Impact case study database

Sheffield research provided rigorous evidence that led to the introduction of adjuvant BPs into routine clinical practice and changes in national and international clinical guidelines and practice for the treatment of postmenopausal patients with early breast cancer. This resulted in reductions in bone metastatic disease, substantial cost savings for the NHS, and increased public awareness.

Changes to national and international guidelines regarding the clinical implementation of adjuvant BPs

The AZURE trial and EBCTCG meta-analysis underpinned changes in key national and international clinical guidance to include the use of adjuvant BPs in early breast cancer. Informed by Sheffield research, in November 2015 the UK Breast Cancer Group (UKBCG) endorsed adjuvant BPs as an urgent priority for implementation, recommending in their clinical guidance that “ adjuvant bisphosphonates should be considered for all postmenopausal breast cancer patients” [S1]. In addition, the Sheffield team developed guidelines on patient selection and prescribing, a patient information sheet, and a business case with financial modelling for Sheffield/South Yorkshire/North Derbyshire, which were also shared nationally and led to the adoption by centres across the UK [S2].

Drawing on [R2-R4] and [R6], the research team wrote 2 of 3 published international consensus papers on the clinical implementation of adjuvant BPs. The 2016 European consensus guidance recommended “ bisphosphonates as routine clinical practice in the prevention of metastases in patients with low levels of female sex hormones - age 55 and over and/or postmenopausal” [S3].

Sheffield researchers have a long-standing collaboration with Breast Cancer Now (BCN, the largest UK breast cancer charity) to carry out health economics assessments and to employ the underpinning research [R3-R6] in lobbying the Department of Health to make BPs available for the prevention of secondary breast cancer [S4, S5].

The UK National Breast Clinical Reference Group guidance, the open letters to the Department of Health [S5] and presentation of the research to NICE by Coleman, were used to provide evidence on the use of adjunct (adjuvant) bisphosphonates to NICE [S6]. In 2018, Nice Guidance (NG101): Early and locally advanced breast cancer: diagnosis and management recommended offering bisphosphonates (ZOL or sodium clodronate) as adjuvant therapy to postmenopausal women with node‑positive invasive breast cancer, and considering adjuvant BP therapy for postmenopausal women with node‑negative invasive breast cancer and a high risk of recurrence [S6].

In North America, the Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline recommends that, “ if available, zoledronic acid (4 mg intravenously every 6 months) or clodronate (1,600 mg/d orally) be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy” [S7].

Impact on the use of adjuvant BPs in regional and national routine oncology practice in the UK

Prior to 2016, routine commissioning for the use of adjuvant BPs was not available nationally, and in Sheffield/South Yorkshire/North Derbyshire, no postmenopausal early breast cancer patients received adjuvant BPs as the standard of care. Following the research team’s regional health economic modelling, the NHS commissioning of adjuvant BPs was agreed upon [S6], and the use of BPs was embedded into clinical practice across the whole of the NHS. As a result, by the end of 2016, 24% of UK oncologists were using adjuvant BPs [S4]. Following the publication of international clinical guidelines informed by Sheffield research [S1, S3, S7, S8] and the sharing of the Sheffield guidelines [S9] for adjuvant BPs, this percentage increased to >70% in 2018 [S9]. Nationally (in England), the use of adjuvant zoledronic acid increased 4-fold from 1^st January 2017 to February 2020 [S10].

In the Sheffield/South Yorkshire/North Derbyshire population, the number of patients treated with adjuvant BPs increased from zero prior to November 2016 to 572 in 2017, with continued increases to the end of the submission period [S11].

Currently, the strategy is to routinely provide adjuvant BPs to all patients with an adverse prognostic factor of a >12% 10-year risk of cancer death. BCN determined that 94% of UK NHS Trusts are now routinely using adjuvant BPs. Furthermore, a Sheffield-led national UK survey completed in March 2019 ( Brown, Wilson, Holen) demonstrated that 99% of UK centres are now using adjuvant BPs [S9].

Health and economic impacts

BPs were found to be acceptable and well-tolerated as adjuvant treatment [S2], and the introduction of adjuvant BPs has resulted in cost savings for the NHS and reduced mortality in South Yorkshire [S2] and across the UK. Calculations within the business case for Sheffield/South Yorkshire [S9], which has been shared nationally, show that the costs of adjuvant BP treatment range from £325-£561/patient depending on the BP and scheduling.

