Impact case study database

Meningococcal disease is a leading infectious cause of death in young children in the UK. The disease progresses rapidly even with appropriate treatment and can leave survivors with severe disabling after-effects, including amputation, skin scarring and neurological damage. At the time of initial model development for this work, a broadly effective vaccine against group B meningococcal disease was not available, though several candidate ‘MenB’ vaccines were in late stage clinical trials.

Impact on vaccination policy in the UK

In January 2013, once the first broadly effective vaccine against MenB disease (Bexsero) was granted an EU license, policy makers needed to urgently consider if and how to utilise it. In the UK, the requirement for the JCVI to only recommend vaccines that are cost-effective means that mathematical models are used as a key tool to inform policy making, as they can explore multiple different scenarios.

The underpinning research by UoB had indicated which introductory vaccine strategy would have the greatest impact in terms of meningococcal case reduction and estimated the cost-effectiveness of the programme [1]. As a result of submitting evidence on UoB’s research results to a JCVI call for evidence on issues relating to meningococcal vaccination in 2011, Dr Christensen was invited to present the findings of the ongoing model development at closed JCVI meetings in February, April, June 2013, and February 2014 [A].

In March 2014, the JCVI recommended the introduction of Bexsero in the UK with a schedule from UoB’s model that offered the greatest direct protection at reduced cost [2], subject to a cost-effective vaccine price [B]. JCVI’s position statement on the use of Bexsero explained that a “key component” in JCVI’s assessment of the drug was “a study on the impact and cost-effectiveness of different vaccination strategies using Bexsero® conducted by the University of Bristol and London School of Hygiene and Tropical Medicine” [Bi p.2]. UoB’s research is discussed at length (pp.2-3) and cited on five occasions in the statement [Bi]. The vaccine has been offered free on the NHS to babies at 2, 4 and 12 months of age since September 2015 and forms part of the ongoing national programme [B].

Public Health impact in the UK

Bexsero vaccine uptake has been high. In 2019/20, 92.5% of 12 month olds had been vaccinated [C]. The programme has been effective at reducing cases of meningococcal disease [D] and the associated morbidity and mortality. Cases in vaccine-eligible infants halved in the first 10 months of the programme, irrespective of the infants’ vaccination status, and subsequent data have shown a sustained reduction in MenB cases compared with pre-vaccine levels in those targeted for vaccination (Figure 1). By the third year of the programme there was a 75% reduction in MenB cases in children who were fully eligible for vaccination [E]. Due to the vaccine’s composition, it also offers some protection against other capsular groups and, whilst case numbers are small, there is evidence that the vaccine has also reduced MenW disease in infants [D].

Economic impacts for the NHS

UoB’s models suggested vaccination would only be cost-effective at a low vaccine price [2]. The JCVI can only recommend introducing a vaccine if it is deemed cost-effective, thus UoB’s models were critical to their decision to recommend the vaccine and at what price.

These were the only independent models considered by JCVI [B]. The list price for the Bexsero vaccine in the UK was GBP 75 per vaccine dose; however, UoB’s final model results suggesting ≤GBP 7 per dose [2] were used to inform the procurement process, thus leveraging a considerable saving to the NHS. As for all vaccines procured for the NHS, the final price paid for the vaccine is confidential. Notwithstanding, if the negotiated price of the vaccine was close to that suggested by UoB’s final model, it can be assumed that the research could currently save the Department of Health approximately GBP 136 million annually on delivering the programme (difference between GBP 75 and GBP 7 for a 3-dose vaccine given to a birth cohort annually of 722,881 UK infants with 92.5% uptake).

Impact on international vaccination policy

The models developed for the UK have been adapted by the UoB-led group in collaboration with international researchers to inform Bexsero policy decisions in Belgium (2014) [G] and Germany (December 2013) [H]. Our group was approached by researchers at the Robert Koch Institute and the Belgian Healthcare Knowledge Centre and commissioned to undertake the work. Models for these countries [3] indicated that whilst vaccination could reduce case numbers, immunisation would be beyond that normally considered cost-effective; consequently, these countries have not recommended widespread introduction of the vaccine [G, H].

Figure 1: MenB cases in children under 5 years of age during 2013/2014–2018/2019 surveillance years (September–August following year) in England (solid line) compared with MenB cases predicted by trends among unvaccinated childhood cohorts (dashed line) over the same period. The arrow indicates the start of the MenB infant immunisation programme. Only around half of the birth cohorts in children under 5 in this figure were eligible for the Bexsero vaccine, thus underestimating the true impact of the vaccine in those who actually received it [F]. In children who were fully eligible for vaccination there was a 75% reduction in MenB cases by the third year of the programme [E].

IRIS was a landmark trial [1] in DVA research, evaluating a training and support programme, including a referral pathway, designed to improve the response of general practice to women experiencing domestic violence. It had an initial impact on national policy and service implementation in the two years after its publication in 2011. Here we focus on its impact post-August 2013.

Benefits to women and practitioners

Figure 1 - Cumulative total referrals to IRIS from across England, Wales and Northern Ireland (2011 – 2020) [A].

Up to March 2020, 48 localities in England and Wales have commissioned the IRIS programme; 1,036 practices have been trained and over 20,544 women (Figure 1) referred from these practices to DV services [A]. The other benefit for patients is a safer and more appropriate response of clinicians to disclosure of domestic violence, a core feature of the IRIS intervention. We have evidence for this impact from feedback from patients who disclosed abuse to their GPs and were referred to an IRIS advocate educator [A (p.12)] and evidence of the sustained effectiveness of the IRIS model from an interrupted time series study of IRIS implementation in north London [5].

A total of 302 general practices received training during April 2019 – March 2020, with 265 clinical training sessions, 157 for reception staff, and 132 refresher courses. IRIS reaches an older demographic of women who we know are less well represented in specialist DVA services. It is a positive feature of IRIS being able to reach an otherwise invisible groups of survivors.

In response to the COVID-19 pandemic, IRIS moved from a fully face-to-face to a fully virtual programme, including webinar versions of all training packages. As a result, all IRIS Advocate Educators have been able to continue supporting patients during the pandemic. National data shows an initial reduction in referral cases (March-April 2020) followed by a renewed increase in referrals (May-June 2020). IRIS has been able to collect feedback on their support from 1,500 women. 98% were pleased to have been referred to an Advocate Educator. In response to other questions, more than 80% said they felt safer, more confident, more able to cope, and optimistic about the future. For example: “I was unaware of what types of abuse I have been going through and it has opened my eyes for a better and brighter future for my unborn child and myself. Thank you for everything it has been appreciated”. [A]

Furthermore, IRIS ADVISE – an adaption of IRIS for sexual health settings – has been piloted in east London and Bristol [6]. It is now being commissioned in Manchester [Bi] and commissioners in other areas have expressed an interest.

