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- University of Strathclyde
- 3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
- Submitting institution
- University of Strathclyde
- Unit of assessment
- 3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
- Summary impact type
- Technological
- Is this case study continued from a case study submitted in 2014?
- No
1. Summary of the impact
An outstanding, novel anti-infective drug discovered at Strathclyde is reaching the final stages of clinical trials. In the class known as DNA minor groove binders (S-MGBs), it completed Phase-IIa clinical trials in 2020, achieving total cures for the treatment of Clostridioides difficile infections, out-performing the existing benchmark (vancomycin), and is now approved for a Phase-III trial. Its novel multi-target mode of action explains why, to date, antibiotic-resistance is not seen. MGB Biopharma, a new biotechnology company formed to develop the drug and sponsor the clinical trials, has raised over GBP11,000,000 in equity and public funding. MGB Biopharma expects the drug to be fully licensed and commercialised in 2024/5.
2. Underpinning research
‘Antimicrobial resistance’ (AMR) is a current global issue. The 2016 O’Neill report on Antimicrobial Resistance highlighted 0.5M global-deaths annually due to drug-resistant infections. Without action, 50M people could die annually by 2050. Discovery of novel antibiotics to treat resistant infections is therefore a priority.
Since 2000, a multidisciplinary team of chemists and biologists at Strathclyde has developed a novel class of compounds, originally distinguished by their ability to bind to the minor groove of DNA (MGBs). From their library of ‘Strathclyde-MGBs’ (S-MGBs), compounds with anti-infective activity were characterised by defining/refining the specificity of binding to nucleic acids, demonstrating selectivity in interrupting cellular processes in pathogens. The compounds form a family of putative anti-infective agents with a number of clinical applications. To realise this potential, the Strathclyde research team has partnered with a new company (MGB-Biopharma) to translate their research to the clinic.
Key research findings
The initial design of the S-MGBs was based loosely on the structure of distamycin. The key initial discovery was design of a novel S-MGB that demonstrated exceptionally high antibacterial activity [ R1]. A World Patent [ R2]) and cognate patents were filed and awarded.
Iterative development of new compounds in the S-MGB library came through providing biological data to the chemists, who then varied the S-MGB template to make subsequent molecules with improved physicochemical properties desirable in a medicine: potency with respect to the infectious organism, and selectivity with respect to the animal or human host. The biology has shown that specific S-MGB members have high and selective activity against specific disease targets, including (separately) bacteria Staphylococcus aureus & Clostridioides difficile; animal parasite Trypanosoma brucei brucei; fungal pathogen Cryptococcus neoformans; and bacterial pathogen Mycobacterium tuberculosis [ R3, R4].
The biologists within the team played a key role in the in vitro evaluation of the S-MGB library (2005-2013) that led to identification of MGB-BP-3 as lead compound for development. All members (~200) of the S-MGB family at that time (in 2013) were evaluated in vitro against a panel (>200) of pathogenic bacteria and fungi, including those isolated recently from the clinic as being resistant to multiple antibiotics. S-MGBs were also tested in vitro with human cell lines to establish the potential toxicity of each MGB in human therapy. From these collective data, a priority list emerged: compounds that killed bacteria (at around 0.2 g/mL) but were not highly toxic (the so-called ‘therapeutic window’). It transpired that the best anti-bacterial candidates were active against Gram-positive bacteria, which resulted in prioritisation of disease state Clostridioides difficile, which is the most prevalent causative pathogen of healthcare-associated diarrhoea world-wide, responsible for high levels of hospitalisation and morbidity.
Proof of concept in animal models was an important gateway for approval by the Medicines and Healthcare products Regulatory Agency (MHRA) of the Phase-I clinical trial of MGB-BP-3 in 2015. Strathclyde staff validated MGB-BP-3 using a murine thigh infection model, with S. aureus as the infective agent.
Approval by MHRA for the Phase-I trial also required determination of the frequency of mutation that could lead to resistance to MGB-BP-3. Further exhaustive tests, beyond the MHRA requirements, observed no mutation to resistance [ R5]. This is an extremely important result in the context of MGB-BP-3’s longevity as a clinical antibiotic and antibiotic use in general.
To support applications for final clinical approval, we undertook an extensive study of the mode of action of MGB-BP-3, using advanced molecular biological techniques such as RNA-Seq and DNase protection of target sequences when MGB-BP-3 is bound [ R5]. The results are entirely consistent with multiple loci of action by MGB-BP-3 on the bacterial chromosome. This explains why no resistance is observed, as multiple mutations will not occur simultaneously. The identities of these loci are also consistent with the metabolic debilitation that results from action by MGB-BP-3 and kills the bacteria.
3. References to the research
(Strathclyde-affiliated authors in bold; FWCI at 02/02/2021)
Anthony N., Breen D., Clarke J., Donoghue G., Drummond A., Ellis E., Gemmell C., Helesbeux, J-J., Hunter I., Khalaf A., Mackay S., Parkinson J., Suckling C. and Waigh R. (2007). Antimicrobial lexitropsins containing amide, amidine, and alkene linking groups. Journal of Medicinal Chemistry, 50: 6116-6125 https://doi.org/10.1021/jm070831g [FWCI:1.59]
Suckling et al. (2008). Novel Minor Groove Binders. World Patent WO/2008/003698. Published 23.04.2008; US 8,012,967. https://bit.ly/3siALei
Hlaka L., Rosslee M., Ozturk M., Kumar S., Parihar S., Brombacher F., Khalaf A., Carter K., Scott F., Suckling C. and Guler R. (2017). Evaluation of Minor Groove Binders (MGBs) as novel anti-mycobacterial agents, and the effect of using non-ionic surfactant vesicles as a delivery system to improve their efficacy. Journal of Antimicrobial Chemotherapy, 72: 3334-3341 https://doi.org/10.1093/jac/dkx326
Suckling, C., Khalaf, A., Scott, F., Tucker, N., Niemenen, L., Lemonidis, K., Hunter I. (2017). Why antibacterial minor groove binders are a good thing. In 3rd International Electronic Conference on Medicinal Chemistry. https://doi.org/10.3390/ecmc-3-04651
Kerr, L., Browning, D., Lemonidis, K., Salih, T., Hunter. I., Suckling, C., Tucker, N (2020). Novel antibiotic mode of action by repression of promoter isomerisation. bioRxiv. https://doi.org/10.1101/2020.12.31.424950 [Uploaded to online repository 31/12/2020, evidence available from HEI on request]
Notes on the quality of research:
R1-R4 were peer-reviewed ahead of publication. The body of underpinning research has been supported by over GBP945,000 of peer-reviewed funding, including:
Tucker, N., Hunter I., Suckling C. Systematic Investigation of the extent and mechanisms of Minor Groove Binders in antibacterial and anticancer activity. Scottish Universities Life Sciences Alliance, 01/08/2013-31/07/2014, GBP49,073.
Hunter I., Suckling C., Tucker N. The differing biological fates of DNA minor groove-binding (MGB) antibiotics in Gram-negative and Gram-Positive bacteria. BBSRC, 17/02/2014/16/02/2018, GBP369,782.
Hunter I., Suckling C., Tucker N. The differing biological fates of DNA binding MGBs. MRC Confidence in Concept, 2013-2014, GBP112,902.
Scott, F., Tucker N., Hunter I., Dancer S., Suckling C. Accelerating clinical introduction of novel antibacterial drugs. Chief Scientist Office (Scotland), 01/11/2016-31/10/2017, GBP116,784.
Tucker N., Hunter I., Dancer S., Suckling C. Investigating a novel class of gram-negative active antibiotics suitable for clinical use. Chief Scientist Office (Scotland), 01/11/2020-31/10/2022, GBP296,999.
4. Details of the impact
The discovery and development of S-MGB anti-infective compounds by the Strathclyde researchers has led to:
An effective new drug with novel mode of action for the treatment of serious C. difficile infections, to combat hospitalisations and mortality;
Formation of a new biotechnology company;
Progress to successful international clinical trial programmes;
A new class of antibiotic.
Economic Impact
Following the discovery of several highly active anti-bacterial compounds [ R1] and the submission of patent applications with broad coverage of active compounds (US 8,012,967 [ R2] and cognate patents), the University of Strathclyde sought a commercial partner to discover and develop new anti-infective drugs, particularly antibacterial drugs, based on Strathclyde’s intellectual property of S-MGBs. A license was granted to Pharma Integra, a privately-owned drug development company, which was able to raise funds to establish a new, Scottish-based company, MGB Biopharma, for this purpose. MGB Biopharma began operations in 2009.
MGB Biopharma has established itself as a commercially successful company. Since its formation, the company’s researchers have worked closely with Strathclyde, undertaking the development of clinical candidate molecules selected from the range of compounds created at the University [ S1]. MGB Biopharma is the sole licensee of the patented S-MGBs for anti-infective applications world-wide.
Since August 2013 the company has raised GBP5,980,000 in equity funding from investment syndicates and over GBP4,100,000 from public funds [ S1], including a highly competitive GBP2,780,000 grant from Innovate UK in 2018 [ S2]. In 2019, funding to complete MGB-BP-3’s Phase-II trials was oversubscribed [ S1]. Companies House lists 110 shareholders, the majority having taken equity as a result of this crowdfunding initiative [ S3]. This demonstrates how MGB-BP-3, as a pre-clinical drug candidate, has caught the imagination of a broad range of investors – in a business area (often called the ‘Valley of Death’ for projects) that has been historically difficult to fund at this stage of development.
MGB Biopharma has also benefited from the Generating Ant ibiotics Incentives Now (GAIN) initiative in the USA [ S4], which extends commercial exclusivity of MGB-BP-3 by five years (to 2032), making it a much more attractive commercial investment. GAIN is applicable to a limited number of target pathogens including C. difficile, so treatment with MGB-BP-3 falls directly within the programme. As part of the GAIN initiative, MGB-BP-3 was granted Qualified Infectious Disease Product (QIDP) status by the US Food and Drug Administration in 2019, which accelerates its progress through subsequent clinical trials and simplifies its route to market [ S1, S4].