Fewer DEXA scans: Routine bone density monitoring (done by DEXA scanning) is expensive but is not required for patients on adjuvant BPs, amounting to a UK savings of £6.8 million with the European Consensus guidelines or £4.5m with the South Yorkshire guidelines [S9].

Fewer women developing metastatic breast cancer:** The EBCTCG meta-analysis showed a 3.3% absolute reduction in breast cancer mortality at 10 years with the use of adjuvant BPs in postmenopausal women, equivalent to around 1,000 lives saved per year in the UK. According to a large meta-analysis conducted in 2018, the average estimated saving in treatment costs per patient at 2015 prices was $62,000 (~£50,000) [S12]. This corresponds to £50m per annum for the 1,000 UK lives saved per annum [S12].

Impact on public awareness

The research on the use of adjuvant BPs to treat early breast cancer received wide media coverage in scientific news media such as ScienceDaily, The ASCO Post (the newsletter of the American Society of Clinical Oncology) and CancerNetwork, as well as in UK news and media such as The BBC and The Guardian resulting in the communication of the research results to the wider public [S13]. Coverage on the BBC and BCN websites around BP’s potential use attracted attention on BCN’s patient forum around lobbying the NHS to provide this treatment, with one patient posting ‘Looks like I have found my place to campaign!’ [S13]. The above and subsequent media coverage raised awareness amongst patients and highlighted the potential of adjuvant BP treatment to save thousands of lives.

Based on the research of Professors Snowden and Sharrack, AHSCT is now the “standard of care” in clinical practice as recommended through public policy changes with direct benefits to patients worldwide and reduced costs to the NHS.

Impact on national and international public policy

The Sheffield research [R1-4] has provided an evidence base for national and international professional society guidelines, position statements and recommendations on the use of AHSCT for MS and other ADs, which has extended the reach of the impact to the global level. As a core member of the Joint Accreditation Committee-ISCT & European Society for Blood and Marrow Transplant (EBMT), Snowden contributed to the EBMT consensus guidelines for immune monitoring and biobanking [S1] and produced general guidance for patients, families and carers considering hematopoietic stem cell transplantation [S3]. As a member of the Transplant Center and Recipient Issues Standing Committee for the Worldwide Network for Blood and Marrow Transplantation, Snowden also participated in developing their 2019 recommendations for establishing a hematopoietic stem cell transplantation program [S2]. In 2019, Sharrack coordinated the EBMT consensus guidelines on the use of HSCT in neurological immune-mediated disorders [S4].

Based on the results of the MIST trial, AHSCT has been approved as a treatment for RRMS in Wales, Scotland and is now provided through the NHS England commissioning route [S5]. The Belgian consensus protocol for autologous haematopoietic stem cell transplantation in MS was also informed by the Sheffield research [R4] and the EBMT guidelines [S6]. The American Society for Blood and Marrow Transplantation quoted the MIST study when revising the recommended indication for AHSCT in MS from ‘developmental’ to ‘standard of care, clinical evidence available’ for patients with relapsing forms of MS (RRMS or progressive MS with superimposed activity) [S6].

Impact on clinical practice

As a result of the changes in guidelines underpinned by the Sheffield research, the use of AHSCT in the treatment of ADs has increased by approximately one-third since 2016. The majority of this increase relates to the treatment of RRMS [S4].

Impact on patient quality of life and public understanding

Direct and long-lasting impact has been achieved for the patients who participated in the MIST trial [R4]. As noted in Section 2, 68–70% of the AHSCT-treated patients showed no evidence of disease activity, and progression-free survival was achieved in 70%–91% of these patients.

The improvement in patient quality of life after AHSCT is described by the recipients interviewed by the media. In a BBC Panorama documentary (2.5 million viewers) and major newspapers [S7], one patient who was wheelchair bound after the birth of her daughter reported that this new treatment has transformed her life. “ It worked wonders,” she said. “ I remember being in the hospital... after three weeks, I called my mum and said: 'I can stand'. We were all crying. I can run a little bit, I can dance. I love dancing, it is silly but I do. I enjoy walking my daughter around the park in her pram. It is a miracle but I can do it all." Another patient, who had active MS, remained relapse free for three years after having AHSCT. He said, “ Several of my symptoms have now disappeared – I no longer get spasms that go down my spine when I flex my head forward, and my right leg hasn't given way for three years.”

