Impact case study database

FRDA mouse models are considered essential for the development of effective drug-based therapy for this lethal disease. Additionally, they have potential in the development of therapies aimed at treating much more common neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease or Huntington’s disease.

Murdoch Children’s Research Institute states that the FRDA mouse models that have been developed and characterised by Drs Pook and Anjomani-Virmouni are the “best mouse model for Friedreich ataxia.” This is because they incorporate the same genetic mutation as FRDA, and as such are available for drug treatment strategies that are aimed at specifically targeting the mutated human frataxin gene. ( Source 5)

These mouse models have been donated to The Jackson Laboratory (in 2014 and 2016) for cryopreservation and distribution to research groups and Pharma throughout the world to progress their FRDA preclinical research studies and support FRDA clinical trials ( Source 1). Through the utilisation of the “unique ‘humanised’ YG8R-derived FA mouse model” Drs Kemp and Wilkins at the University of Bristol have been able to focus on utilising “bone marrow stem cell mobilising drugs as regenerative therapy” for FRDA patients. Their research, using the Pook model, has provided the ‘proof-of-concept’ basis for clinical trial. ( Source 8)

Brunel has granted licences to the following Pharma to obtain Pook FRDA mouse models from The Jackson Laboratory for use in their preclinical FRDA studies: RaNA Therapeutics Inc., Cambridge, MA, USA (2015), Biomarin Pharmaceuticals Inc., Novato, CA, USA (2016), Vertex Pharmaceuticals Inc., Boston, MA, USA (2016), Ionis Pharmaceuticals Inc., Carlsbad, CA, USA (2017). Dr Pook has also performed collaborative FRDA mouse model studies with Takeda California Inc. in the development of their compound named TAK-831. As concluded by Dr Jordi Serrats of Takeda California Inc. “Dr. Pook’s work with TAK-831 has been instrumental in supporting clinical trials in FRDA patients”.

Overall, the results of preclinical studies using the FRDA mouse models developed in the Pook laboratory have provided evidence in favour of proceeding with the following 10 international FRDA clinical studies that have involved a total of 786 FRDA patients:

1. RG2833 Epigenetic Therapy of Friedreich’s Ataxia, sponsor Repligen Corporation, Waltham, MA, USA. (20 FRDA patients) ( Source 2).

2. Interferon Gamma-1b in Friedreich’s Ataxia (FRDA), sponsor Children’s Hospital of Philadelphia, USA. ClinicalTrials.gov Identifier: NCT01965327 (12 FRDA patients) (Source 3)

3. Safety, Tolerability and Efficacy of ACTIMMUNE® Dose Escalation in Friedreich’s Ataxia (STEADFAST), sponsor Horizon Pharma Ireland, Ltd., Dublin, Ireland. ClinicalTrials.gov Identifiers: NCT02415127, NCT02593773 (92 and 86 FRDA patients, respectively) (Source 3)

4. Long-Term Safety Extension Study of ACTIMMUNE® (Interferon γ-1b) in Children and Young Adults With Friedreich’s Ataxia (STEADFAST), sponsor Horizon Pharma Ireland, Ltd., Dublin, Ireland. ClinicalTrials.gov Identifiers: NCT02797080 (38 FRDA patients) (Source 3)

5. A Study of Resveratrol as Treatment for Friedreich Ataxia, sponsor Murdoch Childrens Research Institute, Melbourne, Australia. ClinicalTrials.gov Identifier: NCT01339884 (27 FRDA patients) (Source 4 and 5)

6. Effect of Nicotinamide in Friedreich’s Ataxia, sponsor Imperial College London, UK. ClinicalTrials.gov Identifier: NCT01589809 (40 FRDA patients) (Source 6)

7. Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia (NICOFA), sponsor RWTH Aachen University, Aachen, Germany. ClinicalTrials.gov Identifier: NCT03761511 (225 FRDA patients estimated) (Source 6)

8. RTA 408 Capsules in Patients With Friedreich’s Ataxia – MOXIe, sponsor Reata Pharmaceuticals, Inc., Irving, TX, USA. ClinicalTrials.gov Identifier: NCT02255435 (172 FRDA patients) (Source 7)

9. Efficacy, Tolerability, and Pharmacokinetics of Multiple Doses of Oral TAK- 831 in Adults With Friedreich Ataxia, sponsor Takeda Pharmaceuticals, Deerfield, IL, USA. ClinicalTrials.gov Identifier: NCT03214588 (67 FRDA patients) (Source 9)

7 of these clinical trials (1-6 and 8) have already reported data regarding safety and efficacy outcomes. They have shown the drug to be well tolerated, with no serious adverse events, but the levels of efficacy varied. The RG2833, resveratrol, nicotinamide and RTA 408 clinical trials (1, 5, 6, 8) have each shown increased levels of frataxin protein and/or improved neurological function as beneficial effects of the drug treatment.

As well as having clinical impact the research carried out by Drs Pook and Anjomani-Virmouni has had impact upon FRDA patients and their families world-wide. A total of 786 FRDA patients have taken part in, or registered to take part in, these clinical trials, providing potential or actual clinical benefits to many FRDA patients and providing psychological benefits to the well-being of the participating FRDA patients and their families.

