Impact case study database

Context

NHL comprises over 60 subtypes of B and T malignancies. Over 500,000 people annually worldwide are diagnosed with NHL, over 14,000 in UK. Although most NHL patients respond well to initial treatment, the majority eventually relapse and ultimately die of their cancer. Novel therapies are needed to further improve outcomes.

Pathways to impact

Illidge was lead specialist clinician for EMA approval of BV.

BV was granted Breakthrough Therapy Designation by the US FDA in 2016.

Reach and significance of the impact

Availability of more effective cancer drugs: BV in NHL

In November 2018, the FDA approved BV with chemotherapy for untreated systemic anaplastic large cell lymphoma (sALCL) and Peripheral T Cell lymphomas (PTCL), rare types of fast growing NHL [Ai, 2]. It was the first treatment for previously untreated PTCL including sALCL to receive FDA approval.

Takeda and Seattle Genetics market BV as ‘ADCETRIS’. Takeda Executive Medical Director confirmed UoM work “provided early research results of brentuximab vedotin (ADCETRIS) in PTCL as well as key contributions to the pivotal ECHELON-2 phase III trial.” Illidge’s “ contributions, including serving as a Steering Committee member of ECHELON-2, were instrumental in the approval by the U.S. Food and Drug Administration (FDA)…FDA approval was received 11 days after submission…..demonstrating both the strength of the trial data and the critical unmet medical need in this patient population” [B].

In May 2020, BV (with chemotherapy) was approved in the EU for frontline treatment of adult untreated sALCL [Aii, 2]. Takeda noted this marked “ a significant milestone for people diagnosed with this devastating condition. ADCETRIS is the first and only targeted therapy approved in first-line sALCL in several decades” [Aii].

| | Figure A shows a baseline scan of the first BV clinical trial patient in the UK, a 42 year old male with ALCL. Figure B demonstrates complete remission after four cycles of BV. Nine years later, this patient remains in remission. ### Impact on Clinical Guidelines: BV In August 2020, BV with CHP chemotherapy was recommended by the National Institute for Health and Care Guidance (NICE) as a treatment for adult untreated sALCL [C, 2]. NICE committee noted clinical advantages and concluded “ that brentuximab vedotin with CHP would replace CHOP (the previous standard of care) for sALCL in | | --- | --- |

the NHS”. Patient experts noted they “ experienced an improvement in their symptoms and had fewer side effects” and it was noted that BV with CHP “ is given in an outpatient setting, reducing time in hospital”, a significant benefit in time and resources [C].

National Comprehensive Cancer Network^® (NCCN^®) is an alliance of 30 leading US cancer centres. There are >1,200,000 registered users of NCCN Guidelines^® globally and they have been downloaded in >180 countries. NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines^®) for T-Cell Lymphomas recommend BV + CHP as the preferred first-line therapy regimen for ALCL and other CD-30 positive PTCL subtypes [D, 2].

Availability of more effective cancer drugs: Obinutuzumab in B cell NHL

In September 2017, Obinutuzumab (marketed by Roche as Gazyvaro in the EU) received EMA approval to treat (with chemotherapy) advanced FL based on GALLIUM [Ei, 6]. Roche announced “ Every year an estimated 19,000 people in Europe are diagnosed with follicular lymphoma, which is considered to be incurable.… these patients now have an improved initial treatment option available to them” [Ei].

In November 2017, the FDA approved Obinutuzumab (marketed by Roche as Gazyva in the US) in the same indication for the first time, based on GALLIUM [Eii, 6]. Roche stated, “ We’re pleased we can now offer patients…an initial treatment option shown to improve upon Rituxan, the standard of care in this setting for more than 10 years” [Eii].

In July 2018, Obinutuzumab received approval from the Ministry of Health Labour and Welfare (MHLW), Japan, and was listed on Japan’s National Health Insurance reimbursement price list the following month based on GALLIUM [Eiii, 6].

Impact on clinical guidelines: Obinutuzumab

In March 2018, a NICE technology appraisal recommended Obinutuzumab as an option for untreated advanced FL based on GALLIUM [F, 6].

The British Society of Haematology’s FL management guidelines 2020 cited GALLIUM [6], noted NICE approval and recommended either “ rituximab or obinutuzumab with chemotherapy for people who require treatment”, allowing clinicians greater treatment choice to account for individual patient factors and resistance [G].

Impacts of later work based on preclinical science

Illidge’s initial preclinical research discovering Obinutuzumab's mechanisms of action [3, 4] has directly led to further external clinical research, which in turn has generated new treatment options, that otherwise would not have occurred. For example, the international phase III CLL11 trial led to FDA and EMA approval of Obinutuzumab with chlorambucil for previously untreated CLL in November 2013 [Hi] and July 2014 [Hi], respectively. NICE recommended this use in June 2015 [Hi]. There are around 21,000 new cases of CLL in US each year, around 3,800 in UK. Based on the international multicentre GADOLIN trial, the FDA and EMA approved Obinutuzumab plus bendamustine chemotherapy for treatment of some relapsed/refractory FL in February 2016 and June 2016 [Hii].

Commercial impact of new drugs

BV is available in 72 countries. Seattle Genetics reported sales of USD477,000,000 in the US and Canada in 2018, 55% increase on 2017 and USD628,000,000 in 2019, 32% increase on 2018. The 2019 annual report stated global sales (including Takeda’s) “ exceeded $1 billion in 2019, underscoring the importance of ADCETRIS to physicians and patients around the world”’ [I]. Seattle Genetics confirm by end of 2019 ADCETRIS (BV) “ has been used in the treatment of more than 60,000 patients with lymphoma worldwide” [I].

Roche reported Obinutuzumab sales of CHF390,000,000 in 2018 rising to CHF552,000,000 in 2019, a 43% increase on the previous year [J]. Obinutuzumab is available in >70 countries for untreated FL, in >80 countries with bendamustine for previously treated FL and in >90 countries with chlorambucil for untreated CLL [J].

Context

UoM researchers led an international work programme delivering treatments for Mucopolysaccharide and related lysosomal diseases. Although rare, one baby born every eight days globally will be diagnosed with an MPS or related disease. These multi-organ storage diseases cause progressive physical disability and, in many cases, severe progressive mental deterioration resulting in childhood death.

Outputs from UoM programme have led to:

1. Clinical impact from trials run in Manchester including market authorisation of new treatments.

2. Economic impact through establishing a company (Orchard Therapeutics) to test new gene therapies, and licencing of two Manchester gene therapies to US companies (AvroBio, Phoenix Nest) (MPSII, MPSIIIC), with the advantage of increased enzyme expression from a single treatment.

Reach and significance of the impact

Enabling new treatments for lysosomal storage disorders

Over the past six years, Manchester recruited five global first patients and the majority of patients onto 13 multicentre lysosomal storage disease studies. Two treatments gained market authorisation as a direct result of UoM work in these trials, leading to >90 LSD patients in England and >1,000 worldwide being treated [A].

Example 1: LAL-D

Prior to Sebelipase Alfa availability (marketed as Kanuma, Alexion Pharmaceuticals, Inc.), treatment options centred upon supportive interventions, including blood transfusions and nutritional supplementation, but average infant life expectancy was less than four months from diagnosis. Through UoM’s research, in collaboration with other centres [1], ERT Sebelipase Alfa for LAL-D has been approved worldwide: European Medicines Agency (EMA) September 2015) [Bi]; US Food and Drug Administration (FDA) December 2015 [Bii]; Japan’s Ministry of Health, Labour and Welfare (MHLW) March 2016 [Biii]; and Health Canada December 2017 [Biv].