The Sheffield team who pioneered this treatment for people living with MS has been recognised by the 2019 National Future NHS Parliamentary Award for their research having a life-changing impact “ on a number of patients who previously failed to respond to standard therapies, with some now being able to walk, run and even dance as a result of being involved in the trial” [S8]. With other neuroscience researchers, the team received the national 2020 Queen Anniversary Award for research that has improved patient outcomes for people living with some of the most devastating neurodegenerative diseases [S8] and an international 2020 Clinical Research Forum (USA) Top Ten Research Achievement Award which honours outstanding accomplishments in clinical research [S8].

In further recognition of the benefit from AHSCT in RRMS, national and international patient organizations such as the MS Societies in the UK and US/Canada and the NHS directly refer to the MIST study in their patient information pages to help them make treatment decisions [S9].

Impact on health economics

Approximately 18,800 people in England are eligible for treatment with AHSCT. The recurring annual cost for the previous best available treatments is £15,000-£35,000 per patient, whereas the one-time cost for the AHSCT procedure is £30,000 (these estimates exclude clinical care costs). In the USA annual costs for DMT per patient are $80,000-100,000 compared to the one of cost of $85,184 for AHSCT. Therefore, although the initial costs may be similar, the cost savings for Healthcare providers continue to accumulate [S10].

Impacts include: health and welfare, public policy and services, practitioners and services.

Main beneficiaries include: ALS/MND patients, practitioners, NHS, and NICE.

Beneficence and non-maleficence are fundamental medical ethical principles. This impact case study highlights the importance of the rigorous safety and regulatory requirements in the UK in upholding these principles. If DPS had been implemented based on FDA approval in the US, it is likely that significant harm would have been caused in a vulnerable patient group where there are limited/no treatment options available. Proving robust evidence of the harm has not only removed the risk of harm, it has also saved the NHS significant funds.

Preventing harm to ALS/MND patients

The initial impact of the DIPALS study is on the life of ALS/MND patients participating in DPS trials worldwide by ensuring they were not adversely affected by DPS; this is evidenced by the early termination of the Sheffield DIPALS trial and the RespiStimALS trial in France [S1], and the suspension of recruitment of the further 122 participants in the NEALS study in the US [S2]. This has led to the safeguarding of all ALS/MND patients worldwide from possible harm caused by DPS treatment. Approximately 82% of ALS/MND deaths are attributable to respiratory failure. Given that respiratory muscle weakness in ALS/MND will progress eventually to a point where even tolerated intermittent/overnight NIV is ineffective. It is highly plausible that DPS would have become standard care, as an upper estimate, to the 82% of patients with late-stage ALS/MND. Accordingly, the DIPALS trial protected approximately 80-100,000 patients worldwide at the time of the trial from harm. Furthermore, with an incidence rate of ALS/MND of approximately 2 per 100,000 people, the DIPALS study continues to prevent harm to over 5,000 newly diagnosed ALS/MND cases year on year.

Impact on UK guidelines

In 2011, the NeuRx 4/4 DPS received HDE approval from the FDA for use in ALS/MND on the basis of one non-randomised study which compared patients treated with DPS with published historical data for NIV as the control. However, the data from the NeuRx 4/4 DPS trial on which the FDA based their decision was not published, and this was questioned in a cautionary commentary that urged for further RCTs. At the time of the DIPALS trial, the FDA HDE approval on humanitarian grounds was wrongly seen as a proxy for high-quality evidence. As a result, many centres worldwide, including in the UK, were proceeding to offer pacing to ALS/MND patients, despite a lack of robust, independent, high-quality evidence from RCTs to support its use.

In the UK, National Institute for Health and Care Excellence (NICE) approval had not been received, restricting the access for ALS/MND patients with respiratory difficulties to DPS. The DIPALS trial, motivated by the lack of RCTs into use of DPS in ALS/MND, was required in order for NICE to decide on whether to recommend DPS or not. Following the full analysis and reporting of the DIPALS results, the NICE interventional procedures programme published its recommendations on DPS, quoting the DIPALS study. The NICE recommendation followed the conclusions of the DIPALS study and states “ Current evidence on intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by motor neurone disease suggests that there are serious long-term safety concerns. Evidence on efficacy is limited and therefore, this procedure should not be used to treat this condition” [S3]. It is highly likely that if the DIPALS trial had not been conducted that the use of DPS would have grown to the point it was accepted as standard care, and that within a few years it would have been seen as unethical to conduct the DIPALS study.