The situation for wheelchair users with complex and changing needs has been called “intolerable”, especially for children. Clinical provision and care has been enhanced as a result of impacts of this research on policy through evidence regarding the value of EPIOCs in enabling employment, education, social integration, health status and improved QoL allowing users to participate more fully in society, and enhancing personal comfort and lowering their risk of serious complications from EPIOC use.

Using this research (REF1), the NHS warned that wheelchairs poorly matched to users’ needs adversely affected activities, participation, lifestyle goals and health status, adding to cost and/or non-use or abandonment of the wheelchair (E1). Brunel research outputs underpinned the case for growing support, internationally for providing EPIOCs to encourage social and community interaction. They emphasised that driving assessment including functional and cognitive abilities and education on safety were essential for EPIOC users; a recommendation from this research into young EPIOC users. Brunel research (REF1, REF2, REF4) was used to underpin key targets for health service improvements and core service delivery standards for therapists who support people with disabilities, benefiting 1,200,000 potential chair users in the UK and an estimated 72,000 potential users in NSW Australia (E2).

Impacts on practitioners and services internationally

Professional standards, guidelines and evidence-based sources have been shaped by the research

By transforming understanding of the importance of EPIOCs for children’s development and successful transition to independence in adulthood, this evidence has broadened assessment to include provision based on the social development needs of children and young adults, not just their mobility needs. Internationally, practitioners have improved evidence-based guidelines and recommendations to enhance the quality of their professional practice.

This research has been used internationally to recommend that for children with inefficient mobility, EPIOCs enhance independence and facilitate participation in family, school, and community life. Direct use of study REF3 highlighted that to enhance EPIOC use without contributing to problematic posture and pain, supportive seating, powered seating functions and adequate suspension are important features to consider in prescription (E3, E8). Brunel research highlighted widespread debilitating suffering caused by pain (E3) and that EPIOC users related their pain to underlying medical conditions and to improperly configured wheelchairs. EPIOC users opined that wheelchair tilt functions can be used to manage pain/discomfort. This research informed influential position statements to support the application of seat functions to assist clinicians in decision-making and justifying funding (E4).

Brunel research (REF2) underpinned advice on when children should start using power mobility. The evidence was used to recommend that early utilization of EPIOCs for children with mobility limitations enhances independence, improves development in multiple areas, and enables children to grow to become productive and integrated members of society (E5, E8).

Expert international consensus now endorses the therapeutic use of wheelchairs beyond mobility assistance. Using this research (REF6), international recommendations advocate short orthoses for daytime use to prevent ankle deformity and prolong gait ability and emphasise that correctly adapted wheelchairs can prevent skin ulcers and slow scoliosis progression thereby counteracting life-threatening complications for children with muscular dystrophy (E6). Drawing directly on these findings (REF2) an international consensus group published clinical practice guidance for powered mobility in children of different ages, needs, and abilities. Recommendations based on these publications highlight the importance of EPIOCs in enhancing independence and facilitating participation in family, school and community life and that enhancing EPIOC use without contributing to problems of posture and pain, supportive seating, powered seating functions, and adequate suspension are essential features to consider in chair prescription (E7).

The research on children has been utilised by clinicians for the prescription of EPIOCs and to develop and provide hand-outs for advanced training and safety for different types of child learners and to inform and support their parents (E8). One of these hand-outs has recently been translated into Norwegian (E9) further illustrating the need internationally for evidence-based information to support child EPIOC users and their parents/carers.

Impacts on commercial companies

Material provided by companies for chair prescribers, users, payers and other purchasers has been informed by this Brunel research and used as part of the justification for costs. The research (REF5) has provided evidence-based information to prescribers and purchasers of wheelchairs, demonstrating that appropriate seating interventions, alongside competent assessment, can reduce pain and suffering, but at a financial cost which is justifiable by the enhanced wellbeing of chair users (E9). Brunel research (REF4) changed funding decisions in Canada from the provision of power tilt and recline chairs for pressure relief to the provision tilt-in-space features that give users the ability to autonomously control comfort, rest and pain reduction (E10). Brunel research has changed perceptions of the role of EPIOCS from mobility aids to enhancing the engagement of severely disabled adults and children in society. It has contributed to developing the market and international clinical guidelines impacting 1,200,000 UK, 1,700,000 USA wheelchair users and approximately 131,800,000 people needing wheelchairs worldwide.

The research teams, UNICEF, and the publishing journals all disseminated the stream of research evidence about the benefits of breastfeeding extensively. It made an impact not only on, but also through, the advocacy activities and policies of the diverse organisations promoting breastfeeding, including ones linked to the research. This was Impact 1, which, despite the research’s UK focus, was significantly wide-reaching, covering governments, professional bodies, advocacy groups and other organisations in many countries as well as multinational organisations. The advocacy, guidelines and policies have directly promoted an increase in the levels of breastfeeding in order to generate health gains, and cited the research as a major reason for doing so. In this, the identified cost savings were often highlighted as a key justification for investing in efforts to boost breastfeeding. Overlapping with this, Impact 2 was informing discussions as policymakers considered which specific strategies were financially justifiable to boost breastfeeding in order to improve health and equity. The research provided an evidential background that improved the quality of debates. Impact 3 was informing debates on regulatory policies where breastfeeding campaigners aimed to ensure it had a level playing field with commercial breast-milk substitutes.