In 2020, the US Senate approved the ‘ Pioneering Antimicrobial Subscriptions To End Up-surging Resistance’ (PASTEUR) Act, which is an innovative financial model for development of antibiotics serving critical needs. It provides between USD750,000 and USD3,000,000,000 for each drug. MGB-BP-3 is eligible for development via PASTEUR [ S1] on commencement of a Phase-III trial. In the pipeline of US legislature, the ‘ Developing an Innovative Strategy for Antimicrobial Resistant Micro-organisms’ (DISARM) Act will improve critical Medicare reimbursement of new infection-fighting drugs. The CEO of MGB Biopharma has indicated the applicability of MGB-BP-3 to this initiative [ S1]. Taken together, it is clear that MGB-BP-3 addresses a critical market need for rapid development of a novel antibiotic that addresses antimicrobial resistance.
Health-care Impact
In 2019, the US Centre for Disease Control (CDC) cited Clostridioides (Clostridium) difficile (C.Diff) as the second biggest issue in antimicrobial resistance in the USA, with 223,900 people requiring hospital care and linked mortality of 12,800 per annum [ S5].
In clinical trial, MGB-BP-3 has shown outstanding activity against infections caused by C.Diff, which is the most prevalent causative pathogen of healthcare-associated diarrhoea worldwide. To date, an oral formulation of MGB-BP-3 has successfully completed an integrated Single Ascending Dose and Multiple Ascending Dose Phase-I clinical trial [ S6] and Phase-II clinical trials [ S7]. In the Phase-1 trial (2015 – 2016) carried out at Hammersmith Hospital, London, MGB-BP-3 caused no serious adverse effects and decreased/limited the proportion of Firmicutes (of which C. difficile is a member) in the gut microbiota, completely consistent with expectations from Strathclyde’s laboratory research. In the Phase-IIa trial (2019/2020), carried out at several locations in the USA and Canada where there are stable populations of C. difficile patients, MGB-BP-3 fully met the requirements for safety, efficacy, and dose selection, demonstrating better-than-expected efficacy at its lowest dosage level, with no serious adverse effects [ S7a].
The most significant benefit shown by MGB-BP-3 in the Phase-IIa trial was a complete absence of disease recurrence at the optimum dose, a unique advantage. In terms of its rapid and sustained action against C.Diff and its resilience to the generation of resistance, these trials have shown MGB-BP-3 to be superior to the current principal treatment for C. difficile, vancomycin. As reported by the CEO of MGB Biopharma:
‘In 2020 MGB-BP-3 completed its Phase IIa clinical study in which it showed efficacy of 91% - 100% in both initial and sustained cure. These results compare favourably with vancomycin, the current standard of care, which has published data showing sustained cure of between 42% - 75% across several studies. This efficacy, together with its novel mechanism of action, excellent safety profile and lack of observed resistance make MGB-BP-3 a distinctive and commercially attractive drug.’ [ S1]
The Clinical Lead and Principal Investigator of the Phase-II trial commented, ‘I am most pleased to have contributed to the success of the Phase 2 clinical study of MGB-BP-3. There is a real need for new agents to address CDI and it is gratifying to see this agent progressing onto its next phase of study’. [ S7b] With a plan for a Phase-III clinical trial approved by the United States FDA (January 2021) [ S7b], MGB Biopharma expects the drug to be fully licensed and commercialised in 2024/5 [ S1].
MGB Biopharma also reports that it is developing an intravenous formulation of MGB-BP-3 for the treatment of systemic Gram-positive infections such as MRSA, which is currently at the late pre-clinical stage. The Company is also conducting feasibility studies of topical applications of MGB-BP-3 for the treatment of serious Gram-positive skin infections [ S8a, b].
The combined work of the University of Strathclyde and MGB Biopharma has been acknowledged in the TV (2015) and print (2018) media as a significant step in the global fight against anti-microbial resistance [ S9a, b]. The ongoing success and importance of the MGB-BP-3 clinical trials have been stressed by the Clinical Lead and Principal Investigator of the Phase-II trial: ‘C. difficile infection represents a major burden to the Canadian and US healthcare systems. A novel antibiotic that is able to kill this deadly pathogen before it is able to sporulate offers hope to patients and their families who suffer the pain and misery caused by this disease’ [ S7a].
The World Health Organization (WHO) has defined criteria [ S10] to classify a novel antibiotic:
represents a new chemical class;
aims at a new target;
has a new mode of action; and
has an absence of cross-resistance to existing anti-microbials.
WHO cites only four compounds that satisfy their criteria; MGB-BP-3, delivered through the S-MGB project, is the fifth compound publicly recognised as entirely novel [ S10, p.47-48].
Antibiotic discovery and translation to the clinic has been the realm of ‘big pharma’. It is remarkable that this multi-disciplinary Strathclyde team has, in partnership with SME MGB Biopharma, taken its lead compound to the final phase of clinical trials during the assessment period.
5. Sources to corroborate the impact
Corroborating statement from CEO of MGB Biopharma, dated December 2020.
MGB Biopharma. Scottish Biopharmaceutical Company MGB Biopharma Receives £2.78m Grant Award For Phase IIa Clinical Trial. 14th March 2019. https://bit.ly/2XU3tEL
Companies House. Confirmation Statement for MGB Biopharma Ltd. Filed 07/07/2020. https://bit.ly/3r9xXQd
MGB Biopharma. MGB Biopharma Granted Qualified Infectious Disease Product (QIPD) and Fast Track Designation by U.S. FDA for the Treatment of Clostridium difficile-associated Diarrhoea (CDAD) for Tablet Presentation of MGB-BP-3. 28th January 2019. https://bit.ly/3ioRVCU
US Centre for Disease Control. Antibiotic Resistance Threats in the United States. https://bit.ly/3055kHT
Drug Development & Delivery. MGB Biopharma Successfully Completes Phase I Clinical Trial. https://bit.ly/3nShwFq
(a) MGB Biopharma. MGB Biopharma Announces Successful Outcome from Phase II Clinical Study with MGB-BP-3. 19th May 2020. https://bit.ly/35U0eS9
(b) MGB Biopharma. MGB Biopharma Announces Successful End-of- Phase II meeting with FDA for MGB-BP-3. 27th January 2021. https://bit.ly/3b6JdHe
- (a) MGB Biopharma. Our Intravenous Programme. https://bit.ly/2KzIDri
(b) MGB Biopharma. Topical Programme. https://bit.ly/3qCcIWC
- (a) BBC News. New Antibiotic Could Transform C. Diff Treatment. 31st August 2015. https://bbc.in/2Y7ILl3
(b) The Scotsman. MGB Biopharma drug secures £4m funding. 14th September 2018. https://bit.ly/2Nj9LMa
- Access to Medicine Foundation. Antimicrobial Resistance Benchmark 2018 (p. 47-48). https://bit.ly/3q986GO
- Submitting institution
- University of Strathclyde
- Unit of assessment
- 3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
- Summary impact type
- Health
- Is this case study continued from a case study submitted in 2014?
- No
1. Summary of the impact
Extensive national studies, including advanced analysis and modelling from Kavanagh, were the first population-based demonstrations of a reduction of cervical and precancerous disease due to the human papillomavirus (HPV) vaccine, freely available in Scotland since 2008. The studies led the Scottish Government to change the age range of the Scottish Cervical Screening Programme and replace cytology with HPV testing as the initial stage of screening. Wider impact of the research caused UK policy makers to extend HPV vaccination to males, and the World Health Organisation (WHO) to advocate continued worldwide vaccination of girls aged 9-14. Global media coverage of the research also raised public awareness of successful vaccination initiatives at a time of growing misinformation related to vaccination.
2. Underpinning research
Cervical cancer is commonly diagnosed in females, with 80-90% of cases attributable to HPV infection. Organised cervical screening programmes, introduced in the 1980s, dramatically reduced cervical cancer in Scotland by enabling treatment of pre-cancerous disease. Since 2008, HPV vaccination has been available through the NHS to girls, typically 12-13 years old, protecting them against two of the common genotypes of HPV (HPV16 and HPV18) implicated in over 70% of cervical cancer cases, with hypothesised cross-protection against three other similar genotypes (HPV 31/33/45) which also exhibit a high risk of causing cervical disease. To assess the impact of the vaccine in the population, researchers from academia and the Scottish Government established the Scottish Cervical Cancer Prevention Programme in 2008, which modelled the impact of the vaccine on cervical screening and other strategies to prevent the cancer. As part of this programme, two researchers from the University of Strathclyde, Chris Robertson and Kim Kavanagh, collaborated with Health Protection Scotland and the Scottish HPV Reference Laboratory to determine the impact of immunisation on cervical screening and colposcopy, to consider possible future triage of cervical disease, and determine the impact of HPV vaccination on public health. Robertson designed the initial epidemiological studies (REF2014 impact case submitted to B10) and was joined in this activity for studies in the national surveillance programme by Kavanagh who, as detailed below, led on the statistical analysis and modelling of the data, and on leading and co-authoring manuscripts.
Assessing the impact of HPV vaccination on public health (HPV prevalence and pre-cancerous disease)
By annually linking individual vaccination, screening and HPV testing records, a 2009-2012 study with Kavanagh as principal analyst and lead author demonstrated a clear reduction in the prevalence of HPV 16/18, as well as cross-protective effects with other high risk types of HPV, among girls vaccinated at age 13-17 [ R1]. A separate seven-year cross-sectional study, led by Kavanagh, was the first internationally to present population-based evidence of the effectiveness of the bivalent HPV vaccine in girls vaccinated routinely at age 12-13 and attending cervical screening at age 20 [ R2]. The study showed that the vaccine-specific HPV genotypes (16/18) and the cross-protective genotypes (31/33/45) had almost disappeared in this population seven years after the introduction of the vaccine, with evidence of herd protection for all these types.
To better assess the population-level consequences and herd effects following female HPV vaccination programmes, two further studies co-authored by Kavanagh combined the results of the Scottish cross-sectional assessment with those of other international studies, verifying the high efficacy reported in randomised controlled clinical trials of the HPV vaccine [ R3, R4]. Kavanagh was the only academic researcher from Scotland invited to join other leaders in HPV epidemiology in the international HPV Vaccination Impact Study Group. The Group’s purpose was to capture the impact of HPV vaccination on HPV infection levels and precancerous disease in high income countries. Both of the studies conducted by the Group demonstrated the population-level impact and herd effects arising from HPV programmes. The first study focussed on individuals vaccinated at an older age who may not have had maximum benefit from vaccination as they could have been exposed to HPV prior to immunisation [ R3]. The second study analysed evidence collated over a broader timeline. It was able to produce more definitive conclusions because it included individuals much younger than in the first evaluation [ R4]. In both highly cited seminal studies, Kavanagh advised on the combination of the data across studies, validated the rigour of the statistical analysis in publications and the appropriateness of associated public health messages.