Albie, diagnosed with LAL-D at two months, took part in the Kanuma trial, commencing in 2011. His mother Charlotte stated, “ After several weeks of treatment, Albie gradually began to put on weight and improve” [C]. Prior to this treatment, most infants with LAL-D died before reaching six months of age. Albie is now eight years old.

Sebelipase Alfa was initially rejected by the National Institute for Health and Care Excellence (NICE) in 2017 for financial reasons although NICE committee “ recognised that sebelipase alfa is a potentially life-saving treatment in this population, and there is a compelling clinical need” [Di]. The decision is under appeal but the schedule has been affected by Covid-19 and does not currently have a timeline for restarting [Dii].

Alexion reported Kanuma net product sales of USD112,200,000 in 2019, compared to USD92,000,000 in 2018 and USD65,600,000 in 2017, representing a 22% and 40% increase respectively [E].

Example 2: Morquio syndrome/MPS IVA

Resulting from UoM research [2,3], ERT for Morquio syndrome involving Elosulfase Alpha (marketed as Vimizim, Biomarin Pharmaceuticals) has been approved worldwide: US FDA February 2014 [Fi]; EMA April 2014 [Fii]; Health Canada July 2014 [Fiii]; National Health Surveillance Agency Brazil , MHLW Japan, Australian Therapeutic Goods Administration December 2014 [Fiv] and National Medical Products Administration, China June 2019 [Fv]. In all these countries, Vimizim was the first treatment approved for Morquio A syndrome. At the time of EU approval, Chief Executive of the MPS Society, (UK) said, " For patients with Morquio A disease now having a specific drug treatment option provides real hope after decades of sadness and loss for so many families" [Fii].

In December 2015, NICE recommended funding Elosulfase Alfa treatment for Morquio A syndrome [G]. At the time of NICE evaluation (2015), there were 88 people living with MPS IVA in England, with ~3 new diagnoses per year. The company and patient group noted that 74–77 of these were anticipated to be eligible for ERT with Elosulfase Alfa [G].

Biomarin annual reports record Vimizim sales of USD544,300,000 in 2019, up from USD482,000,000 (2018) and USD413,300,000 (2017), a 13% and 17% increase respectively year on year. Vimizim is only used to treat Morquio A [H].

UoM research helped build commercial capacity in the UK and overseas

Gene therapy for MPS IIIA (Manchester preclinical programme) [4] was one of three critical founding programmes for UK-based Orchard Therapeutics, founded in 2015 to improve the lives of patients suffering from rare genetic diseases by designing autologous ex vivo gene therapies. Bigger, Jones and Wynn are members of Orchard’s Scientific Advisory Board and UoM remains a critical collaborator. The MPS IIIA programme (led by Bigger), was critical in the start-up of the company. Orchard CEO stated, “ The University’s research expertise and development work was integral to our success in securing $33 million [USD33,000,000] Series A financing, led by F-Prime Capital, which allowed us to successfully launch the company in May 2016” [Ii]. MPS IIIB [5] was licenced to Orchard Therapeutics in November 2017. Orchard CEO further confirmed, “ The University continues to contribute to the success and growth of our company including our collaboration on a clinical trial for MPSIIIA. The number of people employed by Orchard has risen from 33 in 2017 to over 250 (of which around 85 based are (sic) in the UK) by December 2019” [Ii]. Orchard offered initial shares to the public on the US stock exchange in October 2018 with a market value of USD1,180,000,000 [Iii]. In January 2019 a patient was treated on a compassionate basis with the MPSIIIA genetic therapy and three patients have since been treated on a UoM-sponsored trial. Ten months on from compassionate treatment, Royal Manchester Children’s hospital reported the patient was ‘doing well’ [Ji]. Preliminary clinical trial data showing treatment is safe and well-tolerated was presented in December 2020 at American Society of Hematology Annual meeting [Jii].

Context

COPD is the third leading cause of death worldwide with almost 4,000,000 patients dying each year globally. In the UK, approximately 1,200,000 patients are living with COPD, with >100,000 emergency NHS admissions and >100,000 patients diagnosed each year, the burden is substantial. More effective, simpler to use treatments are needed to improve patient adherence to treatment routines and reduce the risk of exacerbations that can impair quality of life, lead to hospitalisation or death.

Pathways to impact

Establishing excellent trial facilities - Singh is the Medical Director of the charity-owned dedicated respiratory clinical trial unit, Medicines Evaluation Unit (MEU, located on the grounds of Wythenshawe Hospital in Manchester) (36 beds, employs >100 people).

Committee membership - Vestbo and Singh sit on the GOLD Science Committee. GOLD works with healthcare professionals and public health officials worldwide to improve treatments of COPD.

Reach and significance of the impact

More effective and simpler treatments available for COPD patients

Aclidinium bromide /formoterol fumarate (Duaklir Genuair) received European EMA approval to treat COPD in December 2014 [Ai,1]. It was approved by US FDA in April 2019 (Duaklir Pressair) [Aii,1]. At the time, it was the only twice daily LAMA/LABA in the US, which included COPD exacerbation data in its prescribing information [Aii].

In July 2017, Chiesi’s Trimbow was the first fixed-dose triple combination inhaler for COPD treatment approved in Europe [Bi,3,4]. In March 2019, EMA expanded the label as a treatment for patients with moderate to severe COPD not adequately treated with long acting dual bronchodilation [Bii,5].

Both products are simpler to use than traditional separate inhalers. Chiesi confirmed, COPD “ requires patients to be treated with many drugs that, to date, have to be taken through two or even three inhalers. The possibility of taking all drugs needed by using only one inhaler considerably simplifies the treatment of patients, decreasing the burden on patients and may improve adherence” [Biii]. Improved adherence improves clinical outcomes, including exacerbations, which impair quality of life, lead to hospitalisation or death.

Commercial and industrial Impacts

AstraZeneca reported European sales of USD26,000,000 in 2015 following EMA authorisation of Duaklir Genuair. From 2016, it was available in 25 countries across Europe, Asia and Latin America [Ci]. By 2018, European sales had risen to USD91,000,000 [Cii].

Chiesi said of its Trimbow collaboration, UoM “ has been and remains fundamental to the success of these product developments in providing world-leading expertise in shaping the clinical studies, leading their execution and in the intelligent interpretation of their findings.” [D]. In 2018 Trimbow generated sales of EUR40,000,000 and was commercially available in 19 European countries, as at 31 December 2018 [Ei]. Following the label expansion based on TRIBUTE [5], Trimbow sales in 2019 totalled EUR127,000,000 [Eii].

Impact on UK guidelines

In December 2018, NICE updated guidelines for COPD diagnosis and management. NICE stated “ The evidence showed that, compared with other dual therapy combinations and with monotherapy, LAMA+LABA provides the greatest benefit to overall quality of life, is better than other inhaled treatments for many individual outcomes… is the most cost-effective option” and “ minimising the number and types of inhalers prescribed will make it easier for people to use their inhalers correctly” [Fi]. ACLIFORM was part of the evidence reviewed [Fii,1].

In July 2019, NICE recommended triple therapy as an option for some patients, noting, “ from the economic evidence, using a single inhaler device was more cost effective” [Fi,3,5]. TRILOGY and TRIBUTE provided clinical evidence [Fiii].

Impact on global guidelines

GOLD’s 2020 strategy report confirmed “ Combination treatment… reduces symptoms compared to monotherapy” and “ reduces exacerbations compared to monotherapy”. GOLD cited ACLIFORM [Gi, 1]. GOLD stated triple therapy “ may improve lung function, patient reported outcomes and prevent exacerbations.” [Gi,2,3].