Beneficiaries of this research include: policymakers, practitioners and campaigners who promoted breastfeeding, and were provided with a stronger evidence base for their activities; relevant mothers and children whose health might better than it otherwise would have been; and healthcare services that might have lower costs than they otherwise might have had.

Impact 1: informing/strengthening advocacy and policies promoting breastfeeding

The Brunel team participated in the extensive dissemination of the findings, including to the local (ie, Hillingdon) healthcare system, and nationally and internationally. Pokhrel et al’s paper [R2] was reported in the Nursing Times, the Mail Online and other outlets. Networking by Brunel resulted in coverage of the paper on the website of the WHO’s Global Partnership for Maternal, Newborn & Child Health. Also, Reuters and the BBC interviewed Pokhrel and quoted him in their web stories. The BBC News story in December 2014 also illustrates how the study was used by advocacy groups: a co-author from the NCT, which promoted the findings extensively, was quoted as saying there should be more support in the community for breastfeeding [Evidence (Ev)1].

Within individual countries, the research has made a significant impact through providing evidence to inform debates. A Scottish Parliament debate on 12 June 2014 was led by Elaine Smith who called the debate partly to promote R1. The motion debated included a call for the Parliament to note that the UNICEF report “ outlined how increased breastfeeding rates could improve public health, produce long-term health benefits, allow considerable savings to be made by the NHS and provide a mechanism for improving health outcomes across a range of social groups” (p.2) [Ev2]. Smith first mentioned the research in her opening words :“I am pleased to be able to lead a debate today on the important issue of breastfeeding…low breastfeeding rates cost money and lives, as is proved in the UNICEF UK-commissioned report” (p.3) . Later she continued: “The UNICEF UK-commissioned report not only tells us that low breastfeeding rates lead to increased incidence of illness, with a significant cost to the national health service, but supports that fact with hard figures—probably for the first time—showing that moderate increases in breastfeeding translate into huge cost savings” (p.6/8) . She also called for the Minister to meet the report’s authors [Ev2].

National policies in England informed by the research included the 2014 the National Institute for Health and Clinical Excellence (NICE) Local Government Briefing [LGB] 22: Health Visiting. It used R1 as the third of four points in the section on costs and savings introduced by the statement: “Effectively using health visiting to improve the health and wellbeing of children aged 0–5 can lead to the following costs and savings” [Ev3]. In 2016, Public Health England (PHE) cited R1 in parts of its guidance document prepared in conjunction with the UNICEF UK Baby Friendly Initiative: Commissioning infant feeding services: a toolkit for local authorities (Part 2) [Ev4]. The introduction used R1 to support a statement starting: “Commissioning services to increase and sustain breastfeeding would deliver significant cost savings to the NHS and to the local authority” (p.8).

Around the UK, NHS trusts and local authorities cited the research in documents promoting breastfeeding. Examples included Great Ormond Street and also Hillingdon - the opening sentence of the combined local government and health authorities’ strategy, The Hillingdon Infant Feeding Policy, 2014, said: “Hillingdon believes that breastfeeding is the healthiest way for a woman to feed her baby and recognises the important health and well-being benefits now known to exist for both the mother and the child. (Renfrew 2012, Public Health Outcomes 2013)” (p.5) [Ev5].

Policy documents from WHO and UNICEF, such as their 2015, Breastfeeding Advocacy Initiative for the best start in life, stated that increased rates of breastfeeding would help achieve various SDGs. In calling for action, it was claimed that globally over 800,000 children died in 2011 because infants did not receive the health improvements associated with increased breastfeeding. The strategy was supported by many organisations including the Bill & Melinda Gates Foundation, Save the Children and the World Alliance for Breastfeeding Action. Under the heading “Not breastfeeding has economic costs”, it cited R1 to support the statement: “Breastfeeding can save health care systems significant resources due to reduced illness among breastfed babies—even moderate increases in breastfeeding in the UK could save the health service millions of pounds annually” (p.7/8) [Ev6]. Similarly, WHO Europe’s 2016 document, Good Maternal Nutrition, the best start in life, highlighted the importance of achieving the SDGs, and used R2 as the only reference to support a suggestion to policy-advisers that “ Cost savings achieved by improved services should be demonstrated, and the expected benefits quantified. The available evidence should be used, and adapted according to the experiences of other Member States” (Para 11.2) [Ev7].