Impact on national policy

In 2013, IRIS was cited in the Home Office’s Domestic Homicide Reviews – Common Themes Identified as Lessons to be Learned [C], as a way to improve local provision. The 2014 NICE DVA guidelines [Di] had a specific training and support recommendation for primary care, based explicitly on IRIS and directly informing a NICE DVA quality standard [Dii]. In 2016, the UK Home Office’s refreshed Violence Against Women and Girls Strategy (2016-2020) endorsed IRIS as a key part of the strategy and included the programme in its action plan [E]. IRIS was recommended for local adoption by the government’s National Statement of Expectations (NSE) for Violence Against Women and Girls Services and the IRIS programme was promoted in the Home Office’s Modern Crime Prevention Strategy [F (p.13)]. In Wales, IRIS was similarly endorsed as an innovative approach for early intervention in the National Strategy on Violence against Women, Domestic Abuse and Sexual Violence (2016-2021) [G]. IRIS has recently been cited in the MOPAC (Mayor's Office for Policing And Crime) Violence Against Women and Girls strategy: The London Tackling Violence Against Women and Girls Strategy 2018-2021 [H], as an example of good work within the health sector (Greater London Authority, 2018). The UK INCADVA (Inter-Collegiate and Agency Domestic Violence Abuse) forum’s June 2020 evidence submission to Parliament pressed for uniform national implementation of the IRIS programme within the statutory instruments of the UK’s Domestic Abuse Bill [J].

Benefits to NHS staff

Intermediate beneficiaries from the widespread implementation of IRIS have been the doctors, nurses and other members of the practice teams in the 1,036 IRIS practices in England and Wales. Feedback from general practice teams (20,000 individuals) [A (p.13)] following training shows an increase in participant knowledge and described the session as ‘invaluable and addressed a real hole in our learning’. Nineteen out of twenty clinicians would recommend IRIS training to a colleague. Following IRIS training, GP reception teams reported that their confidence to deal with and respond appropriately to patients experiencing DVA rose from 4.2 to 8.3/10. [A]

Impact on international policy

The landmark 2013 World Health Organisation publication titled Responding to intimate partner violence and sexual violence against women: WHO clinical and policy guidelines [I] drew heavily on UoB’s research [1]. Specifically, this research helped frame their approach, and in making recommendations about the training of healthcare providers there was specific citation of the IRIS model [I (p.33)]. IRIS has been the basis of two European projects and is now informing interventions in an NIHR Global Health Group (Healthcare responding to violence and abuse, HERA) in Palestine, Brazil, Nepal and Sri Lanka, including wider country-specific implementation (e.g. implementation in Sao Paulo) [Bii].

Economic impact

Based on the results of our cost-effectiveness modelling [2] which has been updated using our non-trial data [5], we estimate the annual societal cost saving associated with IRIS is greater than GBP2,400,000. This modelling indicated that implementation of the IRIS programme is cost-effective as judged by NICE criteria, generates societal cost savings and is likely to reduce NHS costs. This estimated cost saving is conservative, as it does not include benefits to children exposed to DVA.

The National Institute for Health and Clinical Excellence (NICE) issue technology appraisal guidance on whether new or existing treatments are effective, represent good value for money, and can be provided to NHS patients in England (with the guidance also adopted in Wales). The NHS is legally obliged to fund treatments recommended by NICE’s technology appraisals, and so the appraisals directly impact the treatment options available to patients. NICE also issue clinical guidelines for healthcare professionals to help them decide on appropriate treatments and services for their patients. Whilst NICE clinical guidelines are not mandatory, their uptake is generally good ( www.nice.org.uk/about/what-we-do/into-practice/measuring-the-uptake-of-nice-guidance/impact-of-guidance). NICE technology appraisals and clinical guidelines are based on both clinical and cost-effectiveness, therefore adoption of their recommendations secures more health-related quality of life per pound spent by the NHS and, hence, improves outcomes for patients.

The methods for evidence synthesis and critical appraisal tools developed by UoB researchers are used by pharmaceutical companies [a] and consultancy firms [b] preparing submissions to NICE technology appraisals, academic groups critiquing those submissions, and NICE guideline developers [c]. Here we demonstrate how the methods are routinely used in NICE technology appraisal guidance [c][d] and NICE clinical guidelines [c][e], and so directly influence the resulting recommendations and treatment options available, improving health-related quality of life. Further, the methods have had global impact: they are also recommended and used in submissions to healthcare reimbursement agencies in several other countries [a][b][f], in both insurance- and state-funded health systems, enabling better-informed decisions and supporting equitable and optimum resource allocation by health service purchasers around the world.

Use of UoB methods in NICE Technology Appraisals (TAs) and Clinical Guidelines (CGs)

Two reviews by UoB of the evidence synthesis methods used in all NICE Technology Appraisal (TA) guidance issued [d] and all NICE Clinical Guidelines (CGs) published [e] between 1 October 2017 and 30 September 2020, have determined the percentage that used UoB’s methods [1-6]. The results, presented below, are based on the145 TAs [d] and 62 CGs [e] that were either new guidance or updated guidance containing new analyses during that period.

Network meta-analysis (NMA) methods

NMA was conducted in 51% of the TAs [d]. Across a variety of clinical areas, UoB’s NMA methods [1] were cited in 36.6% and implemented in 35.9% of all TAs [d], and cited and implemented in 33.9% of CGs [e]. We can expect the use of UoB’s NMA methods to be similar for the earlier part of the current REF period (August 2013-September 2017), given that these recent results are in line with those from an earlier analysis (2009-2013), conducted for the research group’s REF2014 Impact Case Study [j]. Among the 2017-2020 CGs, automated node-splitting method to assess inconsistency [2] was cited in 21% of CGs and implemented in 11.3% of CGs [e]. UoB’s review, critique and recommendations for population adjustment indirect comparisons [3] was cited in 24.8% of TAs and implemented in 19.3% of TAs [d].

Reconstruction of survival curve data

Risk of bias of RCTs and non-randomised evidence

The risk of bias tool for RCTs [5] is cited in 22.8% of TAs and implemented in 20.0% of TAs [d]. It is cited in 50% of CGs and implemented in 83.9% of CGs [e]. The ROBINS-I risk of bias tool for non-randomised studies [6] is cited in 19.4% of TAs and implemented in 16.1% of TAs [d] and cited and implemented in 9.7% of CGs [e].