GOLD’s Executive Director confirmed, “ In a 9-month period in 2019, the GOLD website recorded 337,711 hits from 211 countries (28,902 from the UK…), the most recent GOLD strategy document was downloaded 238,536 times demonstrating the reach of our documents and the research cited within them. University of Manchester research on dual and triple inhalers has been critical in progressing the treatment of COPD to more effective and simpler to use inhalers, marking an important change and benefit for COPD patients… The work of Singh and Vestbo on inhaled treatments were important factors in our 2017 and 2019 major revisions, and the updated 2020 guidance” [H].

Australian and New Zealand Guidelines for COPD 2020 (COPD-X Plan), noted that Genuair was one of four LAMA/LABA devices available in Australia, citing ACLIFORM as one of two trials for this treatment [Gii,1]. Regarding triple therapy, it stated “ triple therapy results in a lower rate of moderate or severe COPD exacerbations, and better lung function” and “ Triple therapy delivered in a single inhaler is convenient for patients and may improve adherence” [Gii,3,4,5].

Increasing triple therapy options for patients

As a result of the IMPACT trial, both FDA (April 18) and EMA (November 18) expanded their authorisations for the triple inhaler Trelegy Ellipta, to include a broader population of COPD patients [Ii, Iii, 6]. In EU, it was the first single inhaler triple therapy to be specifically indicated for COPD patients, not adequately treated with dual bronchodilation [Iii]. Trelegy was the first triple inhaler administered by dry powder inhaler, benefiting patients who use this type of inhaler more effectively. In 2018, the product was launched in 26 countries [Ji], increasing to 40 in 2019 [Jii]. GSK reported sales of GBP156,000,000 in 2018 [Ji], rising to GBP518,000,000 in 2019 [Jii]. In July 2020, AstraZeneca’s Breztri Aerosphere was approved by FDA based on the results of ETHOS, thereby bringing a new product to US patients, offering them broader treatment options [Iiii].

Context

Chronic coughing is a significant medical problem affecting approximately 12% of the general population, significantly impacting quality of life, with physical, social and psychological burdens, yet currently there are no licensed therapies available. Cough monitoring permits phase 2a studies with just 20-30 patients, allowing proof of concept to be established rapidly and at reduced costs.

Reach and significance of the impact

Adoption in clinical trials and a catalyst for new clinical trials

The VitaloJAK device developed from UoM research is the only cough monitor approved for use in regulatory clinical trials in Europe and US. Without it, many new trials could not have taken place.

Since commercialisation in 2015, the VitaloJAK has been used as a clinical endpoint in 36 clinical trials, recruiting 6,047 patients and analysing 32,569 cough recordings, evidencing how it has catalysed new clinical trials [A].

The EU Clinical Trials registry lists 10 commercial interventional clinical trials in chronic cough in the 10 years prior to its introduction and 19 new trials since the cough monitor’s launch in 2015, an increase of 90% [B]. Similarly, the US Clinical Trials registry lists 14 commercial interventional trials from 2005 to 2014, whilst 26 are listed from 2015 onwards, over 85% increase; 16 used the cough monitor and also involved UK sites [C], demonstrating the impacts on trial activity. Merck Research Laboratories’ Clinical Research VP explained, “ Cough monitoring provides both drug developers and regulatory bodies with objective evidence that new therapies reduce the amount of coughing experienced by patients, and has changed the standards by which cough therapies are being evaluated” [D].

Examples of clinical trials seeking new chronic cough treatments and utilising the cough monitor include: NCT02993822 (sponsor Nerre Therapeutics, completed June 2019), conducted at 42 study sites across US/UK, including Manchester; NCT03310645 phase I/IIa trial (sponsor Bayer, completed June 2019) at 7 UK sites, including Manchester; NCT04110054 (sponsor Shionogi Inc, completed December 2020) phase IIb trial completed across 95 sites in US, Europe and Japan [E].

In 2018, Attenua Inc. funded a phase 2a trial NCT03622216 (completed May 2019) evaluating Bradanicline as a cough treatment, employing the VitaloJAK as the primary endpoint. Attenua’s CEO said, “ *Professor Smith’s original and innovative method has given this industry a validated tool that allows us, for the first time, to be able to confidently study new pharmaceutical agents with the potential to treat patients who have no other alternatives to treat their cough.*” [F].

Manchester clinical trials activity has also increased because of the cough monitor availability and expertise in UoM/MFT. In the last 5 years, Smith has recruited 153 patients to 15 clinical studies of potential new therapies, bringing access to new therapies for patients attending the clinical cough service at MFT [G].

Stage III clinical trials to develop a new cough therapy

The largest trials to date are two phase 3 regulatory trials of Gefapixant (Merck). VP, Clinical Research, Merck Research Laboratories stated “ The use of the VitaloJAK cough monitoring system…and Professor Smith’s expertise were integral to the phase 2 work performed by Afferent Pharmaceuticals on gefapixant. Since then, Merck has worked with Professor Smith and Vitalograph to use the VitaloJAK system as the primary endpoint in two companion phase 3 trials” [D]. These studies measured cough frequency in 2,044 participants recruited globally from 171 sites, including 18 sites in the UK (NCT03449134 (completed August 20 /NCT03449147 completed Oct 20). Statistically significant reductions in 24-hour cough frequency for Gefapixant have recently been reported from these trials [H].

Commercial and Economic Impacts

The intellectual property associated with the cough detection algorithm was patented by MFT ‘A method for generating output data.’ Inventors: Smith, McGuinness, Woodcock. UK Patent Application No. 0511307.1.2015 and licensed to Vitalograph Ltd.

Vitalograph’s Chief Executive Officer said “ To date, the VitaloJAK is being used in 36 clinical trials… These studies have ranged from small scale proof of concept studies (n~20-30) to global phase 3 trials (n~1500), working with both small biotechs and large pharmaceutical companies. This work has resulted in over £40 million [GBP40,000,000] of revenue for Vitalograph to date… Customers include Merck, Pfizer, GSK, Astra Zeneca, Bayer, Boehringer Ingelheim, Shionogi…. We have also captured 100% of available trials to date” [A]. Expansion of Vitalograph’s clinical trials work, due to the cough monitor, has created new jobs in UK and Ireland. Vitalograph CEO stated, “ In 2017, we invested 12M Euros (EUR12,000,000) and created 50 new jobs at our Ennis and Buckingham facilities (data analysts, software designers and engineers) which was in part a result of the collaboration with the University of Manchester in respect of the VitaloJAK, allowing expansion of our clinical trials work, particularly in the treatment of cough” [A] .

MFT receives royalties via the licence agreement from the clinical trials work undertaken using the VitaloJAK cough monitor (income [text removed for publication] to end March 2020) [I].

Approximately 2,100 people, mostly young adults, develop HL annually in the UK. Long-term chemotherapy and radiotherapy toxicities causing ill health and premature death are of particular concern. A more individualised approach to treatment maximises cure and minimises late treatment toxicities.

Reduced risk of second cancers and heart disease for Early Stage HL

Previously, everyone with early stage HL received chemotherapy and radiotherapy and was at risk of radiotherapy-induced second cancers and heart disease. As a result of UoM research (RAPID), the European Society for Medical Oncology (ESMO) guidelines now state that for Early Stage HL, radiotherapy may be omitted following an interim PET scan for “ individual patients when the late risk of delivering RT (radiotherapy) is thought to outweigh the short-term benefit of improved disease control” [A,1].