Assessing the impact of HPV vaccination on the Scottish Cervical Screening Programme (SCSP) (cytology and colposcopy)
The SCSP in the pre-HPV vaccination era was based fully on cytological screening, the examination of a smear sample of cervical cells under a microscope, as an initial triage to identify individuals with potential cervical disease. As cytology is subjective, it is more difficult to accurately classify abnormalities seen following the introduction of HPV vaccination due to markedly lower rates of precancerous disease. Retrospective analysis of routinely collected data from the SCSP, found that lower rates of HPV in vaccinated women led to significant reductions in positive predictive and abnormal predictive values for detecting precancerous disease, such that cytologists were referring a greater proportion of patients without abnormal cytology for colposcopy [ R5].
To understand possible impacts of HPV vaccination on colposcopy – the diagnostic procedure used to classify cervical disease - routinely collected data were extracted from the Scottish National Colposcopy Clinical Information Audit System for a cohort of women who entered the SCSP and were aged 20–21 in 2008–2012. Analysis revealed a downward trend in the proportion of those referred to colposcopy with abnormal cytology, suggesting that demand for colposcopy as part of the SCSP will continue to fall. It also showed that the positive predictive value of colposcopy for the detection of high grade cervical intraepithelial neoplasia in vaccinated women to be at 65%, the lowest acceptable level of the UK national cervical screening programme guidelines [ R6].
A significant reduction in diagnoses of all stages of the precancerous disease attributable to HPV was observed. These were the first population-based demonstrations of the impact of the vaccine on cervical disease [ R5, R6] and indicated that revision of the SCSP was merited.
3. References to the research
(Strathclyde-affiliated authors in bold; FWCI at 25/02/21)
K. Kavanagh, K.G.J. Pollock, A. Potts, J. Love, K. Cuschieri, H. Cubie, C. Robertson, M. Donaghy (2014) Introduction and sustained high coverage of the HPV bivalent vaccine leads to a reduction in prevalence of HPV 16/18 and closely related HPV types, British Journal of Cancer, 110: 2804–2811. https://dx.doi.org/10.1038/bjc.2014.198 [FWCI: 6.87; REF2]
K. Kavanagh, K.G. Pollock, K. Cuschieri, T. Palmer, R. Cameron, C. Watt, R. Bhatia, C. Moore, H. Cubie, M. Cruickshank, C. Robertson (2017) Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7-year cross-sectional study, Lancet Infectious Diseases, 17(12): 1293-1302 https://dx.doi.org/10.1016/S1473-3099(17)30468-1 [FWCI: 11.58; REF2]
M. Drolet, E. Bénard, M. Boily … K. Kavanagh… (2015) Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis, Lancet Infectious Diseases 15(5): 565-580 http://doi.org/10.1016/S1473-3099(14)71073-4 [FWCI: 31.20; REF2]
M. Drolet, E. Bénard, N. Pérez … K. Kavanagh … (2019) Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. Lancet 394: 497-509. http://dx.doi.org/10.1016/S0140-6736(19)30298-3 [FWCI: 60.92; REF2]
K. Pollock, K. Kavanagh … H. Cubie, C. Robertson, M. Cruickshank, T. Palmer, S. Nicoll, M. Donaghy (2014) Reduction of low- and high-grade cervical abnormalities associated with high uptake of the HPV bivalent vaccine in Scotland, British Journal of Cancer 111: 1824–1830. https://doi.org/10.1038/bjc.2014.479 [FWCI: 5.82; REF2]
T.J. Palmer, M. McFadden, K.G.J. Pollock, K. Kavanagh, K. Cuschieri, M. Cruickshank,S. Cotton, S. Nicoll, C. Robertson (2016) HPV immunisation and cervical screening — confirmation of changed performance of cytology as a screening test in immunised women: a retrospective population-based cohort study, British Journal of Cancer, 114: 582-589
https://doi.org/10.1038/bjc.2015.474 [FWCI: 2.38]
Notes on the quality of research: All articles are published in peer-reviewed journals. Kim Kavanagh was awarded the 2018 Royal Society of Edinburgh Sir Thomas MakDougall Brisbane Medal for ‘outstanding, internationally renowned research in public health epidemiology and health informatics’, based mainly on her assessment of the HPV vaccination programme. The programmes received funding from the Chief Scientist Office, the Scottish Government:
Cruickshank, Robertson (Strathclyde PI). The Scottish Cervical Cancer Prevention Programme: Assessing and modelling the impact of HPV 16/18 immunisation on the performance of current cervical screening performance and the effectiveness of alternative cervical screening strategies to optimise cancer prevention in the HPV immunisation era. Chief Scientist Office (CSO). 01/04/2010-31/03/2016. GBP523,278 (Strathclyde GBP171,695).
Howie, Kavanagh (Strathclyde PI). Development of CINCk (CIN Chemokine panel) as an objective laboratory triage test for HPV infected women with clinically significant cervical disease. Chief Scientist Office. 01/03/2014-29/02/2016. GBP224,788 (Strathclyde GBP11,876).
Cubie, Robertson (Strathclyde PI). Scottish Cervical Cancer Prevention Programme: Establishing an HPV Clinical Research Centre for long-term follow-up of HPV infection and associated disease in a vaccination era, through the creation of a population based sample archive. Chief Scientist Office. 02/06/2009-31/07/2014. GBP671,310 (Strathclyde GBP15,849).
4. Details of the impact
Kavanagh’s analysis and modelling of large observational health datasets in the above body of research demonstrated the success of the HPV vaccine in reducing the prevalence of HPV infection and subsequent precancerous cervical disease in Scotland. The studies have had a substantial public health impact as they have:
Caused the Scottish Government to change the Scottish Cervical Screening Programme;
Stimulated improvements to the UK cervical screening process;
Influenced UK and international policy;
Raised global awareness of the effectiveness of vaccination programmes.
Influenced a change to the Scottish Cervical Screening Programme (SCSP)
In June 2016, a review panel for the SCSP changed the age range for cervical screening from 20-60 to 25-64 on account of the low predictive value of cytology screening for women aged 20-25. The panel directly referred to work involving Strathclyde researchers [ R1, R5] when justifying and communicating the reason for the change [ S1a]. By supporting this delay to the age of screening, research by Kavanagh and colleagues has contributed to reducing the number of unnecessary and potential stressful screenings for low risk young women. The impact of the evidence of reduced disease prevalence has also been mentioned by The Director of the Scottish HPV Reference Laboratory: ‘The change in infection and disease prevalence has been so profound – that Immunisation status is now being factored into standard national reports on disease prevalence and screening performance for the Scottish Cervical Screening Programme. Additionally, [the] impact of immunisation has informed national modelling work undertaken by the Scottish Cervical Screening Programme to support the configuration of screening services planned for 2020’ [ S2]. The interim Clinical Director at Health Protection Scotland (HPS) writes that ‘ the data analysis research carried out by Dr Kim Kavanagh has had a great impact at HPS’ and that ‘ the outputs of this programme of work provided evidence to support changes in vaccine and cervical screening policy’ [ S1b].
Informed improvements to UK cervical screening process
A 2015 report from the Advisory Committee on Cervical Screening (ACCS) to the UK National Screening Committee (UK NSC) [ S3] cited one of the above studies [ R5], which had reported a significant reduction in precancerous disease attributable to HPV following the introduction of HPV vaccination. In particular, the UK National Screening Committee report noted, ‘A recent report from Scotland, where screening still begins aged 20 years, has shown a significant reduction in CIN3 [ Cervical Intra-epithelial Neoplasia – abnormal cells found on the surface of the cervix] … amongst the vaccinated cohort. In a screening programme where HPV status determines the number of women requiring any further action, the expected impact of vaccination would therefore be considerable in terms of the proportion requiring reflex cytology, referral to colposcopy and treatment for high grade CIN’ [ S3 p.5]. In other words, if there is not likely to be much precancerous disease in the screened group, then the current programme is unlikely to be efficient or fit for purpose in the younger age groups.
The research in R5 had predicted a significant drop in the cytological predictive value for precancerous disease (a suggestion later confirmed in R6) and envisaged a consequent drop in the overall efficiency of the cervical screening programme. These findings informed a 2018 policy decision by NHS National Services Scotland (implemented in 2020) to replace cytology as the initial stage of screening with HPV testing, and to reserve cytology for women found to be HPV positive, to provide a more sensitive initial test for underlying disease in a population with decreasing HPV prevalence [ S4].
Supported UK and international vaccination policy recommendations
From 2014 to 2016, results from the underpinning research were fed into and discussed by the UK Joint Committee on Vaccination and Immunisation (JCVI), an advisory body to the Secretary of State on the provision of vaccination and immunisation in the UK. The research findings were used by the JCVI to monitor the success of the vaccination campaign and then advise the UK government on vaccination policy [ S5, S6]. At the 2014 JCVI meeting [ S5], the Scottish data were presented as part of surveillance update on the impact of HPV vaccination in the UK. The Scottish data [ R1, R5] summarised the initial impact of the HPV vaccination on HPV infection and precancerous disease in women who were vaccinated as part of the catch-up campaign (when they were older school children). In 2016, the JCVI were informed about the effect of the vaccination in girls vaccinated at a younger age [ S6]. The committee also learned about the first evidence of cross-protection against the non-vaccine types HPV 31/33/45 and evidence of herd protection in unvaccinated females of the same age [ R2]. The Scottish team also demonstrated equitable coverage of HPV vaccine uptake between deprived and less deprived groups – giving hope for wiping out inequalities in cervical diseased between these groups.
Subsequently, the 2014 study demonstrating the effectiveness of the vaccination in women [ R1] was cited by the British Medical Association in an April 2018 parliamentary briefing supporting the extension of the immunisation programme to males. Later that year the JCVI, after reviewing research including R3, considered gender neutral HPV vaccination to be cost effective compared to no vaccination programme, although they stressed that the vaccination of girls should remain the priority where resources were limited [ S7]. In light of this, by April 2019 the devolved health boards of England, Wales, Scotland and Northern Ireland all made the decision to offer HPV vaccination to boys aged 11-13 from the beginning of the 2019/20 academic year.
The underpinning research studies [ R1, R2, R3, R5] have also informed the recommendations made by the World Health Organization’s (WHO) Strategic Advisory Group of Experts on Immunization (Working Group on HPV Immunization). Specifically, this relates to recommendations that the WHO continues to support worldwide HPV vaccination of girls aged 9-14, as well as the use of multiple age cohort vaccination and gender neutral vaccination as ways of speeding up population level impacts of HPV immunisation. This influence is noted in various documents including the evidence to recommendations framework which confirms that R3 informed ‘SAGE deliberations on the potential of gender-neutral immunization programmes’ in 2016 [ S8, S9].