International examples of the research informing government health service policies include the Breastfeeding Action Plan 2016-21 from the Health Service Executive in Ireland. It cites R1, including once as one of two references for the statement: “International studies have outlined the significant cost savings to the health service to be achieved through even gradual increases in breastfeeding rates” (p.6) [Ev8]. Under the heading: “Breastfeeding reduces health costs”, the Australian National Breastfeeding Strategy 2019 and Beyond, states “A UNICEF UK report authored by Renfrew and colleagues found that even modest increases in breastfeeding rates in the UK were associated with substantial economic and health benefits” (p.23) [Ev9]. Statements advocating breastfeeding from professional bodies citing R2 as important evidence, included the Position Statement on Breastfeeding from the Italian Pediatric Societies, 2015 [Ev10] and the New Zealand College of Midwives consensus statement, Breastfeeding (updated July 2016) [Ev11].

Impact 2: informing specific strategies supporting breastfeeding for better health and equity

The pathways to impact here again involved both the research team and key stakeholders, in this case promoting use of the findings to inform specific strategies for increasing breastfeeding for better health (and equity). The Director of NICE wrote in the Forward to the UNICEF report [R1]: “This is an important report in several ways. It is important scientifically – the methods used are at once rigorous and novel. It is important practically – it shows what can be done to make matters better. And it is important for policy – it shows in stark relief what the nature of the problem is but also presents the potential solutions.” In the continuing dissemination, Pokhrel, for example, drew on the research to present an invited business case for breastfeeding promotion in 2019 at the 14^th International Breastfeeding and Lactation Symposium in London. Online publication of R4 in 2019 led to vigorous debate on TV and in the papers, including a story in the Daily Telegraph on 18 Sept in which Anokye was quoted: “We’ve shown that a financial incentives programme such as this can not only increase rates of breastfeeding, but also provide good value for money.”

In 2018, the breastfeeding section of PHE guidance entitled, Best start in life: cost-effective commissioning, drew on the UNICEF research. This guidance aimed to help local commissioners provide cost-effective interventions for children aged up to five and pregnant women. Part of the detailed analysis of interventions to promote breastfeeding was drawn from three sources: one each from R1 and another report, but R2 provided “All other parameters” (p.35) [Ev12].

Even before this detailed advice, local commissioning groups, covering local authorities and NHS trusts, used the research to inform their specific strategies. For example, of the five references in St Helens Infant Feeding Strategy 2016-19 one was the PHE advice from 2016 [Ev4] another was R1. The start of the strategy’s Executive Summary highlighted the importance of breastfeeding to improving both health and health equity: “Breastfeeding provides both short and long-term health, educational and social benefits for babies, mothers and reduces inequalities” (p.2). In addition to describing the UNICEF study it took figures from R1 on potential gains in economic productivity and applied them to St Helens (p.5) [Ev13]. In 2016, Manchester’s multi-agency Joint Strategic Needs Assessment panel’s statement on breastfeeding was framed by R1 which, it stated in the second sentence, “demonstrates that investing in effective services to increase and sustain breastfeeding would make a significant contribution to reducing health inequalities” [Ev14].

The more recent economic analysis of financial incentives as a specific intervention is also beginning to inform policy and public debate. It was referred to as a study underway in the debate in the Scottish Parliament (29) [Ev2]. A 2018 pre-budget submission to the Australian government described the findings of the NoSH RCT [R3] and continued: “It is likely to be particularly relevant to approaches to increasing breastfeeding among mothers in low income or urban indigenous families in Australia, for whom breastfeeding rates are considerably lower than in the general population of mothers. Such financial rewards could also be attractive to some disempowered mothers with little or no independent sources of income even when household income is adequate" (p.14) [Ev16]. An opening call in the submission was for “ a funded package of measures to align fiscal incentives with public health goals of supporting optimal infant and young child feeding particularly breastfeeding” (p.2). It also drew on R1 and R2 in later analysis.

Impact 3: providing evidence on the benefits from breastfeeding for regulatory debates

The research findings were also used by organisations supporting breastfeeding in debates about regulatory policies. In their submissions they attempted to ensure there was a level playing field for breast-milk, and appropriate regulation of breast-milk substitutes. For example, in a 2015 submission to Commerce Commission New Zealand, related to the need for “the regulation of all breast-milk substitutes”, the New Zealand College of Midwives claimed : “Breastfeeding is economically beneficial in regards to population health” (p.1) [Ev15]. It later devoted a whole paragraph (1.6) to the findings of R2, and a further one (3.3) to discussing key points from R1.

The Brunel team’s research made a significant and often rapid impact on NICE guidelines on PA, and through them an impact on various other policies and implementation efforts to promote PA (Impact 1). Anokye et al’s research played a key role in the production of a novel policy, the NICE Return on Investment (ROI) Tool for PA, that facilitated creation of an improved evidence-base for local health investment decisions (Impact 2). The research stream’s increasing international reach also informs policies and debates, sometimes during collaborative research (Impact 3). The beneficiaries of Brunel’s research included policymakers and professionals who had a stronger evidence base for making decisions to invest in, promote and implement PA interventions. This should result in increased PA, and thus, eventually, improved population health, as noted above.