Illustrative examples of impact arising from NICE TAs and CGs using UoB methods

TA384 Nivolumab for advanced melanoma / TA417 Nivolumab for treated or metastatic renal cell carcinoma

In TA384, Bristol Myers Squibb used the Guyot algorithm [4] to reconstruct survival data to inform the indirect comparison between two forms of treatment for renal cell carcinoma (a kidney cancer): nivolumab and BRAF inhibitors in BRAF mutant positive patients (p.178 of committee papers [g] reference 196). The Evidence Review Group (ERG) considered use of the method to be appropriate (pp. 445-6 in committee papers [g] ref 26), noting that it allows different survival curves to be fitted and compared. They further note that costs of the BRAF inhibitors were sensitive to this choice (costs differ by about GBP18,000, p 488 and p.500 committee papers **[g]**), but that nivolumab remained cost-effective (p.505 of committee papers [g] section 4.3.2). The company used the Cochrane risk of bias tool [5] to critically appraise the included studies (pp. 447-8 of committee papers **[g]**). The committee concluded that nivolumab is likely to cost less than an additional GBP30,000 per quality adjusted life year gained compared with existing treatment options and recommended it as a cost-effective option for the NHS. The NICE impact report for cancer [g] (Figure on p.10 of the report) showed there was a rapid increase in prescriptions of nivolumab after the TA384 guidance was issued in February 2016, from 100,000mg in early 2016 to over 300,000mg within just a few months. This indicates that patients are benefiting from the increased quality of life that nivolumab brings. A similar increase in prescriptions was seen for TA417 (Nivolumab for treated or metastatic renal cell carcinoma) issued in November 2016 [g] which also used the Guyot algorithm [4] (p.459 of committee papers).

TA510 Daratumumab monotherapy for treating relapsed and refractory multiple myeloma

For this TA, individual participant data were obtained for the comparator treatments for multiple myeloma (a bone marrow cancer): (POM+DEX) and (PANO+BORT+DEX) using the Guyot algorithm [4]; this enabled estimation of hazard ratios comparing daratumumab with existing treatment options, which would not otherwise be possible (p.213 committee papers **[h]**). The company performed a matched adjusted indirect comparison (MAIC), which the Evidence Review Group (ERG) critiqued using Phillippo et al [3], highlighting the high level of uncertainty in the MAIC and the need to adjust for more factors and seek validation (pp. 688-9 or the committee papers **[h]**). The company adjusted for additional factors but was unable to validate the adjustment method (pp. 9-10 4.12 final appraisal determination document **[h]**). The committee recommended managed access through the Cancer Drugs Fund to collect data to resolve some of the uncertainties around clinical effectiveness, including the MAIC, as highlighted by the ERG using Phillippo et al [3] (pp. 20-23 final appraisal determination document **[h]**). It is predicted that 705 patients per annum will benefit from access to daratumumab while data are collected to determine if it is a clinically and cost-effective treatment for routine commissioning on the NHS (p.3 section 3.3 managed access agreement **[h]**).

NG158 Venous thromboembolic diseases: diagnosis, management and thrombophilia testing

Recommendations on pharmacological treatment in people with suspected or confirmed deep vein thrombosis and/or pulmonary embolism employed NMA to compare multiple interventions using methods and code from [1] (p.17 point 20 and Appendix O of Document D **[i]**). The automated node-splitting algorithm [2] was used to assess the consistency assumption (p.754 of Document D **[i]**). The Cochrane risk of bias tool [5] was used to assess the RCTs and quasi-RCTs, and the ROBINS-I tool [6] was used to assess the other studies (p.128 of Document D **[i]**). The resource impact report published in March 2020 [i] resulting from recommendations 1.3.8, 1.3.15, 1.3.17 (informed by Document D **[i]**), is estimated to save GBP0.4 million in 2020/21, rising to a saving of GBP2.1 million in 2024/25 (p.3 Resource Impact Report, Table 1 (total a+b) **[i]**).

Use of UoB methods by reimbursement agencies globally

UoB have further reviewed methods guidance for evidence synthesis in submissions to reimbursement agencies (similar to NICE for England and Wales), issued between 2014 and 2020, in Australia (Pharmaceutical Benefits Advisory Committee), Canada (Canadian Agency for Drugs and Technologies in Health), France (Haute Autorité de Santé), Germany (Institut für Qualität und Wirtschaftlichkeit im Gesunheitwesen), Ireland (Health Information and Quality Authority), the Netherlands (Zorginstituut Nederland), the USA (Agency for Healthcare Research and Quality), and the World Health Organisation (WHO) [f]. The Technical Support Document Evidence Synthesis (TSD-ES) series and corresponding Medical Decision Making papers [1] are cited in the methods guidance in Canada, England and Wales, France, Germany, Ireland, the Netherlands, and the USA [f]. The automated method for node-splitting to assess inconsistency [2] is cited in the methods guidance in Ireland, the Netherlands, and the USA [f]. TSD18 [3] and the corresponding paper on population adjusted indirect comparisons is cited in the methods guidance in England and Wales, France, and Ireland [f]. The algorithm to reconstruct survival data from published survival curves [4] is cited in the methods guidance in Canada [f]. The risk of bias tool for RCTs [5] is cited in the methods guidance in Australia, Ireland, the USA and the WHO, and the updated version 2 tool (published in 2019) is cited in the methods guidance in England and Wales [f]. The ROBINS-I tool [6] is cited in the methods guidance in Australia, England and Wales, the USA, and the WHO [f]. The use of UoB methods in international submissions in France, Sweden, Canada, Australia, South Korea and the USA is confirmed in letters from pharmaceutical firms AstraZeneca and Eli Lilly [a], and the consultancy firms Precision Health Economics and Outcomes Research and Clifton Insight [b].

Commercial impact

The use of methods developed by UoB researchers by pharmaceutical firms in about 36% of all submissions to NICE TAs [d] represents a substantial impact in supporting commercial activity, confirmed in the letters from pharmaceutical companies [a] and consultancy companies [b]. These methods are used in submissions to other reimbursement organisations worldwide [a][b][f].

The ProtecT trial outcome papers published in 2016 [4, 5], provided the first (and only) clear and robust comparative evidence about the risks and benefits of the three major treatments for localised prostate cancer. ProtecT had the following impacts: (a) changed health policy to influence clinical practice, (b) changed clinical practice to avoid harm and optimise treatment, and (c) continues to improve health and care by enabling informed evidence-based treatment decisions:

(a) Changed health policy to influence clinical practice

Publication of the ProtecT outcomes led to UK NICE launching an exceptional review “to determine the clinical and cost-effectiveness of treatments for localised prostate cancer”, directly referring to ProtecT as “the only UK-based study, making it directly applicable to current practice in the NHS” [A p.11]. An updated guideline: NG131 Prostate cancer: diagnosis and treatment was issued in 2019 [B] with changes to three major recommendations based on ProtecT evidence:

1. Treatment of low-risk prostate cancer2019-NG131 new recommendation was to “offer a choice between active surveillance, radical prostatectomy or radical radiotherapy to people with low-risk localised prostate cancer for whom radical treatment is suitable” [B p.13]. (Changed from 2014-CG175: “offer active surveillance… as an option to men with low-risk localised prostate cancer”) [C].