Raising global awareness of a successful vaccination initiative
By demonstrating the success of the HPV vaccine, Strathclyde’s body of research has attracted media attention from BBC News, the Guardian and the Scotsman, among others. The 2019 Lancet paper [ R4], in particular, generated substantial global media coverage in North and South America, Europe, Australia, Africa and Asia. By raising awareness of successful vaccination initiatives, this research has provided important pro-vaccination information to the public at a time of unprecedented and growing public scepticism of vaccination. The Chief Executive of Jo’s Cervical Cancer Trust, commented in the Kenyan Star: ‘This study furthers the growing evidence to counteract those who don’t believe that this vaccine works…’ [ S10a]. When reporting the Lancet study [ R4], NBC News mentioned that, ‘Despite the widespread benefits of the vaccine…HPV vaccination rates in the USA are still lagging behind those of other adolescent immunizations’ [ S10b]. This point was also mentioned in the Washington Post’s coverage, which included a statement from a gynaecologist at MD Anderson Cancer Center, ‘I just think it is really important to educate the public that it [i.e. the vaccine] is most effective [for children] both because of the kids’ immune response but also because they haven’t been exposed yet’ [ S10c]. Public communication like this is essential if decreasing HPV vaccine uptake rates in some countries are to be reversed.
5. Sources to corroborate the impact
- a. Public Health Scotland, Cervical Screening Programme Change in Age Range and Frequency 2016, Questions and Answers paper, pp.4,7.
b. Factual statement from Interim Clinical Director of Public Health Scotland (earlier Health Protection Scotland), dated 04/03/2021.
Factual statement from Director of the Scottish HPV Reference Laboratory, dated 20/01/2018.
Advisory Committee on Cervical Screening, Report to the UK National Screening Committee, June 2015, p.5.
NHS National Services Scotland, ‘New HPV test more effective for identifying the risk of cervical cancer’, 8 October 2020.
HPV Sub-committee of the Joint Committee on Vaccination and Immunisation, Minute of the meeting held on Monday 20 January 2014, p.4.
HPV Sub-committee of the Joint Committee on Vaccination and Immunisation, Minute of the meeting held Friday 26 February 2016, p.4.
Joint Committee on Vaccination and Immunisation, Interim Statement on Extending Vaccination to Adolescent Boys, 2017, pp.8,18.
World Health Organization, Strategic Advisory Group of Experts (SAGE) on Immunization HPV immunization schedules and strategies: background paper for October 2016 meeting pp.16-18.
World Health Organization, Strategic Advisory Group of Experts (SAGE) on Immunization, Evidence to recommendations framework noting deliberations at October 2016 meeting, p.1.
Media coverage:
a. The Star, Kenya, Hopes raised of cervical cancer eradication , 28/06/2019;
b. NBC News, USA, HPV vaccine benefits ‘exceed expectations’, may lead to elimination of cervical cancer , 27/6/2019;
c. The Washington Post, USA, HPV vaccine now recommended through age 45 in some cases , 26/06/2019.
- Submitting institution
- University of Strathclyde
- Unit of assessment
- 3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
- Summary impact type
- Health
- Is this case study continued from a case study submitted in 2014?
- No
1. Summary of the impact
Since 2014, Strathclyde’s research and expertise around physical activity in early life has directly informed the development of new guidelines and implementation plans globally (WHO) and nationally (Canada, Australia, South Africa, USA, UK). By providing clear and accessible guidance to enable health professionals and primary caregivers to reduce screen time and increase physical activity in the under 5s, the research has strengthened campaigns to lower child obesity rates in order to improve cognitive development and academic attainment as well as prevent associated diseases in later life. Ensuring a new emphasis on the cognitive and educational benefits of obesity prevention and physical activity promotion for young children, this work has shifted public health messaging globally and laid the foundations for transformative behavioural change.
2. Underpinning research
Conservative global estimates from UNICEF/WHO/World Bank in 2019 put the prevalence of obesity in the under 5s at 6%, equivalent to more than 38,000,000 children globally, with around 88% in Low-and-Middle-Income-Countries (LMICs); more than 124,000,000 school-age children and adolescents were obese globally in 2016. Moreover, more than 250,000,000 pre-school children in LMICs were failing to meet their cognitive potential in 2017.
Seeking to advance understanding of the connections between physical activity levels, obesity rates, and cognitive/educational attainment, from 2013 Strathclyde researchers led a series of studies examining physical activity changes through the course of life. With previous studies being highly inconclusive, particular attention was paid to the non-health effects of obesity and physical activity in order to:
Identify when physical activity declines, to test the widespread assumption amongst researchers, policymakers and practitioners that things ‘go wrong’ at adolescence, not before;
Determine the amounts of physical activity/sedentary behaviour which should be recommended for optimal health and development;
Determine whether low physical activity causes obesity and if intensity alters risk - though seemingly obvious this was not well established; and
Assess the extent to which low physical activity and/or obesity impair non-health outcomes in childhood, specifically educational attainment.
The researchers’ approach was to conduct studies within the Avon Longitudinal Study of Parents and Children (ALSPAC; in collaboration with the University of Bristol and many other institutions including the University of Georgia) [ R1, R2] and the Gateshead Millennium Study, in collaboration with the University of Newcastle [ R3, R4]. These studies afforded the unique strengths of longitudinal design; high-quality, objective measures of physical activity; large and broadly representative samples; measurement of confounders; and testing whether changes in physical activity with age altered health outcomes (obesity) and non-health outcomes (educational attainment, cognition).
These longitudinal studies were supplemented by meta-analyses (including the effects of screen time and physical activity on sleep, and timing of the decline in physical activity). The key findings, which ultimately led the team into guideline development work, were:
Physical activity declines steadily across childhood and adolescence [ R3, R5] and impairs sleep, which increases obesity risk and reduces educational attainment [ R6];
Low childhood physical activity (specifically moderate–vigorous intensity physical activity) [ R4] is a major driver of the obesity pandemic; and
Low physical activity (specifically low moderate-to-vigorous intensity physical activity) [ R1] and obesity [ R2] impair educational attainment substantially.
3. References to the research
(Strathclyde-affiliated authors in bold; FWCI at 02/02/21)
J.N. Booth, S.D. Leary, C. Joinson, A.R. Ness, P.D. Tomporowski, J.M. Boyle, J.J. Reilly, (2014) Associations between objectively measured physical activity and academic attainment in adolescents from a UK cohort: Avon Longitudinal Study of Parents and Children (ALSPAC), British Journal of Sports Medicine, 48: 265–270 http://dx.doi.org/10.1136/bjsports-2013-092334 [FWCI: 5.56; REF2]
J.N. Booth, P.D. Tomporowski, J.M.E. Boyle, A.R. Ness, C. Joinson, S.D. Leary, J.J. Reilly (2014), Obesity impairs academic attainment in adolescence: findings from ALSPAC, a UK cohort, International Journal of Obesity, 38: 1335–1342.
https://dx.doi.org/10.1038%2Fijo.2014.40 [FWCI: 1.5; REF2]
M.A. Farooq, K.N. Parkinson, A.J. Adamson, M.S. Pearce, J.K. Reilly, A.R. Hughes, X. Janssen, L. Basterfield, J.J. Reilly (2018), Timing of the decline in physical activity in childhood and adolescence: Gateshead Millennium Cohort Study, British Journal of Sports Medicine, 52(15): 1002–1006 https://doi.org/10.1136/bjsports-2016-096933 [FWCI: 20.6; REF2]
X. Janssen, L. Basterfield, K.N. Parkinson, M.S. Pearce, J.K. Reilly, A.J. Adamson, J.J. Reilly (2019), Non-linear associations between moderate-to-vigorous physical activity and adiposity across the adiposity distribution during childhood and adolescence: Gateshead Millennium Study, International Journal of Obesity, 43(4): 744–750.
https://dx.doi.org/10.1038%2Fs41366-018-0188-9 [FWCI: 1.32]
- M.A. Farooq, A, Martin , X. Janssen, M.G. Wilson, A.M. Gibson, A.R. Hughes, J.J. Reilly (2020) Longitudinal changes in moderate-to-vigorous intensity physical activity in children and adolescents: a systematic review and meta-analysis, Obesity Reviews, 21(1):
e12953. https://doi.org/10.1111/obr.12953 [FWCI: 9.43; REF2]
- X. Janssen, A. Martin , A.R. Hughes, C.M. Hill, G. Kotronoulas, K.R. Hesketh (2020), Associations of screen time, sedentary time and physical activity with sleep in the under 5s: systematic review and meta-analysis , Sleep Medicine Reviews, 49: 101226
https://doi.org/10.1016/j.smrv.2019.101226 [FWCI: 4.23; REF2]
Notes on the quality of research: All outputs are published in peer-reviewed journals and are highly cited articles. The research was supported with 6 competitively awarded UK and international grants totalling approximately GBP447,000. Key funders are: the World Health Organisation (WHO) (e.g. Reilly et al., Review of infant and young child feeding practices to prevent overweight and obesity and other risk factors for NCDs in children and adolescents, 2014–2016, GBP19,250); Canadian Institutes for Health Research; BUPA Foundation (Reilly et al., Paradigm shift in use of physical activity in treatment and prevention of disease: associations between objectively measured physical activity and cognition in 11–13 year olds in ALSPAC, 01/09/2011-30/11/2012, GBP78,150); and the Scottish Government Chief Scientist Office (Reilly et al., Excessive sitting, in prolonged bouts, in children and adolescents: developing a sound evidence base for future interventions, 01/01/2014–30/09/2015, GBP220,992).
4. Details of the impact
Strathclyde’s research and expertise, channelled through numerous guideline and strategy development groups, has reshaped national and global guidelines on obesity and physical activity to include early childhood. Placing a new emphasis on the cognitive and educational benefits of obesity prevention and physical activity promotion for young children, this has shifted public health messaging globally and laid the foundations for transformative behavioural change. As well as influencing World Health Organisation (WHO) strategy and guidance between 2014 and 2020, Professor Reilly and his team directly informed the US Physical Activity Guidelines (2018) and the Canadian Society for Exercise Physiology Guidelines (2017) which were subsequently translated into international guidelines for New Zealand (2018), Australia (2018), South Africa (2018) and the UK (2019).