National Comprehensive Cancer Network^® (NCCN^®) is an alliance of 30 leading US cancer centres. There are >1,200,000 registered users of NCCN Guidelines^® globally and they have been downloaded in >180 countries. NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines^®) for Hodgkin Lymphoma cite the RAPID trial and state interim PET scans “ may also be useful to identify a subgroup of patients with early…stage disease that can be treated with chemotherapy alone” [B,1].

Reduced risk of lung damage in Advanced Stage HL

Standard treatment for advanced HL includes Bleomycin, a drug causing lung damage and, in 1-2%, death due to respiratory failure. The RATHL treatment approach [2] reduces Bleomycin exposure by 75%. For advanced HL treatment, NCCN Guidelines^® now state, “ If reduced exposure to Bleomycin is desired, the panel recommends omitting Bleomycin from ABVD (chemotherapy) per the RATHL trial” [B].

Changing radiotherapy fields to reduce patient risk

Illidge, with ILROG partners, led the introduction of smaller doses of radiotherapy given to smaller areas (fields) of the body. ILROG international guidelines [3] have profoundly affected clinical practice and changed radiotherapy delivery in lymphoma (see illustration). These changes (now employed routinely in international HL treatment) have fewer late consequences without a reduction in disease control. Their importance is demonstrated by adoption of involved-site radiotherapy (ISRT) in clinical guidelines. NCCN Guidelines^® confirm ISRT as an alternative to involved-field radiotherapy (IFRT) “in an effort to restrict the size of the RT fields and to further minimize the radiation exposure to adjacent uninvolved organs and the potential long term toxicities associate with radiation exposure” [B,3] and states “ ISRT is recommended as the appropriate field for Hodgkin Lymphoma” [B]. European ESMO HL Clinical Guidelines recommend ISRT instead of IFRT after chemotherapy in limited and intermediate disease stages [A,3].

New drug treatment - patient health benefits and impact on clinical guidance

For the 10-15% of patients with recurrent and refractory HL, there were previously few therapeutic options and little prospect of cure. In 2016, Radford provided ‘real world’ evidence to the National Institute for Health and Care Excellence (NICE) committee from an analysis of Manchester patients: “ 8 of 25 patients eligible for allogeneic transplantation proceeded to transplant after BV alone and 5 (20%) are alive and disease-free after a median follow-up of 25.3 months” [Ci]. In 2017, NICE recommended BV for use within the Cancer Drugs Fund as an option for recurrent HL after two previous therapies [Cii]. A Public Health England (PHE) report, based on a questionnaire created with input from Radford, formed part of NICE's review. The report assessed 219 ‘real life’ patients treated between 2013 and 2016: 36% who received BV to bridge to stem cell transplant were able to have the transplant without needing salvage chemotherapy [Ciii]. In June 2018, NICE recommended routine BV commissioning [Civ,4]. Takeda who market BV as Adcetris, estimate it is now prescribed to 190-200 patients per year in the UK for this indication [D].

In advanced HL, the US Food and Drug Administration (FDA) approved first line BV treatment in combination with chemotherapy in March 2018, based on ECHELON-1 [E,5]. The FDA said BV approval represented “ an improvement in the initial treatment regimens of advanced HL that were introduced into clinical practice more than 40 years ago” [E]. In February 2019, EMA approved this indication based on ECHELON-1 [F,5]. Treatment with BV and chemotherapy is also recommended in NCCN Guidelines^® for stage III-IV disease [B].

Policy impact of new nationwide breast screening

Before BARD, screening of patients at high risk of breast cancer following radiotherapy for HL depended on individual patient referral. National guidelines existed but referrals were sporadic. Radford initiated and established BARD in collaboration with PHE to optimise screening and ensure those at risk were informed of screening options at the appropriate time. BARD has been implemented nationwide as a method of referral for women eligible for very high risk screening, and is included in PHE’s guidelines [Gi] and NHS service specifications for the Breast Screening programme 2019-20 [Gii]. BARD’s impact was highlighted in PHE Cancer Blogs [Hi] and Cancer Stories [Hii], which Radford was asked to contribute to, as part of PHE public dissemination. At the BARD Launch Meeting in September 2018, PHE’s Director of Screening described BARD as, “ the model for cancer surveillance in high risk populations” [I] and recently confirmed “ UK CMOs (Chief Medical Officers) are currently exploring policy making in relation to a broader range of screening programmes” and confirmed Radford’s work on BARD “ has been very useful to guide this new policy direction” [J].

Pathways to impact

Community engagement: ‘Hard-to-reach’ at risk residents in some of Manchester’s most deprived areas were engaged through community initiatives, including:

• Macmillan bus roadshows

• participation by local media (61 events)

• recruitment of community champions

• wide-reaching poster campaign in GP and community centres, libraries and pharmacies

Publicity of initial findings via BBC Breakfast (>6,000,000 views), national newspapers (e.g. Independent, Daily Mail) and radio interviews.

Reach and significance of the impact

Transformation of lung cancer outcomes:

Manchester: Early stage lung cancer is potentially curable. Late stage disease is not curable: survival is around six months. Across Greater Manchester during the LHC trial, 18% of non-screening detected lung cancers were stage 1 compared to 65% in the trial; 48% were stage 4 compared to 13% in the trial. Macmillan Cancer Improvement Partnerships reported, “ Almost 8 out of 10 cancers were early stage and only 1 in 10 had advanced lung cancer (stage 4). Potentially curative treatment was offered to 9 out every 10 people with lung cancer” [A]. Manchester City Council’s Director of Public Health said, “ The Lung Health Checks are a game-changer for outcomes in Manchester…This pilot has engaged the most affected communities and offered new hope to many local people” [Bi]. Manchester Health and Care Commissioning (MHCC) subsequently announced an LHC expansion across North Manchester in September 2017, saying of the pilot, “we have developed a risk-stratified screening model that can detect lung cancer and other conditions earlier and can have an immediate impact on saving lives. We are very pleased… to take this forward and enable thousands more people in North Manchester to benefit” [Bii].

Wider NHS: In November 2017, NHS England’s Chief Executive announced a roll-out of mobile lung cancer screening [Biii]. The NHS Long Term Plan (January 2019) confirmed, “we will extend the lung health checks that have already produced strong results...starting in parts of the country with the lowest lung cancer survival rates. This will identify more cancers quickly, pick up a range of other health conditions...and help reduce inequalities in cancer outcomes*" [C]. In February 2019, 10 new LHC projects were announced across England: NHS England’s National Cancer Director said, “These new projects will save lives… but it will also mean thousands of patients will avoid life changing treatments” [Biv]. An independent review of adult screening in England (2019) endorsed community locations for screening in general stating, “ Services in other locations (e.g. close to people’s work) should be explored” [D].

The first LHC pilot scheme in London (August 2018 to April 2019) offered screening either at hospital or at a mobile scanning unit (following Manchester’s model of supermarket lung screening). It was conducted in West London areas with the lowest one year survival and highest smoking rates; 29 of 1,145 participants (2.5%) were diagnosed with lung cancer, one with non-Hodgkin lymphoma and one with breast cancer. 58.6% of cancers were stage 1 [E].

Europe: In 2020, the European Society of Radiology and European Respiratory Society's joint statement paper on lung cancer screening stated, “Europe’s health systems need to adapt to allow citizens to benefit from organised pathways, rather than unsupervised initiatives, to allow early diagnosis of lung cancer and reduce the mortality rate” [F]. It cited Crosbie’s research [2] and other European trials.

Australia: In a report in November 2020, the Australian Government's cancer control programme recommended the creation of a national lung cancer screening programme including mobile screening. It stated, “ there is international recognition of both the effectiveness and feasibility of lung cancer screening” and cited the Manchester LHC as an international example of implementation [Gi]. Lung Foundation Australia’s CEO stated, “ This report will bring hope to thousands of Australians and lead to early detection of lung cancer which is critical to optimal treatment” [Gii].

