actively leading to better outcomes for AML patients.

HGMD is the sector-leading database of disease-causing human gene variations. Several other centralised databases are available that record pathogenic variation, such as Online Mendelian Inheritance in Man (OMIM), ClinVar, dbSNP, and LOVD. The closest competitor, ClinVar, lacks depth compared to HGMD (in terms of variant and literature coverage) and obtains the majority of its pathogenic variant data via direct submission from clinical testing laboratories, thereby limiting its submission base. HGMD is the only database of pathological variants that approaches comprehensive coverage of the peer-reviewed literature, where there is evidence of clinical impact.

4.1 Commercial Market Position

Registered academic users (~150,000) can access a public version of HGMD for free (http://www.hgmd.org\), with a subscription version (HGMD Professional) distributed through QIAGEN GmbH via a Licence Agreement with Cardiff University (distribution was initially through BIOBASE, until QIAGEN GmbH’s acquisition of BIOBASE in May 2014) [5.1].

QIAGEN currently has more than 600 HGMD Professional subscribers across 51 countries worldwide. Dr Frank Schacherer, VP Products and Solutions at QIAGEN, confirmed that the customer base has continued to grow, and the compound annual growth rate of sales over the last five years was 18%, “ thanks to the University’s commitment to keep the database current, comprehensive and competitive” [5.2].

In July 2014, QIAGEN signed an agreement with BGI Tech Solutions Ltd, a subsidiary of BGI Group, the largest genomics organisation in the world. Under the terms of the agreement, BGI now provide HGMD data to the Greater China (Mainland China, Hong Kong, Macau, Taiwan) market as a distributor and provide first level support for the database within this market [5.3].

4.2 Use of HGMD by clients

Both HGMD and HGMD Professional have a wide variety of uses, and as a result, a broad range of end-users worldwide [5.1]. In 2016, surveyed users reported that they used the database to save time trawling through literature, to determine if an identified mutation had been previously published, and to quickly find known mutations for a specific gene, solving challenges such as workflow bottlenecks, delayed processing of patient samples, and prioritising correct mutations [5.4].

Schacherer stated: “ As the global use of genomics in research and development has increased, the Cardiff team has added content and functionality to HGMD to maintain its relevance and increase its utility” [5.2].

a. Private clients

Subscribers who use HGMD Professional to accelerate their diagnostic approaches, include John Hopkins University, Baylor College of Medicine, Mayo Clinic, MD Anderson Cancer Center, Scripps Research Institute, and the Children’s Hospital of Philadelphia. Feedback received by QIAGEN on the use of HGMD by clients includes:

• Dr Ali Torkamani, CSO Human Longevity Inc. (USA): “ HGMD Professional provides the most comprehensive database of human disease associations and is an invaluable resource in both clinical and research-grade genetics and genomics activities” [5.2].

• Dr Yaping Yang, Co-Director of the Baylor College of Medicine DNA Diagnostic Laboratory: “ We rely on HGMD® professional heavily for reporting our clinical tests” [5.5].

• Anonymous lab director at a health care company: “ It has provided up-to-date information about genes and mutations that help facilitate the interpretation of patient results. It is an excellent tool and saves me a lot of time” [5.4].

Schacherer also stated that “ I had one customer who operates a genetic testing laboratory tell me outright that they could not do their work without HGMD” [5.2].

LabCorp, one of the largest clinical laboratory networks in the world, incorporated HGMD within their QIAGEN Clinical Insight licence in 2019 in order to improve identification and interpretation of genetic variants within inherited diseases. Marcia Eisenberg, Chief Scientific Officer for LabCorp Diagnostics, stated: “ Having access to the most comprehensive and up-to-date catalog of known mutations augments our existing variant classification expertise. This will allow us to continue to provide physicians and researchers with the best possible test interpretations, advancing LabCorp’s mission to improve health and improve lives” [5.6].

b. Public Clients

HGMD data are used across the UK for diagnosis and prioritisation of candidate genes for disease analysis in a variety of NHS hospitals and foundations, including the Royal Brompton, Addenbrooke’s, and Great Ormond Street. [5.7]

At a national level, Genomics England, a company set up and owned by the Department of Health and Social Care, uses HGMD Professional to deliver the 100,000 Genomes Project [5.1]. This project has sequenced 100,000 whole genomes from NHS patients with rare diseases (~17,000 patients) and common cancers (~25,000 patients), as well as their families and a control group of volunteers with no known genetic condition [5.8].

The Director of Bioinformatics and Genomics England stated: “ Our experience of using QIAGEN’s HGMD for the 100,000 Genomes Project guided our decision to continue to rely upon this industry-leading resource …it is critical for healthcare providers to be able to interpret NGS data in the context of the vast body of knowledge from research and clinical experience. The exhaustive knowledge in HGMD enables us to do this, by providing the best possible care” [5.9].

During sequencing of genomes in the 100,000 Genomes Project, many examples of HGMD-listed mutations were noted, even for project donors from the general population who appeared healthy, in line with Cardiff’s research [3.3, 3.4]. These results were fed back to these participants via their hospital teams. As of March 2019, potential diagnoses were identified for approximately 3,300 (1 in 5) of the rare disease sufferers enrolled in the programme and for around 40% of those with intellectual disabilities. Clinical trials or more effective medicines were also identified for around half of the cancer patients enrolled (~12,500 patients), enhancing their care and increasing the chances of survival [5.8].

4.3 Summary

Cardiff’s HGMD has become a vital world-leading resource for a wide range of stakeholders (hospitals, companies, universities and governments) across the world, providing rapid access to up-to-date gene mutation data accelerating clinical research. This is evidenced by a significant increase in sales of HGMD Professional, diversifying and growing QIAGEN’s customer base, including provision of HGMD within Greater China for the first time.