The Motor Neurone Disease Association (MNDA), the only national ALS/MND charity in the UK and the founding member of the International Alliance of ALS/MND associations (which has 40 member organisations in 34 countries), does not recommend the use of DPS for their members. In their response to the interim report of a UK government initiative designed to enable patients to get quicker access to innovative new diagnostic tools, treatments, and medical technologies, they used the results of the DIPALS trials as a case study to support the position that “ while treatments remain experimental and unproven, we do not support making them routinely available. Such treatments should be made available to patients only via rigorous methodologies in order to make sure that they can be safely used in the wider patient population” [MNDA Policy Manager, S4].

Impact on clinical practice and guidelines in other European countries

The DIPALS study results informed a Europe-wide halt/no-adoption of DPS in ALS/MND. The European Respiratory Society published a clinical signpost concluding that “ Diaphragm pacing should not be offered to any patient with ALS/MND”, and the German National Guideline for Treating Chronic Respiratory Failure states “ This approach [DPS] is associated with shortened survival [in ALS/MND] and is therefore obsolete” [S5].

In 2019, The University of Sheffield surveyed all non-UK members of the European Network for the Cure of ALS (ENCALS), which includes 54 centres covering 24 countries, by questionnaire. Questions covered guidelines and policy related to use of DPS in ALS/MND and any changes due to recommendations from the DiPALS trial. There were 20 respondents from 12 countries. Six centres from Slovenia, Germany, Norway, Sweden, Spain, and France stated definitely that the recommendations from the studies had affected their use of diaphragm pacing in ALS/MND. Fourteen centres (70% of respondents) replied "completely no use" to the question "How have the recommendations of the Diaphragm Pacing studies affected your clinical practice regarding the application of DPS in patients with ALS?" Free text responses included “ Never implemented because of the published results” and “ We were only preparing to start diaphragm pacing when the results were published. We just decided not to go further with this therapy” [S6].

Impact on clinical practice and guidelines in North America

Based on the DIPALS study, The Canadian Thoracic Society clinical practice guidelines concluded: “We do not recommend diaphragm pacing in patients with ALS/MND” [S7]. In the US, the halting of the DIPALS trial and subsequent publication of results coincides with a sharp decline in implantation of pacing devices in ALS/MND patients [Fig 2, S8].

Fig 2: Use of DPS in the US. Data on DPS in the US obtained from the IBM® MarketScan® Research Databases

Impact on health economics

By preventing DPS from becoming standard care, the Sheffield research caused significant savings to health care providers worldwide. As an indication of the scale of savings, using the UK as example, in 2014 the cost of the devices and operation within the NHS was calculated as £18,000/patient compared to the annual cost of NIV of £3,600/patient [S9].

Approximately 10,000 children suffer from paediatric AI (including CAH) in Europe and prior to research at the University of Sheffield, there were no licensed preparations of hydrocortisone specifically for neonates and infants with CAH and the related disease paediatric AI. Sheffield research led to the formulation of the first licensed and marketed treatment for paediatric AI, Alkindi® hydrocortisone granules. The phase 3 clinical trial results [R6] confirming the efficacy of the drug led to EC authorisation for Alkindi® as a replacement therapy for children from birth to <18 years old across Europe [S1, S3]. Throughout the impact period, Diurnal Ltd., a Sheffield spin-out company, has worked closely in research and development with Sheffield and invested over £528K in the university to progress Alkindi® through regulatory approval and to market [S2].