Cost effectiveness of healthcare intervention delivery for NHS: Analysis of LHC showed cost effectiveness ratio of GBP10,069/QALY (quality-adjusted life year) [H]. UK’s National Institute for Health and Care Excellence's threshold for recommending treatments is usually GBP20,000 to GBP30,000/QALY Treatments above this threshold are usually deemed not cost-effective and are not funded. The cost effectiveness of the LHC is important in confirming its economic viability.

Positive participant feedback: Testimonials from patients recruited to LHC were positive. A patient diagnosed with stage one lung cancer said: “ I’d rather know now than in a few months or years when it will be too late. I honestly feel this Lung Health Check has saved my life” [Ii]. Another patient, given the all clear but having previously lost their partner to lung cancer said, “ It’s an opportunity for people to save their lives” [Iii].

Leveraged funding to expand and develop pilot:

Manchester: The success of LHC led to MHCC providing GBP4,000,000 to roll out the service in North Manchester [Bii].

Yorkshire: Yorkshire Lung Screening Trial built on the Manchester pilot by addressing issues including optimal selection criteria for screening in the community and the population impact of screening. (Crosbie Co-PI, Booton Co-I, GBP5,200,000 funded by Yorkshire Cancer Research) [J].

National 10 site pilots: Announced with GBP70,000,000 NHS funding [Biv].

Context

Osmertinib and Crizotinib are tyrosine kinase inhibitors (TKIs) which specifically target the genetic characteristics of cancers, are taken orally, and are well tolerated even by frail and elderly patients compared to intravenous chemotherapy that is more toxic and resource intense to deliver. The EGFR+ and ALK+ types of NSCLC are identified with genetic tests on cancer biopsies.

Pathways to impact

Ranson and Blackhall’s expertise in cancer biomarkers and phase I-III clinical trials ensured that study designs were fit for purpose and patients readily identified through establishing genetic tests ahead of National Health Service (NHS) availability. Patients were referred nationwide to Manchester for these trials.

Reach and significance of the impact

Impacts on regulatory approvals

Osimertinib (marketed as Tagrisso)** was approved in the US (FDA- November 2015) [Ai], Europe (EMA- February 2016) [Aii] and Japan (MHLW- March 2016) [Aiii]. Approvals were for EGFR T790M mutation-positive NSCLC for patients with metastatic disease who have progressed on or after EGFR TKI therapy (FDA), irrespective of prior EGFR-TKI treatment (EMA) and for EGFR T790M+ patients with inoperable or recurrent NSCLC resistant to EGFR TKI therapy (MHLW) [A]. All were based on the AURA extension [2] and AURA2 (conducted outside UK) clinical trials [Ai,Aii,Aiii]. The Chief Executive Officer of AstraZeneca said “ The FDA approval of TAGRISSO marks an important milestone for lung cancer patients who urgently need new treatment options. We….acted on the breakthrough clinical evidence to ensure this next-generation medicine reaches patients in record time” [Ai].

A National Institute for Health and Care Excellence (NICE) technology appraisal (October 2016), referencing the AURA extension, recommended Osimertinib as an option for locally advanced or metastatic EGFR T790M mutation-positive NSCLC in adults with progression following TKI treatment [Bi, 2]

NICE produced Covid-19 rapid guidance (updated April 2020) endorsing interim treatment regimens for some cancer medicines [Ci] in which Osimertinib was confirmed as a first-line therapy option for NSCLC to delay the need for subsequent chemotherapy [Cii].

Crizotinib (marketed as Xalkori) was approved by EMA (November 2015) for first line treatment of adults with ALK+ NSCLC based on the results of PROFILE 1014 [D, 5].

NICE Technology appraisal Sept 2016 recommended Crizotinib as “ an option for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer in adults” [Bii]. The main trial that presented clinical effectiveness was PROFILE 1014 [5]. PROFILE 1007 [4] was also cited in the final appraisal.

Impact on clinical guidance

The European Society of Medical Oncology (ESMO) September 2016 and 2019 guidelines incorporate Osimertinib and Crizotinib into standard of care treatment for EGFR+ and ALK+ NSCLC respectively, according to their licensed indications. [E,1,4,5].

National Comprehensive Cancer Network^® (NCCN^®) is an alliance of 30 leading North American cancer centres. NCCN Guidelines^® have been downloaded in more than 180 countries. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), updated in April 2016, stated, “ NCCN Panel recommends osimertinib as subsequent therapy for patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on erlotinib, gefitinib, or afatinib therapy” with the Aura Phase Extension trial initially cited as evidence [F, 2]. Crizotinib is recommended as first line therapy for ALK+ patients based on the 1014 trial and FDA approval [F, 5]. In 2019, NCCN’s Non-Small Cell Lung Cancer Guidelines were downloaded 605,446 times.

Patient impacts

Osimertinib

In June 2019, Public Health England reported on the ‘real-world’ treatment effectiveness of Osimertinib during the period October 2016 to September 2018. During this time 386 Cancer Drug Fund applications for treatment through NHS were made. After exclusions, 357 patients who received treatment were studied. Median survival was 13.9 months. Survival at 6 months was 78% and 12 months survival was 56% [Gi].

Crizotinib

Public Health England advised that as of January 2020, 231 patients have now received Crizotinib as treatment for NSCLC through NHS [Gii].

Impacts from further studies based on early work led by Manchester

Follow on trials, such as ‘FLAURA’ for Osimertinib, would not have been possible without the underpinning AURA studies. Based on FLAURA, FDA approval was secured in April 2018 for Osimertinib to be used as first line treatment for EGFR mutation positive NSCLC irrespective of T790M status [Hi]. EMA approval followed in June 2018 [Hii].

Commercial Impacts

Following the results of the Aura trials (involving UK academic leads Ranson [1] and Blackhall [2]), Osimertinib (Tagrisso) is now approved in 80 countries for first line EGFR+ NSCLC and >85 countries for second line use in patients with EGFR T790M NSCLC [Ii]. It realised sales of USD423,000,000 in its first full year (2016) of which USD82,000,000 were from Japan, following launch there in May 2016. (EGFR+ NSCLC is more prevalent, accounting for up to 50% of all lung cancer in Asia). By 2019, total sales had grown to USD3,189,000,000 [Iii].

Global sales of Crizotinib (Xalkori) were USD438,000,000 in 2014 (primary indications were ALK+ NSCLC and ROS1+ NSCLC) [Ji] and peaked at USD594,000,000 in 2017 [Jii]. By September 2017, Crizotinib (Xalkori) had received approval for ALK+ NSCLC in >90 countries worldwide [Jiii].

Pathways to impact

• Parliamentary POST notes: UoM research cited informing MPs about stillbirth issues (POSTbrief 21 July 2016, Bereavement Care, POSTNOTE 527, May 2016, Infant Mortality and Stillbirth in the UK).

• Heazell presented to All Party Parliamentary Group on Baby Loss (2016): Co-chair described Manchester’s hospitals as displaying best practice with their stillbirth-specific integrated pathway.

• Patient guidance: UoM research informed patient-information leaflets from the Royal College of Obstetricians and Gynaecologists (RCOG), Kick’s Counts, Tommy’s (for NHS England), StillAware (Australian charity) and #movementsmatter campaign (published 24 Oct 2016, >65,100 YouTube views).

• International #sleeponside campaign: Launched in 2018, by Tommy’s, to educate mothers about sleeping position in late pregnancy [3]. Tommy’s estimate this reached >2,500,000 women globally.