Diverse actions by the team encouraged impact, including through presentations and the media. While the pathways to impact were sometimes direct to relevant audiences, they were also complex and multi-layered, not always following traditional patterns. The DH, as the main policymaking user of cost-effectiveness analysis, was engaged from the outset. It supported Brunel’s programme of research explicitly because of its potential usefulness in creating a stronger evidence-base for a major policy area – the pattern is now being repeated in the team’s research in Ghana. The research was often conducted for, and sometimes with, DH bodies such as NICE. On occasions, as outlined in Table 1, the co-produced research was incorporated into policy before it was published in journal articles. These NICE policies sometimes had increasing reach as they, in turn, informed further policy documents from NICE and others, who’s networking also encouraged professionals such as physiotherapists to implement the Brunel-informed NICE guidance.

Impact 1: Contributing to NICE guidelines on Physical Activity (PA) and through them informing further policies, implementation and debates

While the original version of NICE PH44 was published in May 2013, it, and then a later refreshed version, made a significant impact throughout the relevant period since August 2013, not only directly, but also through many subsequent policies and implementation activities based on it. Following a regular guideline Surveillance check in 2016, NICE declared that the 2013 version of PH44 should be re-issued, but be refreshed with additional material (see below). The version included as Evidence (Ev)1, is therefore a later version which retains the 2013 wording showing that the Brunel team provided key parts of the evidence on which it was based: “The review of economic evaluations and the review of economic barriers and facilitators... and the economic modelling ...were carried out by Brunel University London/Health Economics Research Group (HERG). The principal authors were Anokye N, Jones T and Fox-Rushby J.” (p.58).

The Brunel reviews behind PH44 cited papers R1 and R2, and, as noted, the economic modelling was later also published as R4. Informed by this, PH44 stated the provision of brief advice to promote PA in primary care was cost effective and the guidance was relevant for the general public, commissioners and “exercise professionals, GPs, health trainers, health visitors, mental health professionals, midwives, pharmacists, practice nurses and physiotherapists” (p.6). This refreshed version of PH44 also stated: “This guideline is the basis of QS84” (p.5). That 2015 NICE Quality Standard supported action to encourage PA when people “ are in contact with the NHS” (p.5) [Ev2]. It listed the organisations that “agreed to work with NICE to ensure that those commissioning or providing services are made aware of and encouraged to use the quality standard” (p.44), including the Chartered Society of Physiotherapy and the Royal College of GPs.

NICE promoted PH44 through its website, and drew on it to inform a range of further NICE policies and actions. It drew on PH44 as a key source for its web-based interactive PA pathways which are regularly updated flowcharts of recommendations for boosting PA in diverse circumstances. For example, PH44 was one of only two sources listed for the pathway on Training for people involved in encouraging others to be physically active (NICE, updated 2019, p.11) [Ev3]. Additionally, NICE promoted use of PH44 in the Shared learning database of its PA website by featuring a 2018 plan for implementing it developed by physiotherapists at Doncaster and Bassetlaw NHS Trust [Ev4].

In 2014, NICE PH54 provided guidance on ERSs [Ev5], which as Table 1 shows was the PA intervention for which Brunel’s economic modelling started. As stated on p.45/6, PH 54 was based on three key sources of evidence. The first consisted of two reviews - one by the team including Anokye was subsequently published as R5, but was made available for NICE prior to publication. That review cited R1 and Anokye et al’s previous reviews for NICE. The second and overlapping source was “economic modelling” – this was the economic modelling (conducted by Anokye) contained in publication R5 that indicted ERSs were unlikely to achieve the cost-effectiveness usually required for an intervention to be recommended by NICE. PH54 drew on the economic evaluation to inform the main recommendations that primary care practitioners should only refer people to ERSs in limited circumstances. PH54 became a source for some NICE PA pathways.

PH54 was also cited along with PH44 as a source in policy documents from diverse other national and local bodies. These included Public Health England (PHE) in their 2017 NHS Health Check: Best Practice Guidance (p.35) [Ev6] and, with calls for implementation of both the guidelines, in the 2015 Hertfordshire Physical Activity and Sport Framework created by Hertfordshire County Council, its 10 District Councils and various bodies in a multi-agency approach (p.5,49) [Ev7].

Findings from the pedometer trial [R6] were rapidly examined by NICE to see if policy updating was required. The report, 2019 Exceptional Surveillance of physical activity: walking and cycling (NICE guideline PH41), concluded that this major trial reinforced rather than conflicted with current advice (p.3) [Ev8]; therefore, the impact here was to strengthen rather than change existing policy.

Impact 2: Helping NICE produce their Physical Activity Return on Investment (ROI) tool

Brunel’s research was central to the development of the NICE PA ROI tool. This was a new type of policy approach. The tool’s software (and accompanying Technical Report) were available and promoted on the NICE website. They could be used by commissioners of local services to estimate the cost-effectiveness of different packages of PA interventions given the known population and current PA levels in their area. The significant role of Brunel’s research was explained in the tool’s Technical Report, dated May 2014 and produced by Matrix. This repeatedly described how the tool drew on the research, in particular the Markov model (as described in publications shown on Table 1, including the eventual R4). One example stated: “The economic model used in this tool is based on the Markov model developed by Anokye et al (2012) for the NICE Public Health Intervention Guidance on Physical Activity.” (p.9) [Ev9].