Alkindi® received a PUMA in 2018 [S1]. Since 2019, it has been prescribed in the NHS [S2] and been made available to over 50% of paediatric patients with AI across Europe, including Germany, Austria, Italy, the UK, the Netherlands, Sweden, Norway, Denmark, and Iceland [S2]. Three new agreements cover the distribution and marketing of Alkindi® in the Benelux Union (consisting of Belgium, the Netherlands, and Luxemburg) [S2], Switzerland [S2], and the US [S1, S2]. In August 2020, Diurnal announced that Alkindi® had also been approved by the Australian Therapeutic Goods Administration (TGA) and the Israeli Ministry of Health [S1, S2], with anticipated launches in these countries in 2021. These approvals make Alkindi® a truly global pharmaceutical product with wide-ranging impact across the world. Thus, through the commercialisation of Alkindi®, the Sheffield research has underpinned commercial impact (measured in sales of pharmaceutical product), health impact (measured by the provision of licensed drug to thousands of patients across Europe and worldwide), and impact on patient and public understanding.

Commercial impact

The research and subsequent development of Alkindi® has had commercial impact for Diurnal Ltd., which floated on the London Stock Exchange (Alternative Investment Market - AIM) in 2015 to commercialise Alkindi® and other endocrine treatments [S2]. It is extremely rare for a UK university spin-out company to take a drug through regulatory approval and to market, and Diurnal is one of only three AIM-listed companies to get a drug approved in the US. Since the launch of Alkindi® (based on strong sales), Diurnal’s revenue streams were reported as £4.7M cumulative at the end of June 2020 [S2]. Diurnal has successfully raised over £55M in investments and generated major industrial contracts with pharmaceutical companies [S2]. Diurnal’s share price has been increasing with the success of Alkindi®. In addition, the company continues to expand; it has created 30 new highly skilled jobs, and the number of staff has increased from five in 2013 to 38 in 2020 [S2].

Health impact

The TAIN project offered unique insights into the realities and challenges of managing paediatric AI from the family perspective. Public and patient awareness of paediatric AI was supported by the collaboration with Genetic Alliance UK, who enabled family participation in the research and shared findings with patient organisations, including Living with CAH, the Addison’s Disease Self-Help Group and the Dutch Adrenal Society (NVACP). Presentations to European and US patient support groups, including to the American CAH patient group CARES (5,000 community members) in 2009, the UK CAH patient group in 2011, and the UK Addison’s Disease Self-Help Group (1,400 members) in 2012 ( http://www.tain-project.org/) raised awareness of the impact of the rare condition amongst clinicians and other stakeholders in the UK and in Europe.

This awareness raising was key to Alkindi®, being prescribed to children and administered by parents across mainland Europe since 2018 [S2] and in the UK since 2019 [S2]. The most significant impact to date is that during the clinical trials there were no reported adrenal crises in young patients receiving the drug compared to the up to 10% of AI children that had a crisis each year, demonstrating that Alkindi® provides live-saving treatment to this vulnerable patient group [S4]

The principal beneficiaries of FRAX are patients who are enabled to receive necessary, or avoid unnecessary, treatment to reduce fracture risk. The tool, integrated with guidelines, provides healthcare professionals with a rational approach to targeting osteoporosis interventions within a wide variety of healthcare systems.

Impact on patient management

Globally, the FRAX website shows year-on-year growth from 1,915,584 usage sessions in 2015 to 2,532,606 sessions in 2019, a 32% increase [S1]. Each session represents management of at least one patient within that session. By 2016, uptake of FRAX in clinical practice was reflected by its inclusion and/or endorsement in 120 clinical guidelines worldwide [S2]. In 2017, NICE accredited the FRAX-based National Osteoporosis Guideline Group’s ( NOGG) thresholds for interventions with osteoporosis medications in the UK [S3, S4]. NOGG provides a direct link between the UK FRAX tool and patient management decisions. Between 2008 and 2014, 488,585 sessions were accessed on the NOGG site, but between 2014 and 2019, this had more than doubled to 981,007 sessions. In an analysis of annual FRAX and NOGG website access published in 2017, there were a total of 348,964 and 208,766 sessions on the FRAX and NOGG websites respectively from UK-based users [S5]. Almost all (95.7 %) of the NOGG website sessions arose from calculations being passed through from FRAX; of these, 74.5% of FRAX calculations were in patients without a bone mineral density (BMD) measurement, confirming clinicians were using FRAX in accordance with the 2017 NICE guidance.