2. Treatment of intermediate-risk prostate cancer2019-NG131 new recommendation was to “offer radical prostatectomy or radiotherapy and consider active surveillance for people with intermediate-risk localised prostate cancer” [B p.19].

(Changed from 2014-CG175: “consider active surveillance for men with intermediate-risk localised prostate cancer”) [C].

1. Informing evidence-based treatment decision-making2019-NG131 new recommendation advising clinicians and patients to use Table 3, comprising “factors to consider … using evidence from a large UK trial (ProtecT) … to discuss the benefits and harms of each treatment option” when deciding on treatment for low- and intermediate-risk prostate cancer [B].( No such Table was included in 2014-CG175) [C].

Major international clinical guidelines rapidly incorporated ProtecT results, e.g.:

• American Urological Association/American Society for Radiation/Society of Urologic Oncology, 2017, citing ProtecT evidence for treatment of localised prostate cancer [Di].

• European Association of Urology/European Society for Radiation Oncology/ European Society of Urogenital Radiology/International Society of Geriatric Oncology, 2017, citing ProtecT “level 1 data to help patients navigate the choice between active monitoring and treatment, and balance the risks and benefits” [Dii p.8].

• US Preventive Services Task Force recommendation of “individual decision by men” for prostate cancer screening, referring to evidence of “overdiagnosis, overtreatment, and treatment complications” from ProtecT, [Diii p.1902].

(b) Changed clinical practice and avoided harm by reducing over-treatment

Before ProtecT, studies in the UK and USA showed that over 90% of men diagnosed with localised prostate cancer received radical treatment, usually surgery. As ProtecT recruited successfully (2001-9), there was growing awareness of the need to reduce the level of radical treatment. NICE guidelines in 2008 and 2014 relied on expert opinion (including from ProtecT investigators) to “offer” active surveillance as an option, particularly for men with low-risk disease. Further, in 2014, the National Prostate Cancer Audit (NPCA) was established to assess the quality of services in England and Wales. NPCA set a major benchmark – to “reduce over-treatment of men with low-risk prostate cancer” – by auditing the percentage of men with low-risk prostate cancer receiving radical treatment. NPCA estimated 28% of men were over-treated in 2014 [Ei]. In 2016, it was 12%, and NPCA authors commented, “the proportion of men with low-risk disease being potentially ‘over-treated’ is an area of concern, especially given the recent publication of the ProtecT study,” [Ei p.47-8]. In the years after the publication of ProtecT, over-treatment reduced further to 8% in 2017, and to 4% in 2018 and 4% again in 2019 [Eii].

In addition, NPCA reported serious concern that over-treatment varied so widely (from 0% to 94%) across the 51 hospital-clusters in England [Ei]. Following ProtecT study publication, geographical variation in over-treatment largely disappeared (0% to 16%), with no concerning outliers [Eii, Figure 2].

(c) Continues to improve patient health and care through informed evidence-based treatment decision-making

Men newly diagnosed with clinically localised prostate cancer, their families, and the clinicians involved in prostate cancer care (urologists, oncologists, nurses, and general practitioners) can now consider the comparative benefits and harms of the main treatment modalities based on robust evidence from the ProtecT study to inform treatment decision-making. They can balance the clear risks of treatment harms and benefits in the context of similar very low levels of mortality risk, based on ProtecT trial evidence [4, 5]. This affects the decision-making of over 23,000 men diagnosed each year with low- or intermediate-risk prostate cancer in England alone [Eii]. Guidelines across the UK [B], Europe and the USA [D] encourage consideration of the ProtecT evidence in decision-making indicating wide reach and impact.

ProtecT evidence also directly reached men through over 400 media stories (review of 33 published within 30 days [Fi]), popular prostate cancer charity websites (such as Cancer Research UK [Fii] and Prostate Cancer UK [Fiii]), and the high social media presence of the study [Fiv] (paper [4] ranked 5^th for social media impact in 2017 (63^rd in 2020)).

ProtecT evidence reached clinicians and service providers through high citation papers (1,500 [4] and 700 [5], with paper [4] being listed as one of the NEJM’s 12 notable articles of 2016 [Gi] and Altmetric’s 22^nd most impactful paper globally that year [Gii]); and through editorials in key specialist clinical journals [H] as well as updated guidelines [B, D].

Summary: ProtecT outcomes published in 2016 changed clinical practice and health policy, and the evidence continues to improve patient health and care by optimising treatment and enabling informed evidence-based treatment decision-making.

Reduced IVF related multiple birth rate in the UK

Lawlor and colleagues’ research demonstrating the benefit of single embryo transfer in women younger than 40 years, and of a double transfer in older women, has enhanced the efforts of the HFEA to increase single embryo transfer and hence reduce harm associated with IVF [A-D].

Between 2008 and 2012, single embryo transfer in the UK increased from 18% to 45%, and multiple birth rates decreased from 25% to 15% by 2011 [A]. These improvements became static from 2011 and transfer of three embryos was more common in the UK than most European countries [A]. The HFEA used findings from Lawlor and colleagues’ research [1] to promote single embryo transfers in younger women and double transfer in older women. This has led to a further increase in single embryo transfers (45% to 60% from 2013 to 2016) and associated decreases in multiple pregnancies and multiple births [B, C]. The Chief Executive of HFEA describes the importance of the research in ‘providing continued momentum for our campaign to promote ‘one at a time’ embryo transfers and see IVF related multiple births, with their associated risk of preterm birth and low birth weight, reduced.’ [D]. The statement further confirms the continued declines in multiple births, with HFEA’s target of a maximum 10% of live-births being multiple births achieved by 2017 and further declining to 8% by 2018 [D].

Changing practice in relation to repeat treatment cycles

Prior to work by Lawlor and colleagues, governments and insurance companies internationally limited the number of IVF cycles they would fund. In the UK there was variation across countries, and by clinical commissioning groups (CCG) within England, with no country/CCG providing NHS funding for more than two cycles. Clinicians and funders cautioned against further cycles (even when couple-funded) following a cycle where no eggs were retrieved. Lawlor and colleagues’ research, showing that live-birth rates continued to increase with successive IVF cycles, regardless of the number of oocytes retrieved [2], was cited by the Scottish National Infertility Group in their 2016 government report to request an increase in the number of NHS-funded treatment cycles [E (p.17)]. This resulted in Scotland changing its guidelines to recommend up to three (from the previous limit of two) full cycles for eligible patients to be funded by the NHS from 2017 [F]. As a result of these changes, equity of access to IVF and the number of cycles funded by the NHS in Scotland increased, such that by 1^st April 2017, all newly referred couples who were eligible were provided with up to three NHS-funded cycles [F]. Since publication of this response to Lawlor and colleagues’ research, the proportion of all IVF cycles in Scotland funded by the NHS has increased from 56% to 62% [G]. The action by Scotland was welcomed by patient support groups, ‘We commend the Scottish Government both for recognising the importance of treating this medical condition, and for taking action to help the one-in-six couples affected by infertility’ [H].