The significance of Brunel’s research on the economic assessment of interventions to promote PA was also highlighted in June 2014 in NICE’s press release launching the ROI tool for PA [Ev10]. It highlighted the direct policy impact of Brunel’s research in creating NICE tools, and through that further impacts on local policymakers as the tools “ help councils predict the health benefits for communities - and the money they could save – when they invest in activity...The NICE return on investment tools have been developed in collaboration with Brunel University, LeLan Solutions and Matrix Knowledge.” The press release also quoted PHE’s Dr Varney: “The tool will be invaluable to local authorities who wish to commission cost-effective services and interventions that help to get more people more active more often” [Ev10]. NICE, other bodies and local authorities all used or promoted the tool, for example those supporting Hertfordshire’s PA framework noted above (p.19) [Ev7]. In a 2014 policy initiative, Everybody Active, Every Day, PHE stated it had: “developed a summary of the tools (including the NICE return-on-investment tool)³⁶ that make the case for investment, and of the guidance on what local authorities and commissioners can do” (p.8) [Ev11].

Impact 3: Informing policies and debates internationally to promote Physical Activity

A 2016 position statement by the Canadian Academy of Sport and Exercise Medicine cited R4 as one of only two references for a prominent opening claim highlighting “the cost-effectiveness of exercise prescription in primary care” (second para), however briefly done [Ev12]. This position statement, published in two leading journals, has been endorsed by ten sport medicine societies, including: the Australasian College of Sports and Exercise Physicians, American Medical Society for Sports Medicine, European College of Sport & Exercise Physicians, South African Sports Medicine Association, and Swedish Society of Exercise and Sports Medicine.

Brunel’s ongoing PA research has improved the quality of debate around boosting PA. The research under way in Ghana is under the auspices of the Office of the President whose letter to Anokye corroborating the emerging impact stated it is being: “conducted to inform Ghanaian health policy to reduce obesity. I believe that the team built on the Brunel expertise in reviewing the evidence, especially on physical activity to outline key areas that needed attention. ...Through the activities of research, stakeholder engagement and consensus building I believe your work is already informing the policy debate in Ghana about tackling obesity.” [Ev13]

A number of major health insurance providers in the US have developed their reimbursement policies in light of these reviews. Based on the combined recent membership figures for these 4 insurance schemes (53,400,000 members) and a prevalence of persistent pain of 10-20% these policies apply to between 5,300,000 to 10,600,000 people with health insurance. The reviews have enabled important evidence-based policy decisions which allow for more efficient clinical provision and reduce patient exposure to ineffective and unproven treatments.

Between 2017 and 2019, policies from United Healthcare [2.1], Regence [2.2], UCare [2.3] and the Government Employers Health Association (GEHA) [2.4] used the review on the topic [1.1] to justify not routinely offering non-invasive brain stimulation techniques for chronic pain.

A range of information resources have been designed, underpinned by the evidence in these reviews, for people in pain and clinicians to inform their understanding of the condition and their treatment choices.

The PainHEALTH website [2.5] is a Western Australia (WA) Department of Health government funded website developed through a collaboration of researchers, clinicians and consumers, with the specific goal of promoting timely access to reliable and practical pain management resources for all Western Australian health consumers and improving access to good information to people with musculoskeletal pain in remote and hard to reach communities. At the invitation of colleagues in WA, Dr O’Connell led the development of patient facing online information relating to CRPS for the website.

This information on CRPS was directly based on Brunel reviews [1.3, 1.5] and summarises for the lay reader which treatments show promise and which appear to be unsafe and/or ineffective across the full range of treatments including drugs, invasive procedures and non-pharmacological options. The pages went live in 2017. Tracking use statistics show the website is well accessed with over 1,000,000 visitors per year benefitting from trustworthy, accessible and up to date information about their pain, and has a global reach, with users accessing the resource from over 150 countries. The page on managing CRPS received over 5,000 visitors in January 2019 alone suggesting a reach of approximately 60,000 users per year for this rare condition. A formal mixed methods evaluation of the painHEALTH project included 414 users of the resource and found that users perceived it as filling an important gap in holistic pain care, and that it provided holistic and credible information to support self-management and co-care of pain. Health professionals reported that they perceived it to be a useful tool to complement clinical care and training [2.6]. The website has now been approved for a further 5 years of government funding (2018-2023 AUD125,000, equivalent to GBP70,000 (11-2020) and Dr O’Connell will continue to work with the painHEALTH team to further enhance the information on CRPS based upon this research.