1. Informing WHO strategy and guidance on childhood obesity (2014–2017)
Seeking to drive global action to tackle rising obesity rates, the WHO Director-General established a Commission on Ending Childhood Obesity (ECHO) in 2014 to determine the most effective approaches and interventions. 2 ad hoc working groups were formed to support the Commission, 1of which focused on Science and Evidence. As a recognised expert in birth to age 5 aetiology and prevention, Reilly was asked to join this group (comprising 21 global experts) and through his involvement between 2014 and 2016 [ S1] drew attention to Strathclyde’s cohort study findings [ R1, R2] which shaped the focus and recommendations of the final Report of the Commission on ending childhood obesity published in 2016 [ S2]. This report recognised infancy and early childhood as one of three critical time periods in the life-course and drew attention to the key insight, notably absent in previous guidance documents, that obesity in childhood can ‘reduce educational attainment’ [ S2 p.7]. The report was translated into an implementation plan with six priority areas, including early childhood diet and physical activity, which has driven global action by governments and other partners since 2017 [ S3]. Examples of global and national policy and guidance stemming from this are outlined below.
2. Shaping global guidance on early childhood physical activity (2017-2019)
Building on his work with ECHO, Reilly contributed his technical expertise to the WHO Guideline Development Group (GDG) which produced the first global Guidelines on physical activity, sedentary behaviour, and sleep for children under 5 years of age. This group comprised 16 global experts and Reilly, as the only UK representative, provided expertise in physical activity and sedentary behaviour [ S4, membership confirmed on pp.vi,14,21]. The GDG met in November 2017 to determine the critical questions and outcomes to be assessed and in April 2018 to review evidence, drawing on members expertise to inform discussion [ S4 p.vii]. Published in April 2019 and targeted at a broad range of policy makers, these guidelines provided detailed recommendations to support the development of ‘national plans to increase physical activity, reduce sedentary time and improve time spent sleeping in young children though guidance documents and define critical elements of childcare services and pre-service training for health care and early childhood development professionals’ [ S4 p.vii]. As noted in the document, this guidance ‘fills a gap in the WHO recommendations on physical activity, as children under 5 years of age were not included in the Global recommendations on physical activity for health in 2010 and will also contribute to the implementation of the recommendations of the Commission on Ending Childhood Obesity and the Global Action Plan on Physical Activity 2018–2030’ as well as ‘the broader Nurturing care for early childhood development framework’ [ S4 p.vii]. The guidelines received significant media attention (Altmetric score 999) and were downloaded 144,803 times between April 2019 and 2020 [ S4]. Further resources to encourage their global implementation have also been developed, including the WHO Global Standards for Healthy Eating, Physical Activity, Sedentary Behaviour, and Sleep in Early Childhood Education and Care (ECEC) Settings; (originally scheduled for release in April 2020, but delayed to 2021 due to the COVID-19 pandemic). These Standards describe how early learning and childcare settings should operate (pedagogy, environment, facilities such as ‘loose parts’ for play, space, outdoor time, opportunities for free play) in order to help the under 5s meet the 2019 guidelines. In doing so they explicitly link meeting the standards with health and educational/cognitive developmental benefits as outlined in the guidelines on the basis of Reilly’s research. The document also supports providers to check if they were operating in ways which meet the standards and details how this will be monitored.
3. Driving the development of national guidelines on physical activity (2017–2019)
Reilly’s involvement in the Cold Spring Harbor Symposium on Exercise Science and Health in 2015 informed the US Physical Activity Guidelines (2018), which were promoted via a USD4,200,000 (01-2018) US government social marketing campaign called ‘Move Your Way’ (#MYW https://health.gov/moveyourway/), targeted at families, health professionals and adult physical activity ‘contemplators’. Comprising 18 experts on the effect of physical activity on health across the lifespan, with Reilly being the only international contributor, the group scoped out the scientific evidence to be reviewed for the guidelines and considered novel approaches to ensure effective implementation [ S5]. More specifically, Reilly provided expertise on the influence of physical activity on cognition and educational attainment in children and adolescents, and advised on how this could be used to leverage adoption [ S5]. The value of his contribution is confirmed by the Symposium chair who notes: ‘Prof Reilly’s participation . . . encouraged us to include cognitive/educational outcomes in the evidence review which was the basis of the 2018 Guidelines. His participation also helped inform the approach taken to achieving guideline impact in the US: Move Your Way has used online materials to disseminate the message that higher levels of physical activity are good for school grades. These materials have been used across the US in schools, homes, healthcare facilities, and communities’ [ S5].
The campaign, winning multiple awards such as the US Digital Health Awards Gold Award 2019 for evidence-based, clear and effective public health messaging, successfully encouraged health professionals and families to use its factsheets, videos and interactive tools. To the end of February 2020 there were: over 1,700,000 completed views of the campaign’s videos, #MYW reached over 50,000,000 individuals, and over 26,000,000 impressions from customised social media ads (Facebook, YouTube, Instagram).
Reilly and Janssen joined the Canadian Society for Exercise Physiology Guideline Development group in 2016 and played a key role in the production of Canadian 24-hour movement guidelines for the Early Years (0-4) which provide the first evidence-based guidance on the optimal amount of physical activity, sedentary behaviour, and sleep for babies, toddlers, and pre-schoolers. The group brought together 25 international experts and, as the only UK representatives, Reilly and Janssen contributed subject expertise in physical activity, sedentary behaviour and evidence based medicine. Since their launch in November 2017, the guidelines have been widely promoted across Canada, with the Canadian Minister of Health recommending them as ‘an important tool to help parents and healthcare professionals support healthy growth and development for Canadian children’ [ S6]. Receiving global recognition, the guidelines subsequently informed the development of comparable national guidelines in the UK, South Africa, New Zealand and Australia.
In 2019, Reilly served as a member of the UK Chief Medical Officers (CMOs) Guidelines Writing Group and chaired the Expert Working Group on Under 5s (comprising 7 other experts including Hughes and Janssen) to produce the first evidence-based physical activity guidelines for under 5s in the UK. Comprising 10 members, this working group had a strong Strathclyde presence, with Janssen and Hughes contributing their expertise alongside Reilly [ S7, input acknowledged on pp.5,51,55,56,62,64]. These were incorporated into the UK Chief Medical Officers’ Physical Activity Guidelines (published in September 2019 as an update to the more limited 2011 guidance) with the intention of them being ‘a catalyst for change in our attitudes to physical activity’ [ S7 p.4]. Though wide-spread adoption across the UK has been hindered by the COVID-19 pandemic, a dissemination and implementation plan is under development by the 4 UK Health Departments to ensure it reaches the intended beneficiaries, namely: 3,750,000 under 5s (and their families) and 586,000 health professionals (including groups in primary care most likely to use the guidelines i.e. over 42,000 GPs, over 17,000 practice nurses, over 3,000 school nurses, plus over 3,000 consultant paediatricians).
5. Sources to corroborate the impact
WHO Working Group on Science and Evidence member biographies, confirming Reilly’s involvement as an expert in childhood and adolescent obesity.
WHO (2016) Report of the Commission on Ending Childhood Obesity.
WHO (2017) Report of the Commission on Ending Childhood Obesity Implementation Plan.
WHO (2019) Guidelines on physical activity, sedentary behaviour and sleep for children under 5 Years of Age, with report download figures from WHO website (accessed 6 December 2020).
Factual statement from Chair of Cold Spring Harbor Symposium and Physical Activity Guidelines for Americans, dated 28 October 2019.
a. Canadian Society for Exercise Physiology (2017) Canadian 24-Hour Movement Guidelines for the Early Year (0-4 years); b. ParticipACTION press release, ‘Too much screen time prevents young tots from meeting healthy movement guidelines’ 20 November 2017.
UK Government (2019) UK Chief Medical Officers’ Physical Activity Guidelines.
Laureus Sport for Good Foundation South Africa, ‘Moving, playing, sleeping: starting early with healthy habits’, 4 December 2018 (includes a copy of the guidelines).
Australian Department of Health (2017) Australian 24-Hour Movement Guidelines for the Early Years (Birth to 5 years).
New Zealand Ministry of Health (2017) Sit Less, Move More, Sleep Well: Active play guidelines for under-fives.
- Submitting institution
- University of Strathclyde
- Unit of assessment
- 3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
- Summary impact type
- Health
- Is this case study continued from a case study submitted in 2014?
- No
1. Summary of the impact
:
Thomson and Bennie’s research led to the development of and revisions to dosing guidelines for a range of antibiotics to treat severe infections. These guidelines are available online and used throughout NHS Scotland, NHS England and internationally. Additional resources produced by the researchers have resulted in a substantial improvement in effective antibiotic use in NHS Scotland and research findings were incorporated into commercial software packages to optimise antibiotic therapy for individual patients in USA, New Zealand and Europe. Through these developments, the research has supported optimal dosing of vancomycin, amikacin and gentamicin, which is vital for patient recovery from severe infection and an important aspect of tackling antimicrobial resistance.
2. Underpinning research
The antibiotics vancomycin, gentamicin and amikacin are used to treat severe infections that may be resistant to other antibiotics, including bone and joint infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis. Vancomycin is one of the few antibiotics that is active against methicillin resistant Staphylococcus aureus (MRSA); amikacin is also used for the treatment of multidrug-resistant tuberculosis. Successful use of these particular antibiotics is challenging as therapeutic doses are similar to those that cause toxicity, and dose requirements can vary widely among patients. With vancomycin, amikacin and gentamicin, under-dosing can lead to treatment failure and development of antimicrobial resistance, whereas overdosing can cause kidney damage and permanent impairment of hearing and/or balance (ototoxicity).
Thomson and Bennie have carried out a sustained programme of research to inform, improve and implement guidelines on dosing of vancomycin, gentamicin and amikacin in hospital settings. Population pharmacokinetic (PopPK) data analysis methodology was used to identify factors that influence the antibiotic dose requirements of individual patients. Quality Improvement (QI) methodology was used to evaluate and improve implementation of guidelines in both adult and paediatric settings. Their key findings relate to:
Development and implementation of vancomycin and gentamicin dosing guidelines: The trough level or trough concentration is the lowest concentration reached by a drug before the next dose is administered and is often used as a guide to avoid under-dosing or overdosing the patient. Growing evidence that vancomycin trough concentrations of 5–10 mg/L were insufficient to achieve adequate tissue penetration and kill rates for more resistant species, prompted recommendations for a variety of higher target values, up to and exceeding 15 mg/L. In 2009, Thomson [ R1] developed a PopPK model of vancomycin for adult patients from vancomycin dose and concentration data collected during routine therapeutic drug monitoring of 398 patients. New vancomycin dosage guidelines were developed that achieved trough concentrations of 10–15 mg/L earlier and more consistently than existing guidelines.