Reach and significance of the impact

20% reduction in stillbirth followed Saving Babies Lives Care Bundle’s introduction in 19 UK early adopter trusts

In 2014, NHS England launched the four element Saving Babies Lives Care Bundle. The third element focussing on Reduced Fetal Movements was authored by Heazell and underpinned by UoM research [Ai]. In 2018, UoM conducted the SPiRE study to determine the bundle’s impact on pregnancy outcomes. Stillbirths were reduced by 20% over the implementation period (2015-2017) [Aii]. UoM’s findings informed the bundle’s second iteration (released March 2019) which included the sleep on side message [Ai, 4]. National Clinical Director for Maternity and Women’s Health, NHS England noted, “ Heazell’s research contribution was an important factor in allowing us to make these positive changes. In my view, the development and subsequent evaluation is an excellent example of how translational research can be used to effect positive change in NHS services” [B]. Implementing the bundle was included in NHS planning guidance and incorporated into the standard NHS contract for 2019/20.

Influence on Australian Safer Baby Bundle

UoM findings influenced the Australian Safer Baby Bundle (SBB), launched in 2019. Heazell was an international advisor. SBB handbook states it is “based on the approach used in the UK Bundle Versions One and Two” [Ci,3,4]. Victoria’s Secretary of Department of Health and Human Services confirmed, “ There is no question that we would not have been able to develop the Safer Baby Bundle without the resources and insights…generously shared by Professor Heazell…an example of how sharing research insights can rapidly enable application internationally”. He confirmed, “ initial evaluation of the care bundle in 21 Victorian maternity services is that it has been associated with a reduction in stillbirth by 27%” [Cii] .

National/international clinical guidance

UoM reduced fetal movements work was cited as best practice in: guidance from RCOG (reviewed 2014 and 2017) [Di]; Perinatal Society of Australia and New Zealand [Dii]; American College of Obstetricians and Gynecologists [Diii]; national Perinatal Confidential Enquiries into stillbirth (2015 [Ei], 2017 [Eii]).

Creation of North West Regional Stillbirth Care Pathway

Initiated in 2014/5, updated in 2018, UoM’s research was cited in North-West regional stillbirth care pathway guidelines [5,6,Fi, Fii]. A pathway audit in August 2016 demonstrated 25% more women were: receiving information; being cared for in labour more safely; and accessing investigations to determine the cause of stillbirth [Fiii].

Creation of National Perinatal Post Mortem Consent Package and Bereavement Care Pathway

In January 2013, Sands (Stillbirth and Neonatal Death Charity) launched a perinatal post mortem consent package and training programme. Sands confirmed Heazell’s “research informed the development of the...package and substantially aided our efforts in producing this important resource, which benefits both health professionals and parents” [G,6]. A 2016 maternity unit audit of UK’s bereavement care provision demonstrated 52 UK Trusts use the package and, of these, 85% believed it had improved staff confidence [H].

In 2017, Sands launched a national bereavement care pathway (NBCP) and audit tools, stating UoM “ research into post-mortem consent, the value of investigations and parent’s experiences following stillbirth was instrumental in informing Sands as we developed and launched the…documents” [G,5]. A 2020 NBCP progress report documented, within the pilot sites, that 76% of professionals aware of the pathway agreed that bereavement care improved during the pilot [I]. The pathway was rolled out nationally in October 2018. Sands confirmed, by August 2020, 52% of English sites have fully committed to NBCP and 99% have engaged with NBCP in some way [G]. Additionally 5 Scottish NHS Boards are currently piloting the NBCP as early adopters [G].

In 2014, ‘Listening to Parents after Stillbirth’ reported only half of women whose baby died before labour felt involved in decision making and confident about decisions made at the time. By contrast, NBCP’s 2020 progress report found 89% felt decisions they made in hospital were the right ones at the time, 89% felt communication was sensitive and they received information about relevant support organisations. 92% agreed they were treated with respect [I], demonstrating NBCP’s positive impact for these parents.

Improved care delivered in pregnancies after stillbirth

A clinic model for care in pregnancies after stillbirth was developed from UoM’s systematic review of women and families’ needs in these pregnancies. Over 800 families have been treated at Manchester’s Rainbow Clinic since January 2014, which provides specialist care for pregnant women who have previously had a stillbirth and supports partners and family. It was cited in a Parliamentary debate as an example of excellent care [Ji].

Manchester’s Rainbow Clinic has improved clinical outcomes. A 2016 review showed it had reduced: preterm birth (10% vs 21%); and low birthweight infant numbers (9% vs 18%) [Jii]. An independent study by NEF Consulting found clinic attendance reduced anxiety and post-natal depression [Jiii]. It also demonstrated the Rainbow Clinic gave tangible healthcare financial benefits of GBP6.10 of benefit per pound invested solely from clinical outcomes [Jiii].

Twelve satellite Rainbow Clinics have opened in the UK to date, delivering the UoM care model with a further 25 in development. Further afield, UoM researchers are working with care providers wishing to adopt the model in Melbourne (Australia), Toronto (Canada) and Wisconsin (USA).

UoM’s SCLC radiotherapy research, in collaboration with other European centres, has changed clinical practice, reflected in national and international guidelines. With >400,000 SCLC patients diagnosed annually worldwide, UoM research benefits thousands of patients.

Pathways to impact

Faivre-Finn was a committee member for the European Society for Radiotherapy and Oncology (ESTRO), Advisory Committee in Radiation Oncology (ACROP), European Society for Medical Oncology (ESMO) and American Society for Radiation Oncology (ASTRO) guidelines, ensuring their lung cancer guidelines reflected the trial evidence.

Impacts on LS-SCLC standard-of-care: Europe

Around 61,000 people per annum are diagnosed with SCLC across Europe (UK approximately 6,000). Before CONVERT, optimal chemo-radiotherapy regimens for LS-SCLC were controversial, causing practice disparity. A 2003 UK practice survey showed only 35% of radiotherapy centres used concurrent chemo-radiotherapy, despite phase III trial data showing improved outcome over sequential treatment. A 2018 European survey showed CONVERT had a major effect on standardisation of chemo-radiotherapy use in this disease across Europe: 90% of respondents used concurrent therapy routinely, and there was a 10% increase in use of twice daily radiotherapy following CONVERT publication (32% to 42%) [A].

The UK’s National Institute for Health and Care Excellence (NICE) lung cancer guidelines were updated (2019) to recommend twice-daily concurrent chemo-radiotherapy [Bi] based on CONVERT findings [Bii,1].

In 2019 ESMO started to review their Clinical Practice Guidelines on SCLC, the lead stated, Faivre-Finn’s “ work has been important to ESMO in updating their recommendations” [Ci]. The CONVERT twice-daily radiotherapy regimen is to be their recommended standard-of-care [Cii] (publication delayed to early 2021 because of Covid-19).

Impacts on LS-SCLC standard-of-care: beyond Europe

Approximately 30,000 people per annum are diagnosed with LS-SCLC in US. 2020 US ASTRO guidance, states the twice-daily CONVERT regimen is standard-of-care for radiotherapy in LS-SCLC [D]. National Comprehensive Cancer Network^® (NCCN^®) is an alliance of 30 leading US cancer centres. There are >1,200,000 registered global users of NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) and they have been downloaded in >180 countries. Since 2019, NCCN^® recommend 1) radiotherapy should be given concurrently with chemotherapy, 2) radiotherapy should start early with cycle 1 or 2 of chemotherapy, 3) the time from start of any therapy to end of radiotherapy should be short, as delivered in the CONVERT twice-daily radiotherapy arm [E]. 2020 American Radium Society criteria for radiotherapy in LS-SCLC confirmed, “... strong panel consensus that concurrent chemoradiation is usually appropriate because of the inclusion of early stage disease in the CONVERT (concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small cell lung cancer) trial… the panel rated this as strong evidence to support chemoradiation.” [F].