Patients and clinicians increasingly turn to internet-based information sources to inform decisions about care and it is important that information based on the best evidence to date is freely available. A range of patient and clinician facing online resources independently developed information resources and recommendations relating to various treatment options for persistent pain that are underpinned by these reviews. Patient-facing resources include the respected and award-winning UK-based “Patient.info” website (formerly patient.co.uk) who cite the Brunel review of TENS for neuropathic pain [1.4] in their patient information resource on TENS [2.7], the US Women’s National Health Network who cite the same review in their information on alternatives to drugs for chronic pain [2.8]. Information resources for clinicians include the “Uptodate.com” [2.9] and “Practical pain management” [2.10] websites who provide clinician updates on best clinical practice for CRPS, and ketamine use with the evidence in reviews 1.2 and 1.5 as critical evidence sources. These resources have considerable global reach. According to information on their websites, Patient.info has over 6,000,000 users; UptoDate is used by approximately 1,700,000 clinicians to stay abreast of current evidence across over 190 countries, and Practical Pain Management has a print circulation of more than 41,000 with over 700,000 unique website visitors per month.

This research has directly helped improve healthcare policy for between 5,300,000 to 10,600,000 people in pain with health insurance in the US. It informs trustworthy, accessible information to clinicians and people with pain about pain management that has global reach.

Impact 1 is the significant and direct impact made by Brunel’s research though the co-production of NICE guidance in the form of the NICE ROI tool that it promoted on its website. Impact 2 consists of the many further tobacco control policies from national bodies that, since Aug 2013, have been informed by, and promoted, the ROI tool. Impact 3 is the impact made on local policymaking and practice through using the ROI tool and, in turn, the consequent reductions in smoking which should have contributed to improved health, economic productivity and health equity, particularly in North East (NE) England. Impact 4 covers the research’s increasing international reach on policies, including WHO’s roadmap for Tobacco Control implementation (in line with SDG 3a). Spanish tobacco control policies, introduced in 2020, led to a 300% boost for the funded smoking cessation drugs, with evidence emerging of reduced prevalence.

Beneficiaries of these impacts included policymakers and practitioners in national and local bodies, and tobacco control services, who promoted and implemented tobacco control. The research-based ROI tool significantly improved the quality of information available to them when making decisions. People who stopped smoking benefited from resulting health improvements, which, in turn, should have reduced costs to the healthcare system and the economy.

The co-produced research was regularly disseminated through engagement with stakeholders, as described for development of the NICE tool in R2 above, and throughout and following the EQUIPT project. The latter’s dissemination was to stakeholders engaged in the project (see R6), and more widely, as illustrated by a testimonial from the President of the Spanish umbrella body for many groups interested in tobacco control: “The EQUIPT project, right from the beginning has been presented in the National Conference of Tobacco Prevention [CNPT] in several times and also in international conferences such as the European Network for Smoking Prevention Conference. So, the informing and influencing channels of this project to stakeholders have been several all along the process of the project development” [Evidence (Ev) 1].

Impact 1: Impact on NICE guidance through co-producing its tobacco control ROI tool

NICE, the main source of NHS policy guidance, promoted the ROI tool on its website to provide guidance to local policymakers on tobacco control interventions. Here, therefore, Brunel researchers made a direct and continuing policy impact from August 2013 because the tobacco control ROI tool they had originally co-produced for, and with, NICE in 2012 was continuing to be accessed and used by local decision-makers. Following further research it was updated - in 2014 by the third co-produced edition. Hence, for this co-produced policy the source to corroborate the impact, Ev2, is the 2014 research listed as R2, ie the tool’s Technical Guide, third edition. The majority of authors were Brunel researchers, led by Pokhrel.

Impact 2: Impact of the ROI tool on and through national health policies in England

In addition to the researchers’ own engagement activities, official tobacco control policies from NICE, and other bodies, were informed by, and promoted, the ROI tool as a key mechanism for encouraging and informing local tobacco control policies. In Sept 2013, a NICE Local Government Briefing (LGB10) promoted the ROI tool. It described NICE’s illustrative application of it to Bury: “To illustrate the costs of smoking – and the savings that can be achieved by tackling tobacco use, we ran an analysis for Bury Metropolitan Borough Council using NICE's return on investment tobacco model. This tool was developed to help local decision-making on tobacco control” (p.7) [Ev3]. NICE policy documents continued to draw on the current edition of the ROI tool and promote its use, for example in March 2018 NICE Guideline 92 [NG92]: Stop smoking interventions and services included a Resource Impact Report describing the tool and including a hyperlink to it (p.4) [Ev4]. In Nov 2013, the Local Government Association’s briefing, *Money well Spent, encouraged use of the tool by providing a link and telling councils they could “get tailored estimates on the potential cost effectiveness of their own stop-smoking schemes using NICE’s tobacco return on investment tool” (p.11) [Ev5].

Corroborating the impact, a senior programme manager at Public Health England (PHE) said: “The success of the Brunel model led...(NICE) to produce similar Return on Investment tools for other public health topics” [Ev6]. PHE’s own 2015 national guidance on tobacco control, Health matters: smoking and quitting in England, drew on, and promoted, the benefits of using the ROI tool. It included a worked example from Sunderland, an area with high smoking prevalence and lower health equity indices (p.10/11) [Ev7]. In 2018, PHE published, Tobacco commissioning support 2019 to 2020: principles and indicators, listing questions for local tobacco control partnerships to use to check if they were “following evidence and best practice”. Questions included: one about WHO’s Framework Convention on Tobacco Control; and, “have the partners identified the potential return on investment for funding tobacco control interventions and does this include any economies of scale that could be achieved by commissioning with other local authorities? See the NICE return on investment tool” (p.11) [Ev8].