In the context of secondary prevention of fractures, in 2017 the Royal College of Physicians reported a Fracture Liaison Service (FLS) audit comprising 18,356 patients with fracture in 38 FLS. It found that 35% of all patients, and 42% of those aged below 75, were assessed using FRAX or QFracture as part of their management pathway, suggesting good uptake of NICE guidance [S6].

The SCOOP study in the UK demonstrated that screening using FRAX hip fracture probabilities was associated with a highly clinically significant decrease in hip fracture incidence (28%). Of those participants in the screening arm identified to be at high fracture risk, 75.8% were taking osteoporosis medication by 6 months into the study compared with only 2.0% in the control arm overall [S7]. By 60 months, 56.6% of those identified at high risk of fracture reporting taking medication, compared with 9.7% in the control arm overall. Informing the patient and GP thus had a marked impact on prescribing of treatment and adherence.

In 2018, the United States Preventive Services Task Force (USPSTF) recommended that women under 65 are screened for fracture risk (by various tools including FRAX) and those judged high risk are treated; the effect is to reduce the use of limited BMD resources in younger post-menopausal women [S8].

Increasing global reach of FRAX

In 2014, the FRAX tool catered for 53 nations and 28 languages, and in 2020 it has provided calibrated models for 73 nations and 35 languages. In 2015, it was estimated that the tool provided coverage for fracture risk assessment in more than 79% of the global population. Since REF2014, the FRAX website tool has provided a further 24.8 million calculations globally as of 23 November 2020, with over 31 million calculations in the last 9.5 years [S9]. It should be noted that this is an underestimate as only calculations entered directly to the website are counted. FRAX is also available on densitometric equipment worldwide, on iPhone, and as paper-based models. Recently, access to the tool has been embedded in the electronic patient record system of the Mayo Clinic in the US, an approach that will be increasingly important going forward [S10]. In 2020, FRAX was CE-marked as a Class 1 medical device.

FRAX and the COVID-19 pandemic

The daily usage of FRAX globally, captured via the website, has also enabled examination of the impact of the COVID-19 pandemic on osteoporosis management worldwide [S11]. Compared to February 2020, global access to FRAX in April 2020 was reduced by 58.3%. There were smaller reductions in Asia than elsewhere, partly related to earlier and less-marked nadirs in some countries (e.g. China, Taiwan). In Europe, the majority of countries (24/31, 77.4%) reduced usage by at least 50%. In the UK, the decrease in FRAX usage (65%) was not as marked or prolonged as the interruption in access to BMD services (practically 100% decrease as units closed April-June 2020) reflecting the continuing ability to assess fracture risk without bone density. More recent follow-up shows a good recovery in FRAX usage [S1].

Regulatory approval for ticagrelor 60 mg for long-term treatment after a heart attack

Following the results of the PEGASUS-TIMI 54 study **[R2, R5, R6] **,* European, US and more than 110 global regulatory bodies have approved the 60 mg twice-daily dose so that this can now be used as extended therapy in patients from 1 year after their heart attack [S1, S2]. The change to ticagrelor’s EU labelling to incorporate ticagrelor 60 mg came into effect from November 2016 [S1].

Endorsement of ticagrelor 60 mg in international guidelines

Following guideline recommendations in 2015 supporting the first-line use of ticagrelor 90 mg in the first year after a heart attack [R1, S3], extended treatment with ticagrelor 60 mg beyond the first year has now been supported by the European Society of Cardiology 2019 guidelines on the diagnosis and management of chronic coronary syndromes [S4]; Professor Storey was a member of this task force. Consequently, ticagrelor 60 mg twice-daily has increasingly been adopted for reducing risk in patients with a previous heart attack. These patients now benefit from lower risks of a subsequent heart attack, stroke and death during long-term treatment while avoiding the adverse effect of long-term anti-platelet agent use.

Cost-effectiveness of ticagrelor 60 mg after heart attacks

The National Institute of Clinical Excellence (NICE) were advised by Professor Storey as an external expert on use of antiplatelet agents to reduce risk of secondary heart attacks. They subsequently approved ticagrelor 60 mg twice-daily as a cost-effective option for extended therapy in patients with prior heart attack [S5]. The incremental cost-effectiveness ratio (ICER), determined with a worse-case scenario (probabilistic modelling), is £24,711, which falls within the acceptable quality-adjusted life year (QALY) threshold range set by NICE of £20- 30K, and therefore, a willingness-to-pay was established.