Impacts on early LS-SCLC and LS-SCLC standard-of-care for the elderly: US

Most SCLC occurs in over 60s. Older patients have been under-represented in clinical trials and are less likely to receive treatment due to concerns over poor tolerance or treatment-related toxicity. The subgroup analysis of elderly patients with stage I-II disease in CONVERT provided unique information to aid clinical decisions, such as choosing between surgery and chemo-radiotherapy. US (ASTRO) guidance recommends concurrent chemo-radiotherapy in selected fit patients >70 years [D], a significant step forward for these patients. NCCN Guidelines^® citing the CONVERT trial [2] state, “ Greater attention to the needs and support systems of elderly patients is recommended to provide optimal care. Overall, elderly patients have a similar prognosis as stage-matched younger patients” [E].

Impacts on SCLC staging and routine irradiation of thoracic lymph nodes: UK and Europe

The CONVERT study has led to changes in professional guidelines and radiation delivery for SCLC across Europe. CONVERT was the first randomised study not to include elective irradiation of thoracic lymph nodes in radiotherapy planning processes. Based on improved toxicity and survival in CONVERT over previous studies, ESTRO-ACROP 2020 guidelines for Target Volume Definition in treating SCLC recommend omitting elective lymph node irradiation [G]. They further recommend that PET-CT is not necessary to select patients for concurrent chemo-radiotherapy [G]. By changing radiation delivery for SCLC this recommendation reduces treatment toxicity.

Impacts on ES-SCLC standard-of-care: UK and Europe

In ES-SCLC, the CREST study had a major impact on practice and guidelines in UK and Europe. A 2015 UoM survey evaluating CREST’s impact received responses from 93 centres across 7 countries. It showed: the number using thoracic radiotherapy increased from 25% to 81% following CREST study’s publication [H]; and thoracic radiotherapy is becoming standardised in Europe, 69% of respondents delivering the dose and fractionation used in the CREST study [H]. Updated NICE guidance (2019) recommended consideration of thoracic radiotherapy with PCI for people with ES-SCLC who had responded to chemotherapy [Bi,5], based on three studies, including CREST [Biii,5]. Similarly, ESTRO-ACROP [F] guidelines state, “ As there are limited second line treatment options, consolidation TRT (thoracic radiotherapy) should be considered for patients who respond to first-line systemic treatment but have residual intra-thoracic disease” [G,5]. They further confirm, “ This strategy has been widely adopted in Europe” [G].

Impacts on ES-SCLC standard-of-care treatment: beyond Europe

Cancer Council Australia Lung Cancer Guidelines (December 2015) state chest radiotherapy should be strongly considered in patients responding to chemotherapy. CREST was one of three trials evidencing this recommendation [I,5]. In US, 2020 ASTRO Clinical Practice Guidelines recommended thoracic radiotherapy for patients with ES-SCLC after chemotherapy, based on CREST findings [D,5]. From 2020 NCCN Guidelines also state, “the addition of sequential (consolidative) thoracic radiotherapy may be considered in select patients” and cites CREST’s results, showing improvement in 2-year survival (13% with vs 3% without thoracic radiotherapy) [E,5]. 2020 American Radium Society criteria for radiotherapy in ES-SCLC confirmed, “ There is consensus that thoracic radiation should be considered in patients with residual disease after chemotherapy” citing CREST as one of four studies considered [J].

Impact of the Limit of Detection (LoD) strategy on European guidelines

Through original research led from UoM, validated by collaborative meta-analyses, LoD’s use is now advocated in UK NICE and European guidelines. NICE evaluated hs-cTn assays for early diagnosis of AMI in October 2014, concluding LoD strategy may provide an effective/cost-effective approach compared with current standard of care [A]. In 2016 an updated NICE Clinical Guideline 95 (Recent-onset chest pain of suspected cardiac origin: assessment and diagnosis) recommended implementing LoD strategy in clinical practice “ For people at low risk…consider performing a single high-sensitivity troponin test only at presentation…if the first troponin test is below the lower limit of detection” [B]. This recommendation was unchanged at 2019 review. In 2016, European Society of Cardiology (ESC) recommended employing LoD strategy clinically, extending impact reach [C].

Impact of the 1-hour algorithm on international practice

In 2016, ESC recommended the 1-hour algorithm for clinical use stating “ A rapid rule-out and rule-in protocol at 0hr and 1hr is recommended if a high-sensitivity cardiac troponin test with a validated 0hr/1hr algorithm is available” [C,2]. Economic analysis found UK use of the 1-hour algorithm saves >GBP2,000/patient, representing significant potential healthcare savings if applied to approximately 350,000 UK patients and 39,000,000 world-wide [D].

Since ESC’s recommendations, further European validation has demonstrated patient benefits in participating countries:

• Northern Ireland: 71% of patients discharged early after having AMI safely ruled out within 1 hour. No cardiac deaths within 6 months [Ei].

• Netherlands: 46.7% patients had diagnosis of AMI rapidly ruled out. No deaths or AMIs within 6 weeks follow up [Eii].

• Sweden: Reduced: hospital admissions (59% to 33%, adjusted odds ratio 0.33 [95% confidence interval 0.25-0.42]); length of hospital stay (median 23.2 hours to 4.7 hours); and healthcare costs (USD1,748 to USD1,079/patient) [Eiii].

• Thailand: Reduced time to ‘rule in’/‘rule out’ AMI from mean of 238 minutes pre-implementation to 134 minutes post-implementation (p<0.001) [Eiv].

• Switzerland and Argentina: 2019 study of 2296 patients concluded in real-world settings “excellent applicability, short time to ED [emergency department] discharge, and low rate of 30-day [major cardiac events]” from routine clinical use of the ESC 0/1-h algorithm for management of patients presenting to the ED [Ev].

Impact of the T-MACS decision aid on patient care

While simplicity of LoD and 1-hour algorithms comes from reliance solely on biomarker concentrations, the more elaborate T-MACS decision aid (combining biomarkers, symptoms and ECG findings using a computer algorithm), offers greater diagnostic efficiency [1]. T-MACS has been used by Manchester University NHS Foundation Trust (MFT) since June 2016, after developing local solutions for algorithm implementation to capture data electronically. By November 2020, 11,250 MFT patients had been assessed with T-MACS [Fi]. Whereas over 80% of patients were previously admitted to inpatient wards for investigation, 66% are now managed in reclining chairs, in an ambulatory care environment [Fii]. Low risk patients (62%) have 95% probability of going home on the same day, with no adverse events reported. The project won ‘Trust Transformation Prize 2016’ and gained adoption as a Health Innovation Manchester exemplar project [Fii]. T-MACS was implemented at 6 hospitals across Greater Manchester (GM) by December 2020, with 6 more in progress [Fi]. To date, T-MACS has guided care of >30,000 GM patients and, once fully operational, will guide care of approximately 30,000 patients/year throughout GM.

National implementation of rapid rule-out protocol

In 2019, NHS’s Accelerated Access Collaborative (AAC) initiated a project to implement high-sensitivity troponin rule-out pathways nationally. Implementation was incentivised through NHS’s Innovation & Technology Payment [Gi], leading to adoption by Commissioning for Quality and Innovation scheme (CQUIN) for 2020-2021. CQUIN highlights NHS delivery goals for financially incentivised initiatives. ‘Rapid rule out protocol for Emergency Department patients with suspected AMI’ was included as a best practice pathway [H]. NHS England stated, “this could lead to overall national benefits upwards of £20m as a direct result of this improved rule out” [H]. Body was appointed as one of two NHS England Clinical Champions supporting national implementation. In March 2020 Body was invited to present the first AAC/Innovation Agency webinar about adoption of high-sensitivity cardiac troponin testing in NHS trusts through the COVID-19 emergency, supporting implementation [Gii].