Following Thomson’s recommendations, the Scottish Antimicrobial Prescribing Group (SAPG) introduced national guidance in 2009 to standardise dosage regimens for vancomycin and gentamicin (guidelines also developed by Thomson). These guidelines aimed to reduce calculation errors and improve the monitoring of these antibiotics. Further research in 2010 and 2011 identified limitations in guideline implementation, and a point prevalence study (PPS) in 2011 and a qualitative research study in 2014 led Thomson and Bennie to oversee the design and introduction of new QI resources for practitioners, to improve guideline implementation [ R2]. A follow-up PPS in 2018 demonstrated statistically and clinically significant improvements in gentamicin and vancomycin prescription, administration and monitoring throughout Scotland [ R2].
Intravenous vancomycin therapy typically starts with a loading dose followed by a maintenance dose 12 to 24 hours later. In the acute hospital setting, this often results in doses being administered late in the night. In 2016, Thomson sought to address this issue, which was challenging for staff and disrupted patient’s sleep. Her research examined current practice and developed new guidelines to support greater flexibility in the timing of the first maintenance dose of vancomycin [ R3].
Thomson collaborated in an international, pooled PopPK study (2018) which examined vancomycin handling in a large population of patients ranging from neonates to elderly adults [ R4]. The results were used to evaluate current European and American guidelines and propose revisions. In 2020, this pooled PopPK model was used within a new genetic algorithm methodology to develop and evaluate revised guidelines [ R5]. The study used a novel approach to define a dosing guideline and, due to the extensive patient database, covered a wide range of patient characteristics. This study aimed to optimise dosing during the first 3 days of therapy, to potentially avoid treatment failure.
A series of NHS research projects, led by Thomson (2013 - 2016), identified problems with vancomycin use in a large paediatric intensive care unit (PICU), and with gentamicin use in patients with endocarditis. Subsequent research by Thomson and Bennie led to the development and implementation of new vancomycin guidelines within the PICU in November 2016. QI methodology was used to support the process, which included logistic planning, the development of an in house computer decision support tool, a staff training package, disseminating the guidelines and resolving any problems in implementation. The implementation process was evaluated in 2018.
Development and evaluation of amikacin dosage guidelines: From 2018-20, Thomson supervised an analysis of data from patients within Greater Glasgow and Clyde Health Board (NHSGGC) who were treated with amikacin for multi-resistant mycobacterial infections. The aim was to develop a PopPK model for amikacin then use data simulations to compare the concentrations achieved by internationally recognised (WHO) amikacin dosage guidelines with recommended target ranges and identify whether modifications to guidelines or target ranges would be helpful for this patient group. A maximum daily dose of 1000 mg was recommended by the WHO, although higher doses may be used. Thomson’s results showed that applying this limit would under-dose patients weighing more than 75 kg and that, for higher weights, the limit is inconsistent with the recommended dose of 15–20 mg/kg, for example 1000 mg represents only 12.5 mg/kg for a patient weighing 80 kg. The results of this analysis were used to evaluate the international guidelines and devise new guidelines to address local and national concerns around optimal dosing regimens and monitoring of amikacin. The modified guidelines included a wider range of doses to maximise the efficiency of amikacin treatment with a range of body weights [ R6].
3. References to the research
(Strathclyde affiliated authors in bold; FWCI at 02/02/2021)
Thomson AH, Staatz C, Tobin C, Gall M, Lovering A. (2009). Development and evaluation of vancomycin dosage guidelines designed to achieve new target concentrations. Journal of Antimicrobial Chemotherapy 63:1050-1057 https://doi.org/10.1093/jac/dkp085 [FWCI: 2.31; REF2 in 2014]
Semple Y, Bennie M, Sneddon J, Cockburn A, Seaton RA, Thomson AH. (2020) Development and evaluation of a national gentamicin and vancomycin quality improvement programme. Journal of Antimicrobial Chemotherapy 75:1998-2003.
https://doi.org/10.1093/jac/dkaa096 [FWCI: 1.32; REF2]
Carruthers A, Thomson AH, Semple Y, Rodger R. (2016). Timing of the first vancomycin maintenance dose in an acute hospital setting - room for improvement? Journal of Medicines Optimisation 2: 51-55. https://bit.ly/31fKI00
Colin PJ, Allegaert K, Thomson AH, Touw DJ, Dolton M, de Hoog M, Roberts JA, Adane ED, Yamamoto M, García MJ, Simon N, Taccone FS, Lo Y-L, Barcia E, Eleveld DJ. (2019) Vancomycin pharmacokinetics throughout life: implications for dosing recommendations. Clinical Pharmacokinetics 58:767-730. https://doi.org/10.1007/s40262-018-0727-5 [FWCI: 5.52]
Colin PJ, Elvend DJ, Thomson AH. (2020). Genetic algorithms as a tool for dosing guideline optimisation: application to intermittent infusion dosing for vancomycin in adults. CPT-Pharmacometrics and Systems Pharmacology. 9: 294-302
https://doi.org/10.1002/psp4.12512 [REF2]
- Siebinga H, Robb F, Thomson AH (2020). Population pharmacokinetic evaluation and optimisation of amikacin dosage regimens for the management of mycobacterial infections. Journal of Antimicrobial Chemotherapy. 75:2933-2940 75. (Editor’s choice) DOI: https://doi.org/10.1093/jac/dkaa277
Notes on the quality of research: Key outputs are published in high quality peer reviewed journals. R1 contributed to the award of three further grants to Dr Thomson and Professor Bennie from the Healthcare Associated Infection Task Force from 2010-12 to evaluate the implementation of national antibiotics guidelines. Other funding for a fellowship and further Quality Improvement research includes:
Bennie M, Thomson AH (Fellow: Semple Y). SIRN/CSO Doctoral Training Fellowship in Healthcare Associated Infection - Quality Improvement of antibiotics with a narrow therapeutic index, Scottish Infection Research Network/Chief Scientist’s Office, 01/10/2013-28/02/2019, GBP101,162.
Bennie M, Thomson AH. Guidance on use of gentamicin and vancomycin Quality Improvement Program, NHS National Services, Scotland, 01/02/2010-31/03/2016, GBP165,741.
4. Details of the impact
Guidelines developed by Thomson in 2008-9 on vancomycin [ R1] and gentamicin were implemented at that time across NHS Scotland by the Scottish Antimicrobial Prescribing Group (SAPG). Thomson and Bennie’s research in 2010 - 2014 identified issues with this implementation and led them to produce new resources designed to improve implementation [ R2] and update the existing guidance on these two antibiotics. Until December 2018, Thomson was a part-time NHS pharmacist in addition to her part-time academic position at the University of Strathclyde; she now holds an honorary NHS position as a Research Supervisor for pharmacists working towards higher degrees. Her advice is often sought by NHS colleagues, feeding into further research and new guidelines for antibiotic delivery with different patient groups [e.g. R3, R6]. Close integration of NHS and researcher roles has facilitated production of research which addresses important clinical need, and has resulted in the following impacts:
Updated guidance on antibiotic dosing for vancomycin, gentamicin and amikacin within NHS Scotland and internationally
Various factors affect the optimal dosage regimen for any drug, including the age, weight and kidney function of the patient. The timing of doses is also critical to maintain safe and effective drug concentrations, and to avoid under- or over-dosing the patient. With delivery of any antibiotic treatment, it is of utmost importance that ‘under dosing’ does not lead to bacterial resistance.
The national guidelines for gentamicin and vancomycin dosing, originally implemented in 2009, were updated in early 2013, in January 2015 and January 2017 [ S1] with direct support from Thomson’s research findings. The Project Lead for SAPG confirms Strathclyde’s research to support the safe and effective use of gentamicin and vancomycin ‘has informed national guidance, dosage calculators, prescription charts and education modules first launched in 2013 which are hosted by my organisation, (part of Healthcare Improvement Scotland) and utilised across the NHS in Scotland ’ [ S2]. The SAPG guidelines are frequently consulted by practitioners; they were viewed online 8,767 times between September 2016 and September 2017 alone. Between March 2018 and Jan 2020 there were typically between 100 – 400 page views every month [ S2]. Since August 2013, the SAPG guidelines for gentamicin and vancomycin have informed the development of similar guidelines in the UK, including NHS bodies at York, Norfolk & Norwich and Salford. SAPG guidelines have also generated international interest and have been implemented in the Czech Republic [ S5] and Malta [ S6]. The SAPG Project Lead confirms ‘these resources are also referred to outwith Scotland and you [Dr Thomson] have supported our group with expert advice to answer any queries about the methodologies used in their development which I receive on a regular basis ’ [ S2].
The underpinning research has also directly informed dosing guidelines for gentamicin, vancomycin and amikacin in the NHS Greater Glasgow and Clyde (NHSGGC) health board, which represents about 30% of all hospital beds in Scotland [ S2]:
Guidelines for gentamicin dosing in patients with endocarditis were developed from a pharmacokinetic study carried out by an NHS pharmacist, supervised by Thomson. These guidelines were introduced within NHSGGC in 2015 and nationally via the SAPG website in October 2016 [ S1].
Recommendations arising from Thomson’s [ R3] investigation into the timing of vancomycin doses were adopted by NHSGGC in February 2017 and implemented within the NHSGGC mobile app in 2020 [ S3]. These revised guidelines removed the need to disturb patients in the middle of the night to administer vancomycin.
New paediatric intensive care guidelines on vancomycin dosage, devised by Thomson, were implemented in the Paediatric Intensive Care Unit (PICU) of the Royal Hospital for Children, Glasgow in November 2016 [ S4].
The PopPK analysis of amikacin for patients with mycobacterial infections [ R6] led to the development of new amikacin dosing guidelines for NHSGGC during 2018 - 2020. Hospitals in the Glasgow area are seeing more patients with non-tubercular mycobacterial infection and amikacin is increasingly used for these patients [ S3]. The amikacin guidelines have been available for use in Scotland by specialised NHS staff since early 2020.
Thomson presented draft recommendations for further guideline revision from the SAPG guidelines to NHSGGC antimicrobial pharmacists in July 2020 and submitted final recommendations in November 2020 [ S3]. In addition, she updated the online dose calculator with new doses which were approved by the NHSGGC Antimicrobial Utilisation Committee in November 2020.