Impact 3: Impact on local policymaking and smoking rates, especially in the North East

Starting in 2015-16, PHE regularly published an outline joint strategic needs assessment (JSNA) support pack for tobacco control. This included a ROI section encouraging local authorities and others to apply Brunel’s NICE ROI tool in local strategies. PHE published the packs with relevant ROI data completed by authorities across England, from Northumberland to Plymouth. For example, the ROI section in Coventry’s 2017-18 version suggested investing GBP1,064,089 in local stop smoking services, plus the sub-national service, would, according to the tool, provide a ROI after 5 years of GBP1.7 for every GBP invested (p.9) [Ev9].

The importance of NICE’s 2014 tobacco control ROI tool to policymakers was seen in the 2015 HM Treasury report on its tobacco levy consultation [Ev10]. Of the 58 responses, 13 from across NE England cited the tool, including those from County Durham Health and Well-Being Board; Gateshead Council; NE Trading Standards Association; Newcastle Upon Tyne Hospitals NHS Foundation Trust; and Fresh - Smoke Free North East, the region’s stop smoking service. NE England not only saw public bodies draw on and promote the ROI tool, but was also the region with “the biggest drop in smokers nationwide…[the rate] fell from 22.3% of people smoking in 2013 down to 19.9% in 2014” [Ev11] . In this press release, the tool’s importance to Fresh’s work was shown by its use as the reference at the end of a paragraph stating: “Ambitious plans to cut smoking rates to 5% across the North East by 2025 were backed by health and local government leaders and young people in the North East earlier in the year. It was estimated getting down to 5% would save thousands of lives and an estimated £100 million a year” [Ev11].

The Director of Fresh corroborated the impact: “The tobacco control ROI tool developed by Brunel has been particularly valuable to us in Fresh in our activities in promoting tobacco control.... The tool allowed local commissioners...to make more informed investment decisions to improve the health and health equity through adopting the most cost effective package of tobacco control interventions. I believe our local promotion of the ROI tool has contributed to making the North East the region of England where there was most progress in reducing the rate of smoking, which in turn leads to improved health and health equity”* [Ev11]. The senior PHE manager also stated: “I can verify that the tools that Brunel has developed have allowed local commissioners (both within the NHS and local government) to better understand the estimated impact of various packages of interventions, and to make more informed investment decisions to improve the health and health equity of local populations” [Ev6].

Impact 4: Impact of the ROI tool and EQUIPT on policies and smoking rates in Europe

WHO Europe used the tool in their 2015 roadmap of actions to strengthen implementation of the WHO Framework Convention on Tobacco Control as the sole reference for saying: “In addition to the health gains, there are substantial returns on investment from effective tobacco control measures with significant productivity gains and savings to health and social care” (p.4) [Ev13].

The increasing reach is also seen in EQUIPT’s stakeholder engagement to develop ROI tools for Germany, Hungary, Spain and for The Netherlands [R3,5,6]. The President of Spain’s CNTP described EQUIPT’s impact on policy: ‘’the EQUIPT project has influenced and informed many stakeholders about the efficiency of the different smoking cessation interventions, and jointly with other actions in the country, has convinced the [Spanish] Government for financing smoking cessation medications for quitting smoking.’’ [Ev1]. Similarly, the Director General of Public Health in the Spanish Health Ministry said of EQUIPT, the “project and its results, has influenced and informed decisions on the Ministry of Health in Spain and, it has been the key factor for financing the use of the two medicines for quitting smoking at National level” [Imp14].

Implementation of the new policy began on 1 Jan 2020. On Feb 7 2020, Diariofarma, a newsletter providing pharmacy information in Spain, reported that Cofares, the Spanish Pharmaceutical Cooperative made up of over 10,000 pharmacy partners, claimed that demand for the two pharmacological treatments being provided under the new policy “skyrocketed in these first weeks of the year" [Ev15]. Cofares alone dispensed 18,700 units throughout January, “a figure well above the 4,700 units that were dispensed in January 2019. Therefore, the increase recorded is around 300% compared to the same month last year.”

Referring to the new policy’s introduction on 1 Jan, the President of CNPT noted: “ Since then, there has been a dramatic increase in the number of units of these therapies dispensed, mainly varenicline. This, in turn, should imply a reduction in smoking rates....There is no official published data in terms of decreased prevalence, but studies on Autonomous Communities indicates so” [Ev1]. The Director General of Public Health also said: “For this first year there has had a large increase in the number of dispensed units, mainly varenicline. Although it is pending yet to do a evaluation of the results...it is expected a reduction in smoking rates, which should eventually contribute to a reduction in mortality and morbidity in medium and long term” [Ev14].