Roche and introduction of high-sensitivity cardiac troponin assays in US

In Europe, Roche Diagnostics, used RAPID-AMI findings to market its hs-cTn assay, citing UoM studies in product information [Ii,3,4,5]. In January 2017, Roche’s Elecsys Troponin-T Stat Assay became the first hs-cTnT assay approved by US Food and Drug Administration. Clinician education was vital for transition to high-sensitivity testing in US. Roche stated, “Professor Body has worked with Roche Diagnostics as part of advisory boards to plan the implementation of high-sensitivity cardiac troponin in England and Wales; and in the United States. He has presented at our international symposium…and participated in a Roche-sponsored webinar…produced by Medscape” [Iii]. The webinar was commissioned to support US implementation and was co-authored by Body [Ji]. Roche confirmed UoM research, “ has played a pivotal role in getting these diagnostic pathways into clinical practice” [Iii]. Among the first to begin high-sensitivity testing in 2018 were San Diego Health Center and Massachusetts General Hospital. Campbell County Health, Wyoming, confirmed they began using high-sensitivity testing in 2019 stating in August 2020 that afterwards “ a number of our regional hospitals followed suit, …it is quickly becoming the standard of care across the United States, helping us provide better, safer care for our patients”[Jii]. In 2019, American College of Cardiology recommended transition to hs-cTn for all hospital services, publishing their expert panel recommendations for institutions transitioning to high sensitivity troponin testing. Body was an expert panel member [Jiii,1].

Context

Aspergillus fumigatus is the most common species to cause human aspergillosis infections. It causes multiple disease entities, which are diagnosed and managed differently. UoM researchers have transformed disease concepts and management of pulmonary aspergillosis.

Reach and significance of the impact

Global health impact of Voriconazole

Denning’s seminal research with Voriconazole [1] led to licensure in 2002 and continued worldwide use as first-line therapy for invasive aspergillosis. Voriconazole remains the globally recommended treatment for invasive aspergillosis [A] and its extensive use in other forms of aspergillosis evidences its effectiveness in ABPA, ‘fungal asthma’ CPA and Aspergillus bronchitis [3].

Pfizer’s annual reports show total Voriconazole sales between 2013–2017 of over USD3,000,000,000 [B]. In 2014/15, prior to introduction of generic products, UK National Aspergillosis Centre (NAC) expenditure on Voriconazole was GBP2,800,000, 67% of its total antifungal spend, demonstrating the importance of the drug in treatment [C].

Following a 2017 application citing several UoM papers and supported by Global Action Fund for Fungal Infections (GAFFI), UoM and others, Voriconazole was granted World Health Organization (WHO) ‘Essential Medicine’ status [D]. This status is given only to the most effective and safe medicines needed in healthcare systems and is used by countries as a basis for their essential medicine lists.

Voriconazole is now available in >115 countries globally and generic versions registered in >35 countries [E].

Clinical guidelines for CPA

Denning, working with the European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society, published the first clinical guidelines specifically for CPA (2016). These recommended treatment with Voriconazole [1]; Posaconazole [3] was recommended as a potential alternative [F]. Denning co-authored Infectious Diseases Society of America guidance recommending Itraconazole and Voriconazole as preferred oral antifungals with Posaconazole a “ useful third-line agent for those with adverse events or clinical failure” [Ai].

Enabling effective treatment via accurate diagnosis

UoM researchers have described new clinical entities caused by Aspergillus in addition to SAFS, namely cancer-mimicking Aspergillus lung nodules, and renamed/defined diagnostic criteria for Aspergillus bronchitis in non-immunocompromised patients and cystic fibrosis. The June 2018 revision of WHO’s International Classification of Diseases (ICD11) includes CPA (and sub-types) and Aspergillus bronchitis for the first time [G]. This code is used in health systems worldwide for documenting disease. As a cornerstone of good medicine, accurate diagnostic labelling means these diseases can be treated appropriately.

Guidelines for diagnosing ABPA

Guidelines for diagnosing ABPA resulted from Denning’s collaboration with the International Society for Human and Animal Mycology [H]. They are routinely used by clinicians and in prospective clinical studies. The Chief Executive Officer of Pulmatrix, a US company developing an inhaled antifungal medicine, stated: “ Dr Denning’s collaboration with a global group of experts was central to the development of clear guidelines for the diagnosis of ABPA… clear and consistent diagnostic criteria are fundamental for the development of a clinical program of treatment and form the foundation of our ongoing clinical program to develop such a treatment’ [Iii].

Increased serological testing

Increased recognition of CPA as a clinical entity led to a resurgence of interest in Aspergillus serological testing and radiological interpretation. For example, in 2018, the first point-of-care assay for Aspergillus IgG antibody was launched by LDBio, a French diagnostic company. LDBio’s Research and Development Director stated, “ the important work done by Manchester on aspergillosis, with its global perspective, was one of the key factors that led us into attempting to produce our LDBio Aspergillus assay” [Ii]. LDBio have product distributors in 17 countries and their assay is shipped worldwide [Ii].

Pulling antifungal drug development into new areas of need

UoM’s SAFS research [4] opened new fields of clinical study and drug development. Amongst four companies developing the first inhaled antifungal therapies are Pulmatrix and Pulmocide, both attracting significant financing for their work.

Pulmatrix’s inhaled antifungal is in phase II study in asthmatic patients, initiated in 2019. Their CEO stated, “ Pulmatrix has raised over $60 million [USD60,000,000] through partnership and financing efforts to support all R & D efforts. These efforts have been heavily influenced by the work of Dr Denning and his colleagues at the University of Manchester” [Iii].

UK company, Pulmocide, are developing PC945, a novel triazole inhaled antifungal. Their Chief Scientific Officer (CSO) stated Denning’s research “ has enabled Pulmocide to focus on indications of highest unmet clinical need…Publications from the Manchester group have clarified the diagnostic criteria for infections caused by Aspergillus” [Iiii].

PC945 is currently in phase II trials, including patient recruitment at NAC. It has been used on a “special needs” basis in nine patients, unresponsive to multiple antifungal therapies. Pulmocide reported in July 2020, of nine patients treated, eight showed positive clinical results [J].

On commercial impact, Pulmocide’s CSO stated, “ Manchester publications on disease prevalence have clarified indications of maximal future commercial potential. This has been supportive of the Pulmocide ability to attract venture capital investment for the company” [Iiii]. Pulmocide are supported by top-tier investors including SV Health Investors, Johnson & Johnson Innovation and SR One, GlaxoSmithKline’s corporate venture capital arm [Iiii].

Nationally commissioned infectious disease service

Founded and directed by UoM’s Denning (2009-2020), Manchester’s NAC was the UK’s first nationally commissioned infectious disease service, and the world’s first national clinical centre for a fungal disease. National commissioning was based on Denning’s clinical research expertise [2, 3], clinical care complexity, need for specialised investigations, and antifungal drug cost. NAC and Mycology Reference Centre were awarded European Confederation of Medical Mycology’s Diamond Centre of Excellence status in January 2017, the only such UK centre. From August 2013 to March 2020, >2,500 patients were referred to NAC, >800 were diagnosed with CPA and >9,900 outpatient follow up appointments were attended [C].