Improvement in resources available to medical practitioners
Thomson and Bennie’s QI study led to the implementation of online calculators and training modules. Software packages that aid in the interpretation of measured antibiotic concentrations are increasingly being used to help modify doses for individual patients, based on models of drug handling in large patient populations. Online gentamicin and vancomycin dose calculators, originally devised by Thomson, were introduced across Scotland in August 2013. Usage has been continuous and sustained from this point. For example, between January 2018 - October 2019, the gentamicin calculator was viewed 13,178 times and the vancomycin calculator 4,984 times [ S2]. These calculators were transferred by external developers to an NHSGGC phone app that was released in August 2014, and available to practitioners in the health board. The smartphone app was released across the UK in August 2016 [ S9] commissioned by SAPG and registered as a medical device with the Medicines and Healthcare products Regulatory Agency. The SAPG app has been downloaded over 2,500 times in the UK and in other countries since launch. The Project Lead (SAPG) confirms that this app ‘gives prescribers access to guidance and online calculators at the point of care to support best practice’, with between 200 – 300 users per month (gentamicin calculator) and 400 - 600 users per month (vancomycin calculator) [ S2]. Educational materials to support gentamicin and vancomycin prescribing and monitoring were also created and implemented on LearnPro, an online training platform, and made available to NHS staff throughout Scotland in August 2013. This module was taken 1,299 times by NHS doctors, pharmacists and nurses between September 2013 and end 2016 [ R2].
The two PopPK vancomycin models developed by Thomson [ R1, R4] have been implemented since early 2017 by US based company InsightRx, in a commercial software package used to interpret vancomycin concentrations in clinical practice [ S7]. The company has a user base of 80 hospitals in the USA and Europe, and the module for personalisation of vancomycin dosing is the most frequently used across their platform. The Chief Scientific Officer for InsightRx confirms that the Thomson 2009 model is ‘often the best model in terms of its ability to predict future exposure to vancomycin within the patient… It is the model we recommend for new sites and it is included in all our training material. Over 2019 - 20 the model has been used in the dosing of 22,163 patients across 36 hospitals using our platform ’ [ S7]. The 2009 vancomycin model was implemented in a similar package, TCIWorks, and since August 2013 this has been in continuous use in Christchurch Hospital, the largest tertiary, teaching and research hospital in the South Island of New Zealand, serving 510,000 residents [ S8].
Patients being treated with vancomycin, amikacin and gentamicin are usually seriously ill with infections which may be resistant to other antibiotics. The Lead Antimicrobial Pharmacist for NHSGGC states that ‘work done by Thomson has allowed us … to update our therapeutic vancomycin and amikacin monitoring guidelines ... for patients with serious infections who also have penicillin allergy.’ [ S3] NHS Scotland funded QI work by Bennie and Thomson between 2013 and 2014, which led to major improvements in clinical practice for patients treated with gentamicin and vancomycin. Following the QI programme, the percentage of patients who received the recommended gentamicin dose doubled from 44% (baseline in 2011) to 89% in 2018. Appropriate blood sample times increased from 63% to 75% between 2011 and 2018. For vancomycin, the correct loading dose increased from 50% to 85% and the correct maintenance dose from 55% to 90% by 2018 [ R2].
Implementation of the vancomycin guidelines in a large Czech hospital in 2015 improved the achievement of target trough concentrations from 45.4% prior to introduction of guidelines to 63.1% after introduction. A publication [ S5] on the implementation states that ‘the adopted Scottish model of vancomycin therapeutic dose monitoring (TDM) resulted in very significantly higher achievement of recommended trough concentrations during first measurements and significantly more effective maintenance of subsequent concentrations, without increased nephrotoxicity.’
New paediatric intensive care guidelines, devised by Thomson, were implemented in the PICU of the Royal Hospital for Children, Glasgow in November 2016 . A consultant paediatrician confirms that ‘achieving therapeutic target range is challenging in the diverse range of patients seen within the PICU due to multiple pathologies and large variations in patient size and renal function… A follow-up evaluation of this implementation found that the percentage of satisfactory concentrations increased from 45% to 55% and the risk of under-dosing fell from 41% to 29%. These guidelines are still used (Dec 2020) within PICU and have significantly improved patient management of this highly complex patient group’ [ S4].
Improved guidance, with related online tools to assist practitioners has led to better delivery and monitoring of the dosage regimens of an important group of antibiotics, notably in Scotland, and used in the treatment of severe infection in hospitals across the UK, Europe and the US. This ultimately has led to benefits for patients, avoidance of over-dosing which can cause toxicity, and reduction of under-dosing which can lead to treatment failure and antimicrobial resistance.
5. Sources to corroborate the impact
:
Scottish Antimicrobial Prescribing Group. Gentamicin and vancomycin. https://bit.ly/3b4FiuB
Corroborating statement from Project Lead, SAPG, NHS Healthcare Improvement Scotland, dated 4 November 2020, with appended SAPG website data.
Corroborating statement from Lead Antimicrobial Pharmacist NHSGGC, dated 12 November 2020.
Corroborating statement from Consultant Paediatric Intensivist, Paediatric Intensive Care Unit, Royal Hospital for Children, Glasgow, dated 19 February 2021.
Zahalkova K et al, (2018). The Scottish model of vancomycin dosing and therapeutic drug monitoring improves both efficacy and safety of vancomycin therapy Vnitr Lek, 64; 717-724 https://pubmed.ncbi.nlm.nih.gov/30441978/
Dimech A et al (2016). The practice of gentamicin prescription at Mater Dei Hospital (Malta) DOI: 10.13140/RG.2.2.23213.18402
Corroborating statement from CSO of Insight RX, date 12 November 2020.
Corroborating statement from Senior Lecturer of Clinical Pharmacology, University of Otago.
SAPG smartphone app for mobile devices and online at http://www.antimicrobialcompanion.scot
- Submitting institution
- University of Strathclyde
- Unit of assessment
- 3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
- Summary impact type
- Technological
- Is this case study continued from a case study submitted in 2014?
- No
1. Summary of the impact
Advances in immunology by Professor Stimson adopted by Solus Scientific Solutions Ltd. have expanded their food testing products, grown sales, increased employment and extended the company’s reach in microbiological testing. Rapid assays (<24 hours) for all strains of Listeria, Salmonella and Escherichia coli have been devised, augmenting Solus’ automated pathogen detection systems for these bacteria. Dedicated culture media based on the Strathclyde research allows sensitive detection of targeted organisms and control of false positive results. New kits for testing meat authenticity and allergen screen have also been introduced. Sales are up 43% from 2014 to GBP5,400,000 in 2019, with sales in 30 countries; and the number of employees increased from 24 to 43. Customers achieve higher productivity and efficiency owing to the greater sensitivity, simpler methodology and lower costs afforded through inclusion of Stimson’s discoveries in Solus products. In 2019, Perkin Elmer purchased Solus for USD34,000,000, increasing access to global food diagnostics markets.
2. Underpinning research
Relationship to case study submitted in 2014
This case study builds on the version submitted to REF2014. Although the underpinning research includes references mentioned in the REF2014 version of this case, other research by Stimson is described from which additional and extended impact has been derived.
Context
The prevention of food poisoning is a major concern worldwide. Mycotoxins are present in around 25% of foods throughout the world and are associated with many diseases and physiological disorders, including liver damage and cancers. Food poisoning bacteria like Salmonella and Listeria, and increasingly E. coli 0157.H7, cause millions of people to be ill every year. Consequently, testing for food pathogens is of critical importance for food safety. In Europe and North America, food industry regulations indicate the need to detect as little as one single organism in 25g of food. In order to detect such low levels of contamination, which is beyond the current capabilities of assay technology, bacterial numbers must be grown to a detectable level. The more sensitive the assay, the less time is required for bacterial growth, and the sooner detection can be made.
Stimson’s initial research in developing assays for immunology ultimately led him to develop a platform for bacterial detection that was rapid, highly sensitive, stable, simple and inexpensive. A key factor was the development of a novel broth that allowed bacterial growth at the fastest possible rate, and had the capacity to resurrect injured organisms to give the required detection level of 500 bacteria in a few hours, even in the presence of 10 million competing organisms [ R1]. Before this research, bacterial assays required two broths and would take 40 or more hours to grow a bacterial sample to a detectable size. Discovery of the improved growth medium and research in other aspects of immunology led Stimson to form a spin-out company in 2007, which became Solus Scientific Solutions Ltd. in 2009. Further research by Stimson then allowed Solus to expand its product range and impact on the microbiological analysis of food.
Key research findings
Immunology research by Stimson and colleagues resulted in advances in methodology that Stimson recognised could benefit various aspects of immunoassay development. In particular, Stimson aimed to develop assays able to detect the complete range of Salmonella strains (comprising close to 3000 strains in total). This led to the development of highly selective murine polyclonal and monoclonal antibodies capable of identifying the vast majority of strains in a single assay, as opposed to the dozens of tests previously required [ R1]. For Salmonella strains that could not be identified with murine antibodies, assays were developed from related research by Stimson, employing polyclonal sheep antibodies active against specific oligosaccharide or peptide sequences in the Salmonella cell wall. In order to mature the response to the immunogen, immunisation protocols were designed using a human interferon-alpha subtype additive to the adjuvant [ R2]. In addition, pharmacological suppression was employed using mice/rats pre-immunised with whole bacteria and then treated with Cyclosporin A to eliminate any lymphocytes reacting strongly with dominant antigenic determinants. The animals were then re-immunised with the weaker antigenic determinants in order to obtain enhanced antibody recognition of the species/genus-specific carbohydrate sequences, or weakly antigenic sites of importance in bacterial definition [ R3, R4] . Additionally, NZB/NZW F1 female hybrid mice with hyperactive immune responses were also employed to enhance the immune response and provide specific high affinity antibodies of suitable sub-classes (IgG1, 2a/b) for the assay procedures. Combination of these advances from Stimson’s distinctive body of immunology research [ R1- R4] provided the basis for development of more extensive and sophisticated immunoassays for food testing applications.