Lawlor and colleagues’ research made a major contribution to NICE (supported by the HFEA, the Royal College of Obstetrics and Gynaecology (RCOG) and patient groups) increasing pressure on CCGs to implement NICE guidelines. Lawlor and colleagues’ research [3, 4] and bespoke analyses undertaken by Lawlor for NICE, contributed to the economic evaluation used by NICE Fertility guidance (CG156) on access criteria for IVF (Chapter 14) (2013). On the basis of that economic evaluation NICE recommended, for the first time, that funding be provided by the NHS for up to three IVF cycles. In subsequent revisions of those NICE guidelines (in 2015 and 2017) presentation of Lawlor’s economic evaluation remained, and there is greater emphasis on the recommendation that up to three cycles be NHS-funded [Ii]. Lawlor and colleagues more recent (2015) research, showing continued increases in live-birth success with repeat cycles [2], has been used by NICE to further emphasize to CCGs in England why funding three cycles is important [Iii]. In conjunction with the RCOG and patient groups, the HFEA have directly issued guidance to each CCG in England, notifying them of the strong evidence and NICE guidelines, meaning it is imperative that they support up to three IVF cycles [D, J]. The Chief Executive of HFEA notes that ‘As an authority with a remit to support equitable and fair access to infertility treatments, we value research, such as this by Prof Lawlor and colleagues, that we have been able to use in our guidance to commissioning groups in England.’ [D].

A. Impact on international health and agricultural policies

Global pesticide guidance

Suicide reduction is a target set by the UN’s Sustainable Development Goals (SDGs) as an indicator of healthy lives and wellbeing (SDG 3). UoB research “ has been important in

helping WHO formulate its strategy to attain the suicide reduction target” (Head, Mental Health Unit, WHO) [A]. Notably, it has been influential to UN recommendations, made by WHO and Food and Agriculture Organisation (FAO), to ban highly hazardous pesticides. The WHO/FAO’s joint guidance for pesticide regulators to prevent suicide (2019) [B] (commissioned from and co-authored by UoB researchers), draws on UoB’s research findings to state: “ Regulatory action… indicates that many suicide deaths can be prevented by bans on specific pesticides. In Sri Lanka, for instance, bans are thought to have led to 93 000 fewer suicide deaths between 1995 and 2015”. The guidance goes on to recommend: “ identifying highly hazardous pesticides for withdrawal” and “ taking regulatory actions to phase out the most hazardous pesticides”. Furthermore, the guidance cites UoB trial evidence [4] indicating that the industry-preferred alternative (lockable storage devices) is ineffective: “ The one randomized controlled trial that was large enough in scale … to test the effectiveness of lockable household pesticide storage containers found no evidence of effectiveness”.

Gunnell was a member of the WHO expert panel (2018-19) that worked with health economists to model the cost-effectiveness of pesticide regulation, concluding that “ national bans are cost-effective in countries where a high proportion of suicides are attributable to pesticide self-poisoning” [A] [3]. Based on this analysis, pesticide bans were recommended by WHO as a ‘Best Buy’ (a cost-effective and feasible intervention) for non-communicable disease at the World Health Assembly in November 2020 [A].

UoB research on preventing pesticide suicide was included in the 2016 World Bank report on suicide prevention (six UoB research papers cited) [Ci]. In addition, the WHO World Suicide Report (2014) [Cii] cited UoB evidence that pesticide regulations would result in fewer suicide death, as well as UoB’s recommendations to ban high lethality pesticides.

International pesticide bans and impact of bans on suicide rates

Governments/Ministries of Agriculture in several countries have banned highly hazardous pesticides in recent years [D]:

1. Taiwan banned paraquat in 2018 [Di, Dii].

2. Nepal banned aluminium phosphide and five other pesticides in 2019

3. Malaysia banned paraquat in 2020

4. India banned 12 highly hazardous pesticides in 2018 and a further six in 2020 [Dviii].

WHO health economists estimate that pesticide bans in the 14 countries they studied could result in an estimated 28,000 (95% UI 24,000–32,000) fewer suicide deaths each year [4]. Evidence supporting this claim is beginning to emerge. For example, in Taiwan, the annual number of suicide deaths from pesticide poisoning fell by 37% in 2019, almost 200 fewer deaths [Di]. Even larger declines have been seen in Sri Lanka [Div] and South Korea.

B. Impacts on media practice and policy

UoB researchers have raised awareness among UK policymakers, UK news journalists, and the global online industry, of the risks of contagion arising from publicising suicide and self-harm methods. As a result, UoB researchers have shaped media policy debate, journalistic practices and online media policy. These steps all promote the safety of media users by limiting access to content that could lead to suicide.

UK policy: online suicide content and user safety regulatory proposal

Evidence from Biddle and colleagues, which scoped ‘encouraging or assisting suicide’ as a distinct form of online harm, fed directly into recommendations made to Government in order to moderate harmful content and support users. The Health Select Committee Report on Suicide Prevention (March 2017) “ urges the Government to closely examine the findings of that [UoB’s] research and to report back to us on the action that it proposes to take as a result” [Ei p.35]. The 2018 All-Party Parliamentary Group on Social Media and Young People’s Mental Health and Wellbeing inquiry report, acknowledging Biddle’s contribution, recommends Government introduces a statutory code of conduct for social media providers to protect the mental health of UK users [Eii]. The UK Government White Paper on Online Harms (2019) [Eiii] subsequently proposed a new regulatory framework for online safety, which will establish “ a new statutory duty of care to make [online tech] companies take more responsibility for the safety of their users and tackle harm caused by content or activity on their services” (p.7). Specifically addressing suicide, it states “ Companies will be required to take robust action to address harmful suicidal and self-harm content that provides graphic details of suicide methods and self-harming, including encouragement of self-harm and suicide” (p.72).

UK media sector’s awareness of contagion

Working with Samaritans – a research/ policy active organisation and the only charitable provider of suicide support in the UK – UoB have delivered training sessions with local and national UK news editors and journalists to advise on how to report suicide to prevent method contagion [Fii-v]. This has included a presentation to the Independent Press Standards Organisation (IPSO) in 2016, which was reported by the Deputy Chair of IPSO in The Press Gazette [Fi], a publication for UK journalists (200,000 unique visitors to its website per month). In the article, the Deputy Chair remarks that speakers from UoB and Oxford University “ provided what was to my mind powerful evidence about the net increase in suicides due to excessive detail in both news reports and dramas” before recommending “ Next time you’re running a story on suicide please stop and consider a simple equation: weigh up the potential benefits to anybody of including those details, and the possibility that by leaving them out you might, realistically, save a life.” [Fi].