Commercial impact

Ticagrelor was reformulated as a 60 mg tablet in 2016, and prescriptions for ticagrelor 60 mg increased 20-fold per month in the 6 months following Professor Storey’s PEGASUS-TIMI 54 platelet substudy publication and a further 20-fold following approval by NICE with 204,991 items prescribed in the month of December 2019, as shown in the figure below (NHS Business Authority English Prescribing dataset). Overall global sales of ticagrelor reached $400M in Q1 of 2019, an increase of 19% from all sales of 2018 [S6]. AstraZeneca successfully secured a patent series to describe the results of the PEGASUS-TIMI 54 study and its platelet function substudy; Professor Storey is designated as an inventor on this series [S7].

In 2019, Professor Storey was the winner of the British Cardiovascular Intervention Society Research of the Year Prize following a presentation that included the beneficial impact of Ticagrelor on stent thrombosis risk in heart attack patients.

Following successful phase II and III clinical trial completion using PARP inhibitor research from Sheffield, AstraZeneca was granted first in class drug status for Olaparib ( Lynparza^®). Since then, the status has been applied to eighteen versions of the PARP inhibitor, four of which are directly attributed to the Sheffield Patent: Lynparza^®, Niraparib, Rucaparib and Talazaparib [S1]. [Text removed for publication].

Building on those initial applications of PARP inhibitors, this work has led to a step-change in the development and accessibility of treatments for cancers with few options. In 2020 Nature Milestones cited R1 as a milestone in cancer research for personalised therapeutics [S3].

In 2014, Lynparza^® became the world’s first PARP inhibitor approved for use in America and Europe [S4]. This success led to further AstraZeneca investment, launching a collaboration with MSD UK to develop treatments for additional cancers with a BRCA mutation. Lynparza^® has now had positive Phase III trial results in four different tumour types: pancreatic and prostate, as well as ovarian and breast [S5].

Initially indicated for the treatment of ovarian cancer, the successful trials led to Lynparza^® expanding to further patient groups in 2017. It is now being prescribed by physicians in 73 countries for the treatment of multiple cancer types. This has increased progression-free survival time for an additional 15,000 patients [S6].

Increased survival of cancer patients worldwide

Germline BRCA1 and BRCA2 mutations account for 72% and 69% breast cancers in women by the age of 80. The BRCA1 mutation increases this risk of ovarian cancer from 1.3% to 44%, and for BRCA2 mutations, the risk increases to 17%. BRCA mutations also increase the risk of breast cancer in men as well as increasing the risk of prostate and pancreatic cancer. Clinical trials with PARP inhibitors have shown to delay progression by an average of 3 months compared to chemotherapy [S5].

Olaparib ( Lynparza^®) was approved for use in Europe (EMA) and the USA (FDA) in December 2014 and Japan in July 2018. In 2015, NICE approved the use of Olaparib and Niraparib for NHS ovarian cancer patients, who had had three or more courses of chemotherapy, through the National Cancer Drug Fund [S4].

In 2018, Olaparib became available through NHS prescription as a first-line maintenance therapy in BRCA-mutated, advanced ovarian, fallopian tube and peritoneal cancer. Olaparib also became the first FDA-approved treatment for patients with gBRCAm HER2-negative metastatic breast cancer [S4].

The phase III POLO trial explored the efficacy of Lynparza^® as 1st-line maintenance monotherapy in patients with gBRCAm metastatic pancreatic cancer whose disease has not progressed on platinum-based chemotherapy. The trial determined that the median progression-free survival was significantly longer in the treatment group. POLO is the first positive phase III trial of any PARP inhibitor in a disease where there is a critical unmet medical need [S8] and has resulted in FDA approval for Lynparza^® in the US for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated pancreatic cancer [S5].

The AstraZeneca sublicensing of the Sheffield patent has led to the development of PARP inhibitors from other pharmaceutical companies for use as treatment of BRCA-mutated ovarian, fallopian tube, primary peritoneal and BRCA mutated breast cancers. Niraparib (GSK) and Talazoparib (Pfizer) have been approved for use in America since 2018 and Rucaparib (Clovis Oncology) was approved for use in America and Europe in 2019 [S1].

In Europe, the use of PARP inhibitors has been extended to ovarian, fallopian tube or peritoneal cancers to delay the next cycle of platinum chemotherapy, as well as increase survival.

Economic impact

Sales of Lynparza^® in the census period have continued to increase each year and have exceeded $1.2 billion in 2020 [S6]. AstraZeneca developed a strategic oncology collaboration with Merck (MSD UK) to expand the uses of Lynparza^® to other forms of cancer [S7]. This collaboration, which involved MERCK buying 50% of Lynparza^® for $8.5 billion, has achieved phase III clinical trial success in BRCA-mutated pancreatic cancer, which has the worst survival rate of all common cancers [S7]. The collaboration went on to work with Myriad Genetics Inc on their BRACAnalysis CDx test to identify BRCA mutations in patients. This test is now used in the USA and Japan to better target PARP inhibitor treatment [S7].

The sublicensed patent enabled other companies to produce PARP inhibitors for additional cancer types. Tesaro’s agreement with AstraZeneca contributed to the development of Niraparib launched in 2016 for the treatment of ovarian, fallopian tube and primary peritoneal cancers [S8]. In January 2019, GSK bought Tesaro, for $5.1 billion, to strengthen their commercial oncology capability [S8].

The Sheffield group was recognised by Universities UK as one of the 2019 Nation’s Lifesavers – the top 100 individuals or groups based in universities whose work is saving lives and making a life-changing difference to health and wellbeing [S9].

Impact on PSA screening policy and guidance in the UK and USA:

Sheffield research findings informed the UK National Screening Committee’s position on PSA screening [S1] and were cited as the key reference regarding the harms of TRUS biopsy in the NICE guidelines in both 2014 and 2019 [S2]. In addition, our findings on the harms of TRUS biopsy [R3] were used by School of Health and Related Research, University of Sheffield [S1], to create a model of PSA testing that was commissioned by the National Screening Committee. Based on the evidence, both the National Screening Committee and NICE concluded that the harms of TRUS biopsy (from over-treatment, inaccurate diagnosis and biopsy) outweighed the benefits. As a result, in 2015 the NHS Prostate Cancer Risk Management Group recommended against PSA screening [S1], and the National Screening Committee and the NHS continue to take this position in 2020.

In the USA, a combination of opportunistic PSA testing and private healthcare has made overdiagnosis and overtreatment for prostate cancer prevalent. By defining the harms of biopsy, our research informed the 2012 guidelines, and the 2018 revision of the guidance of the U.S. Preventive Services Task Force (USPSTF), newly advocating a discontinuation of PSA testing among asymptomatic men (“ Appendix 2: Information related to the harms of biopsy is derived from the work of Rosario and colleagues (ref 6)”) [S3].

Impact on patients, physicians, and healthcare providers due to reductions in PSA testing rates and the avoidance of biopsy

Our research was used to justify the NHS and USPSTF recommendations against PSA testing. This contributed to PSA-based prostate cancer screening not being introduced in the UK and a significant reduction in PSA testing rates in the USA. In the USA, PSA testing dropped by 8%, which led to the detection of 28% fewer new prostate cancers in 2013 and the reduction in PSA testing rates has since been maintained [S4]. Most of the detected cancers (57%) were of low or intermediate risk and unlikely to be clinically important. As such, these men were spared overdiagnosis and overtreatment and did not have their risk of advanced prostate cancer increased. The results of a modelling study supported this data, estimating that if non-selective PSA testing in the USA were to continue, 710,000-1.1 million men would be over-diagnosed with prostate cancer [S5].

The reduced PSA testing rates underpinned by our research have had a major economic benefit for healthcare providers in the USA. Routine PSA testing of the 38.7 million men in the USA aged 50-70 yrs would cost $1,355 million for the blood tests, and lead to the biopsy of 3,251,640 men (based on 8.4% of the cohort having PSA >4.0 ng/mL), with a TRUS biopsy cost of $585/person, for a cost of $1.9 billion [S6].

Our work [R3, R5] has had further impacts on patients through its use in the development of an informational website by Prostate Cancer UK to guide men in determining whether to undergo PSA screening or a prostate biopsy [S7]. Furthermore, biopsy-related anxiety and uncertainty has been used to encourage men to stay in active surveillance regimes or to inform abdominal aortic aneurysm screening [S7].