Global online provider guidelines: reducing access to suicide and self-harm content

In 2017, UoB and Samaritans co-hosted a series of awareness-raising engagements for the online industry including roundtable events held with safety and policy leads with jurisdictions encompassing the UK, Europe, the Middle East and Africa from Google, Twitter, Facebook, Wikimedia, Apple, YouTube and Instagram. This culminated in the establishment of a three-year strategic partnership between Samaritans, the online industry and the Department of Health and Social Care to improve management of suicide content online. A key output from this partnership is Samaritans’ guidelines for online providers published in 2020, with Dr Biddle as academic advisory panel member [G]. Aimed at policymakers and moderators of sites, platforms, forums and search engines hosting user-generated content, these guidelines are the first to provide best practice principles for managing self-harm and suicide content online [I].

Facebook and Instagram self-harm prevention policies

Biddle was consulted by Facebook and Instagram (over 2.7 billion and 1 billion monthly users, respectively) to provide expert input into their review of safety policies relating to self-harm content. This led to participation in an international expert roundtable and a subsequent change to Facebook’s [Hi] and Instagram’s [Hii] policies, published February 2019, and listing Dr Biddle as an advisor. Reflecting UoB’s research recommendations [1,6] the updated policies disallow users to share graphic content of self-harm. For instance, Instagram announced: “ following a comprehensive review with global experts and academics on youth, mental health and suicide prevention… We will not allow any graphic images of self-harm, such as cutting” [Hii].

Improving online help

UoB findings [1,6] around suicidal individuals’ preferences for live and immediate online help services were used to inform Samaritans’ digital strategy, which has been fundamental to the establishment of an ‘online chat’ service now running three evenings a week [I]. Samaritans receive over 3 million requests for support annually.

Prostate cancer places a significant burden on public health globally, causing an estimated 6 million years of life lost in 2016, a figure that is forecast to rise to 12 million by 2040. Amongst UK males, prostate cancer is the most commonly diagnosed cancer, affecting 1 in 8 men, and is the second commonest cause of cancer death.

The CAP trial provided the first and only robust evidence comparing a low-intensity PSA-based screening strategy (a single screen) for prostate cancer with no screening, minimal contamination [3.3], and was designed to reduce overdetection and overtreatment while seeking a mortality benefit. It showed that while PSA-based screening increases the detection of low-risk prostate cancers, it does not save lives. The results were disseminated widely, including through print and broadcast media locally, nationally and internationally that involved interviews with Martin and Turner. The CAP trial won the 2018 Office for National Statistics (ONS) Research Excellence Awards, recognising outstanding use of ONS research data for public benefit . (“The award winning submission from Emma and her team shows the fantastic public benefit that can be achieved through innovative methodology, exceptional collaboration and excellent use of Secure Research Data” Director for Methods Data Research at the ONS). The CAP trial is cited as a highlight in CRUK’s timeline of lifesaving research [5.1ii].

In the current REF period, the results of the CAP trial have informed UK and international guidelines on the use of the PSA test for prostate cancer screening, helping to avoid harms to men and reduce unnecessary costs to the NHS and globally (such as in the USA).

1. Impacts on UK and international health policy and professional practices

The research has helped policymakers make evidence-based decisions about the population impact of PSA-based screening for prostate cancer. The CAP trial led to changes in health policy and professional guidelines around the world, with clinicians and health services now advised to encourage individualised shared decision-making (informing men of the possible harms and benefits and supporting decision making) rather than routine screening. These new guidelines help ensure that patients (men aged 50-69 years), GPs and urologists are better informed about the benefits and harms of PSA screening for prostate cancer.

1.1 New UK guidance on PSA tests

The CAP trial provided the UK National Screening Committee (NSC) with high-quality, UK-based evidence to inform new Public Health England (PHE) guidance for GPs on the balance of benefits and harms of PSA-based prostate cancer screening, published in January 2020. The importance of the CAP results in these guidelines is confirmed in writing by the Director of the UK NSC [5.2i].

On 6 March 2018, the Royal College of General Practitioners released a statement [5.3] in response to the CAP paper published the same day [3.1]. This stated that “ the College does not recommend that the PSA test is offered routinely to men who do not present with prostate cancer symptoms”. Further, it praised CAP as a “ large, high-quality study” that is “really useful in backing up our calls for GPs to have better access to a more specific and sensitive test than the PSA test” [5.3].

1.2 New international guidance on PSA tests

In the USA, the results of CAP had a major influence on the recommendations of the United States Preventative Services Task Force (USPSTF), a public health body, published in May 2018 [5.4]. These advised that the decision to screen is a complex one, and that men should be carefully counselled about the benefits and harms of screening to make a fully informed decision. The Bristol research team liaised regularly with the USPSTF in the year prior to publication once they had undertaken the CAP analysis, providing USPSTF with a draft manuscript and advising on the timing of publication. The USPSTF recommendations, published May 2018, cited CAP’s results [3.1] and were delayed until the CAP trial publication (March 2018) so that the results of CAP could be included in the Evidence Report that informed USPSTF’s recommendations [5.4]. The American Urological Association (AUA) also included CAP (citing 3.1) in its body of evidence underpinning clinical guidelines on Early Detection of Prostate Cancer (June 2018) [5.4]. The AUA also argues for shared decision-making for men aged 50-69 years who are considering PSA screening.

In other countries, the trial results [3.1] were cited in updated urological and oncological guidelines for the early detection of prostate cancer. For example, Clinical Guidelines for the Screening and Early Detection of Prostate Cancer in Denmark were updated in 2019: “Neither systemic nor opportunistic screening of prostate cancer is recommended”, evidence rated as strong [5.5i]. Italian guidelines also updated in 2019 “informed of the (many) risks and (limited) benefits associated with the test” [5.5ii]. The European Urology Association (EAU) cites CAP results in their review of the frequency and intervals of PSA testing [5.5iii]. The Canadian Urological Association (CUA) cited initial CAP results [3.4] in its guidelines published in 2017. The Canadian guidelines precede the publication of CAP’s full trial results in 2018, but it recognised that these results would likely feed into future reviews [5.6].

In September 2018, a rapid recommendation on prostate cancer screening with PSA testing was published in the BMJ [5.7]. This guidance, developed by an international panel for urological surgeons, was triggered by the results of CAP [3.1], published earlier that year: “ The Rapid Recommendations executive felt [CAP]— taken together with extended follow-up data from existing trials—required a new appraisal of the body of evidence for patients and clinicians.” Drawing on evidence from CAP and other studies, the Recommendation advises: “ Shared decision making is needed for men considering screening to make a decision consistent with their individual values and preferences. However, clinicians need not feel obligated to systematically raise the issue of PSA screening with their patients”.

2. Economic impacts: reduced costs to healthcare providers

Health policy changes occurring as a result of the trial, will reduce unnecessary costs to the health authorities around the world who adopt the revised screening guidelines. In the UK, the costs of annual routine screening have been estimated to be GBP1 billion, were it to be introduced by the NHS, according to a School of Health and Related Research (ScHARR) report to the NSC in March 2013 [5.8]. The ScHARR report explains: “ Routine screening for prostate cancer clearly will have a significant impact on resource use, both for screening and diagnosis of cancers, but also for the treatment or monitoring of cancers that would otherwise remain unidentified. The resources most impacted are those required for screening itself. [Annual screening] would result in almost 10 million more PSA tests per year and 1.4 million biopsies. Whilst a large increase in many resources would be required (e.g. GP nurse sessions, PSA tests, radical treatments, outpatient appointments) there would be some small savings in others relating to the diagnosis and treatment of more advanced disease.”

The impact of introducing PSA-based screening test has a measurable effect on secondary care costs. In an intention-to-treat analysis of the CAP trial [3.5], offering PSA-based screening was associated with additional secondary care costs of circa GBP40 per man in the intervention compared with the control arm in the first year following randomisation, suggesting that if PSA-based screening was to be offered to all men aged 50-69 in England and Wales, the impact on the secondary care budget (over and above current NHS practice) could be over GBP250 million in the first year.

3. Impact on patient and clinician understanding through new information sources on PSA-based screening

• A CRUK public information page on prostate cancer screening [5.1i] has received 55,574 unique views since the CAP trial results were published, with a spike of 3,089 views on the day of publication, which CRUK described as “by far the biggest driver to the page”.

• PHE developed a leaflet for well men [5.2iii], published in January 2020 (with the impact of the CAP trial confirmed in writing by the Director of the UK NSC [5.2i]).

• Authoritative summaries of the CAP trial results (NIHR Signal; CLAHRC Bite) [5.9] were written to provide information to clinicians about the trial and its implications.

4. Impacts on health and wellbeing

The conduct of the trial underpinned the UK NSC longstanding policy of awaiting the publication of the primary results of CAP before making a final decision on the introduction of a national screening programme (Minutes, Nov 2015) [5.10]. The decision to await the results has potentially prevented harms of overdetection for between 129,948 (reasonably assuming a lower limit of 20% overdetection) and 259,896 (reasonably assuming an upper limit of 40% overdetection) men aged 50-74 per year.

According to the World Health Organisation, musculoskeletal conditions are the leading contributor to global disability. In the UK, treatment consumes 30% of NHS primary care consultations and 25% of surgical interventions. Two of the most common interventions are hip and knee replacement, with over 100,000 each performed in England and Wales annually. Hip and knee replacement rates range between 150 and 300 each per 100,000 in developed countries. Annual NHS expenditure on hip and knee replacements is over GBP1 billion and over GBP3 billion in the United States.

Around 10% of joint replacements fail, requiring complex revision surgery, and 20% of patients experience long-term pain. NICE provide recommendations on implants used in joint replacement, surgical approaches and the use of injections around the surgical site on the basis of the UoB research in order to reduce revision rates, improve outcomes and decrease pain. The UoB research showing that metal-on-metal hip replacements should not be used, and will avoid 8,000 excess revisions, led to the virtual cessation of the use of these implants in the UK, Australia and Canada by 2018.

1. Identifying failing implants and changing practice

NICE identifies acceptable revision rates as 5% at 10 years; the research team found rates far in excess of this when metal-on-metal stemmed hip replacements (1) and hip resurfacings were used. This led to the MHRA issuing a Medical Device Alert [Ai], reinforced by the British Orthopaedic Association and British Hip Society [Aii], recommending against their use in all but exceptional circumstances and that targeted surveillance should occur for any such recipients. The NICE Technology appraisal guidance [Ci] cites UoB’s work (1) and evidence from the NJR annual reports [B], in its recommendations on revision rates and implants for hip replacement.

The US Food and Drugs Administration has cited UoB’s research (1) and further work on the risk of cancer following implantation of metal-on-metal hip implants in its recommendations on market approval for hip replacements (FDA 2013) and Biological Response to Metal Implants [D]. The FDA now approves no stemmed metal-on-metal hip replacement systems and only two resurfacing systems for marketing in the US. Of those approved, one has strictly limited indications in the manufacturer Field Safety Notice informed by UoB’s recommendations and findings. The New Zealand Medicines and Medical Devices Safety Authority (2013) and the European Commission Scientific Committee on Emerging and Newly Identified Health Risks (2014) [E], have issued guidance citing UoB’s research on the outcomes of metal-on-metal hip replacements, including research on the risk of developing cancer, in their recommendations.

Prior to publication of UoB’s research (1), over 1 million metal-on-metal total hip and resurfacing implants were implanted worldwide. The research team identified that the use of approximately 70,000 of these implants in the NJR were responsible for 8,000 excess revisions, at a cost of over GBP100 million. This equates to over 110,000 avoidable revisions worldwide. UoB’s recommendations have led to the virtual cessation of the use of these implants (UK: 466 in 2018 vs 13,630 in 2008 [B]; Australia: 1% (2013-2018) vs 9.8% (2006-2012) (peak 17% 2007) [F]). Citing UoB’s work, the FDA recommends the use of Unique Device Identifiers [G] to allow monitoring and prevent recurrence of the devastating impact of these implants. The NJR, for which the research team have been responsible for statistical analysis and specialist research for over a decade, was cited as a “global exemplar” of medical device registries by the Under Secretary of State for Health and Social Care, Jo Churchill MP, in her report to Parliament (2020).

2. Identifying the most clinically and cost-effective implants

The research on the cost-effectiveness of hip implants (2) has informed recommendations of the Analysis and Policy Observations (APO) of Australia and New Zealand 2019 [Hi], and the research on how long hip replacements last has been cited by the Dutch Institute of Health [Hii]. In the UK, the Getting it Right First Time (GIRFT) initiative is a leading NHS Improvement programme. Data utilised by GIRFT are provided by the UoB team’s analysis of NJR data [I]. The programme has adopted UoB’s recommendations in terms of implant selection (2, 5) [I], and change in clinical practice is demonstrated by data from the NJR which demonstrate increased use of cemented stems and abandonment of larger heads [B]. If all hip replacements performed were conducted as cemented hip replacements, this would save between GBP252 million and GBP281 million in England and Wales alone over the next decade. The success of the GIRFT programme, underpinned by UoB data, has seen it rolled out across all surgical specialties in the UK.

3. Improved patient care and reduced perioperative mortality

The UoB research has explored treatment factors that are associated with peri-operative mortality for patients undergoing hip and knee replacement. The research (1) was cited by NICE Technology Appraisal guidance [TA304] (2014) providing evidence-based recommendations on artificial hips and hip resurfacing for treating end‑stage arthritis of the hip in adults [Ci], specifically in making recommendations aimed at decreasing peri-operative mortality. The latest NICE guidance on hip and knee replacement [Cii] cites the UoB research on surgical approaches and anaesthesia to improve outcomes for patients undergoing joint replacement. These recommendations have been widely adopted as demonstrated by NJR data, showing an increase in the use of mechanical and chemical thromboprophylaxis and the use of spinal anaesthetic for total hip replacement [B]. In 2011, prior to the UoB team’s published research, the percentage of patients not receiving chemical prophylaxis for hip replacement was 13% (~ 13,000 patients); this fell to 2% in 2019. For knee replacement, the proportion not receiving chemical prophylaxis fell from 15% (~ 15,000 patients) in 2011 to 1% in 2019. The proportion of patients undergoing hip replacement who received a spinal anaesthetic in the period 2008-2012 was 42%, increasing to 59% in the period 2013-2017 (~17,000 more cases per annum); the corresponding proportions for knee replacement were 43% and 57% respectively (~ 15,000 cases per annum) [B]. Also, 90-day mortality rates have decreased by 7% in hip replacement and 10% for knee replacement in the period 2014 to 2019 [B].

4. Reducing pain after joint replacement

The UoB publications showing the efficacy of peri-operative wound infiltration in reducing post-operative pain (6) have contributed to widespread adoption of these techniques, particularly in rapid recovery pathways. The research team’s work was cited in guidance from the Canadian Agency for Drugs Technology and Health [J] and NICE guideline NG157 [Cii] in the UK, with NICE now recommending peri-operative wound infiltration in all patients.

Globally, HCV affects 71 million infected individuals and causes 400,000 deaths each year. UoB research has made an important contribution to reducing this burden through research that has defined effective and cost-effective interventions that has underpinned the development of global and national strategies to manage and eliminate HCV. These have led to measurable improvements in patient health.

Impact on HCV prevention guidelines

UoB research strengthened the weak evidence for the impact and cost-effectiveness of opioid substitution therapy and needle and syringe programmes. This evidence has been central to HCV prevention guidelines around the world [ D,E,Hi,Ii]. In the UK, UoB’s modelling and evidence synthesis underpins UK National Institute for Health and Care Excellence (NICE) Public Health Guidance (2008 and 2014) on needle and syringe programmes and has influenced recent recommendations for the crucial role of needle and syringe programmes and opioid substitution therapy for achieving HCV elimination in England (2019) [ E], Scotland (2019) [ Ii] and Georgia (2017) [ Hi]. It has also underpinned recommendations to scale-up needle and syringe programmes in the US (2019) [ D].

Impact on HCV treatment guidelines

UoB research on the impact and cost-effectiveness of HCV treatment as prevention among PWID and MSM has been instrumental in changing HCV-treatment guidelines globally. In 2017, WHO commissioned modelling research from UoB, which showed that a ‘treat-all’ policy would achieve prevention benefits; this formed part of the evidence used to change WHO’s HCV treatment guidelines published in 2018 [ C] to a treat-all policy. These new guidelines contrasted with prior guidance that had restricted HCV treatment to people based on disease stage. Further, the European Association for the Study of the Liver (2018) [ A], and the American Association for the Study of Liver Disease (2020) [ B] have both primarily used UoB modelling evidence to advocate for the prevention benefits of HCV treatment and to recommend treatment for patient groups at risk of re-infection, including PWID [ A,B] and MSM [ A].

These new treatment guidelines have been central to development of national HCV elimination strategies in Georgia, Scotland and Australia, which now recommend the prioritisation of HCV treatment to PWID alongside scaling up other prevention interventions [ Hi,Ii,Ji].

Impact on elimination strategies

UoB research uncovered the extent to which treatment and prevention scale-up will be needed to reduce HCV-transmission to negligible levels in different global settings. In particular, the research was crucial for the WHO 2016 Global Health Sector Strategy (GHSS) on Viral Hepatitis [ Fi], which proposed the elimination of viral hepatitis as a major public health threat by 2030. Our modelling showed elimination was possible by 2030 and was used to produce the prevention and treatment targets needed for eliminating HCV as proposed by WHO [ Fii]. The WHO strategy to eliminate HCV has been instrumental for many countries developing National HCV elimination initiatives (124 by February 2019 [ Fiii]), resulting in substantial increases in treatment in many countries (including Georgia and Australia, see Figure 1) and globally [ Fiii]. Our prevention and treatment targets are the foundation for all National HCV elimination initiatives.

UoB research has also guided HCV elimination programmes in Georgia (through their yearly technical advisory group) [ Hi,Hii], Scotland (strategy cites nine UoB studies) [ Ii], Australia (strategy cites UoB research (1) as primary evidence for using HCV treatment as a prevention strategy among PWID) [ Ji] and Pakistan [ G]. The UoB researchers presented their findings on how to optimise the costs of achieving HCV elimination in Pakistan at an invitation-only Technical Meeting for World Hepatitis Day in 2019. This policy-shaping meeting was hosted by WHO and the Pakistan Ministry of National Health Services, Regulations and Coordination (NHSRC). The outcome of the Meeting was the Islamabad Declaration for Hepatitis Elimination 2019 and an official announcement by Dr Arif Alvi (President of Pakistan) of a Prime Minister’s plan for eliminating viral hepatitis in Pakistan [ Gii]. Our work has supported Pakistan’s treatment targets and budget requirements for achieving HCV elimination, published in Lancet Global Health ( 5) with associated press articles in all major English language newspapers in Pakistan [ Giii].

Impacts on patient health

(b) Chronic prevalence in Georgia

(d) Chronic prevalence in PWID in Australia

(c) Australia treatment scale-up in PWID

(a) Georgia treatment scale-up There is empirical evidence from Scotland and Australia that national elimination strategies, underpinned by UoB’s research, have had a profound effect on the number of PWID who have been treated over time (Fig.1). Emerging data from Scotland shows that after four years of treatment scale-up in Tayside (2017-2020; Fig.1e/f), chronic HCV prevalence fell by 71% among PWID, as motivated and predicted by UoB research [ Iii]. Similarly, chronic HCV prevalence decreased by 42% in the first two years (2016-2017; Fig.1c/d) of scaling up HCV treatment in Australia [ Jii]. In Georgia, our modelling suggests chronic HCV prevalence has reduced by 37% and mortality by 14% by February 2019 (Fig.1a/b) as published in Lancet Global Health [ Hii].

(f) Chronic prevalence in PWID in Tayside

(e) Tayside treatment scale-up in PWID

Figure 1: Treatment scale-up and impact in Georgia (a and b; modelling from [ Hii]), PWID in Australia (c and d; data adapted from [ Jii]), and PWID in Tayside, Scotland (e and f; extension of data from [ **Iiii]**). Treatment figures also show dates over which our initial Main papers were published (2011-2013), when EASL (European Association for the study of the Liver) first recommended treating PWID (August 2014), and when WHO published their Global Health Strategy to eliminate HCV (June 2016; WHO GHSS).