Additional research [ R5] to refine the composition of the culture growth medium and improve other aspects of the methodology optimised the immunoassay procedures for different microbiological targets including Salmonella, Shigella and Listeria species. The discoveries included changes to the selection of a detergent that reduces the bacterial cell wall into the smallest units possible, thus providing the greatest numbers of detection entities. Methods for detection of bacterial lipopolysaccharides using an antibody to a core oligosaccharide epitope were described [ R5]. Infrastructure for automation of the assay was also developed [ R6]. For luminescence detection, Stimson recommended a chemiluminescent derivative which provided significantly enhanced light output compared to alternative molecules, producing useful light for up to 8 seconds, which allowed detectability in the attogram range. This has resulted in pathogen detection fifty times more sensitive than alternative colorimetric devices [ R6]. Together, these advances led to a reduction in overall assay time without increasing costs, to the point where automated mass microbiological screening of food products could be achieved within the one day, if required.
3. References to the research
(Strathclyde-affiliated authors in bold; FWCI at 02/02/2021)
- S. Rahman and W.H. Stimson (2001) Characterisation of monoclonal antibodies with specificity for the core oligosaccharide of Shigella lipopolysaccharide, Hybridoma 20(2):85-90.
Published online in 2004 https://doi.org/10.1089/02724570152057571
W.H. Stimson (2014, 2019) Composition and methods relating to the treatment of diseases. International Patent WO 2014/037717 13 March 2014; EU Patent, EP 2892556 B1, 15 May 2019. https://bit.ly/3vPhRxT
M. Khan, V. Ferro and W.H. Stimson, W. H. (2003) Use of a highly specific monoclonal antibody against the central variable amino acid sequence of mammalian gonadotropin releasing hormone to evaluate GnRH-I tissue distribution compared with GnRH-I binding sites in adult male rats, American Journal of Reproductive Immunology, 49(4):1-10
https://doi.org/10.1034/j.1600-0897.2003.01202.x
V. Ferro, R. Costa, K. Carter, M. Harvey, M. Waterston, A. Mullen, C. Matschke, J. Mann, A. Colston and W.H. Stimson (2004) Immune responses to a GnRH-based anti-fertility immunogen, induced by different adjuvants and subsequent effect on vaccine efficacy, Vaccine, 22(8):1024-1031 https://doi.org/10.1016/j.vaccine.2003.08.043 [FWCI: 1.36]
W.H. Stimson (2010). Culture media and detection means for food microbiological analysis. UK Patent GB 2463369, granted 17 March 2010. https://bit.ly/3cUQREg
D. Cowan and W.H. Stimson (2015). Automated assay. International Patent WO 2015/114316 A2, 6 August 2015. [Available from HEI on request]
Notes on the quality of research: All journal articles are published in peer-reviewed leading journals in the field.
4. Details of the impact
This impact study builds on a case submitted to REF2014, which described how initial research by Stimson and colleagues led to a new immunoassay concept and formation of a spin-out company Solus Biologicals Ltd., which became Solus Scientific Solutions Ltd in 2009. Advances in propriety anti-bodies and immunoassay methods derived from Stimson’s research have had a major impact on Solus’s success during the current REF period. In July 2013, the company make the decision to adopt the Strathclyde technology for its Enzyme-Linked Immunosorbent Assay (ELISA) products for Salmonella and Listeria. Further product development influenced by Stimson’s research has followed, generating significant benefit for the company and its customers. The main impacts since August 2013 have been:
Economic – expanded product range, increased sales, job creation, and growth in customer base;
Food safety – through wide adoption of the Stimson-inspired Solus testing kits.
1. Growth in the commercial success of Solus Scientific Solutions Ltd.
According to the then Chief Executive Officer of Solus, ‘Over the period since 2013, Solus has continued to refine its product portfolio taking advantage of discoveries from Stimson’s original research’ [ S1]. As of 2020, Solus provides a broad and expanding range of products including:
Automated pathogen detection systems for Salmonella, Listeria and E. coli 0157 [ S2]. Each system comprises a specifically designed immunoassay kit, dedicated selective enrichment media and automated liquid handling. These assays have received independent accreditation from the Association Française de Normalisation (AFNOR) and Association of Official Agricultural Chemists (AOAC) [ S3].
‘Solus One’ rapid assays for all strains of Listeria, Salmonella and E. coli that are completed in less than 24 hours rather than the previous industry standard of 48 hours [ S4]. The tests are also cheaper and easier to apply than alternative molecular methods and give better performance especially for spices and cocoa products owing to novel features incorporated from Stimson’s research [ S1]. ‘Solus One’ assays for Salmonella have achieved AOAC approval [ S4].
Dedicated culture media for the ‘Solus One’ and ‘Solus ELISA’ ranges, allowing for the sensitive detection of target organisms as well as the control of false positive results due to overgrowth of any background flora [ S5].
Meat species identification kits for determining the authenticity and adulteration of raw meat for food manufacturers and contract testing laboratories [ S6]. The immuno-assays are available in ELISA and rapid flow-through formats.
Allergen screening range for the detection of gluten, casein and soya contamination in raw materials, production equipment and food samples [ S7].
In June 2018, Solus opened a regional office in Cincinnati, USA, which now employs three people. As of 2020, 43 jobs had been created by Solus – an increase of 19 since 2013.
Table 1 (below) shows sales from 2013 to 2019, by which time the annual turnover of the company had reached GBP5,400,000 and EBITDA had grown 75% from 2014 [ S1]. The total sales in the period 2014-2019 were just over GBP26,500,00. In early 2016, Solus gained a USD1,000,000 contract with Toho Technology, Japan, to develop range of assays for pathogens on environmental swabs [ S1].
In 2019, attracted by the strong financial performance of the company, Perkin Elmer - a major US-based diagnostics company - purchased Solus for USD34,000,000 [ S1, S8]
2013 actual | 2014 actual | 2015 actual | 2016 actual | 2017 actual | 2018 actual | 2019 actual | |
---|---|---|---|---|---|---|---|
Sales (k GBP) | 4,135 | 3,801 | 3,553 | 3,892 | 4,625 | 5,245 | 5,442 |
EBITDA* (k GBP) | (145) | 434 | 125 | 391 | 424 | 617 | 759 |
EBITDA (%) | -3.51 | 11.43 | 3.52 | 10.05 | 9.17 | 11.77 | 13.94 |
* Earnings before interest, tax, depreciation and amortization
Solus is now a leading supplier of pathogen food tests in the UK and is currently expanding into other regions. Productivity has increased in line with demand: in the first half of 2018, Salmonella kit production was up by 18% and Listeria by 49% compared to the same period in 2017 [ S1]. As of 2020, Solus products are sold and used in 30 countries around the world, including countries in Europe, North America, Africa and the Asia-Pacific region [ S1].
Customers include global food testing companies such as Eurofins, Bureau Veritas and Intertek, food manufacturers Kerry Foods and Bakkavor, and major retailers such as Tesco and Marks & Spencer in the UK, Walmart (USA) and Woolworth (South Africa) [ S1].
In recent years sales and marketing have increased in the UK, USA and Asia-Pacific, benefitting from the wide distributer network that now exists [ S9]. The 2019 purchase by Perkin Elmer allows Solus even greater access to the global food diagnostics market, especially in Latin America, India and China [ S1].
2. Increases in efficiency and reliability of food testing
In Europe and the USA, food producers must conduct rigorous testing of their own food product ranges, or employ other companies to conduct testing on their behalf, to meet strict food hygiene standards. Large food testing laboratories have grown up to meet the demand for rigorous testing from food manufacturing companies and supermarkets. Intertek, Eurofins, and ALS Ltd are some of the leading players in this sector and all are supplied with testing kits by Solus [ S1].
Food safety testing technologies produced by Solus are in demand by food manufacturers and food testing laboratories because of their advantages over molecular methods including: lower cost, simplicity, ease of automation and rapid detection rates. These benefits have been reported by ALS Ltd. which purchased automated DS2 Solus Pathogen Detection Systems for its Rotherham testing laboratory [ S10]. Within 6 weeks of installation, the instruments had improved testing rates by 95%. According to the ALS laboratory manager, ‘ The Solus Pathogen Testing System has bedded down well in the laboratory equalling and soon surpassing the productivity achieved with alternative methods. The cost and time savings are significant’ [ S10].
Solus’s food testing kits have provided efficiency gains and time savings to companies who carry out rigorous food testing on behalf of producers, wholesalers and supermarkets supplying food in the UK and Europe, North and South America and the Far East. The time savings remove the need for expensive refrigerated holding facilities, which are required while waiting for assay results. Not only does this reduce refrigeration costs for food testing laboratories, but it allows for the early release of products and so extends their shelf life, reducing the waste arising from food spoilage. This benefits the producers, wholesalers and supermarkets by lowering the chances of food recalls and leading to longer shelf life of food products. This in turn allows customers to buy fresher foods.
5. Sources to corroborate the impact
Factual statement from Chief Executive Officer (2012-2019), Solus Scientific Solutions Ltd., dated 11 February 2021.
Solus Scientific website, ‘Solus Pathogen Detection System’, https://www.solusscientific.com/pathogen-detection-system/
Solus Scientific website, AFNOR and AOAC accreditation: ‘Solus Listeria and Salmonella kits’,
https://www.solusscientific.com/pathogen-testing-solutions/salmonella/
Solus Scientific website, ‘Solus assays’, https://www.solusscientific.com/solus-assays/
Solus Scientific website, ‘Solus dedicated media’, https://www.solusscientific.com/dedicated-media/
Solus Scientific product information sheet, ‘Solus meat speciation solutions’, https://www.solusscientific.com/wp-content/uploads/2015/07/Solus-A4-Inners-Meat-Species.pdf
Solus Scientific product information sheet, ‘Solus AllergenScreen range’ https://www.solusscientific.com/wp-content/uploads/2015/07/Solus-A4-Inners-Allergens.pdf
HMRC documents showing transfer of Solus to PerkinElmer in 2019.
Solus Scientific website, ‘Distributor network’ https://www.solusscientific.com/distributors-2/
Solus Scientific, ‘Increasing pathogen testing throughput and efficiency at ALS Rotherham by employing Solus™ Pathogen Testing System’, https://www.solusscientific.com/wp-content/uploads/2018/02/Rotherham-article-final.pdf
- Submitting institution
- University of Strathclyde
- Unit of assessment
- 3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
- Summary impact type
- Health
- Is this case study continued from a case study submitted in 2014?
- No
1. Summary of the impact
Research led by Bennie on high-risk medicines (HRM) has shaped healthcare systems, providing clinicians with information to improve patient care. The team’s evaluation of the Scottish Patient Safety Programme – Pharmacy in Primary Care (SPSP-PPC) guided national policy including a Scottish Government commitment to support the safer use of medicines. This led to service redesign initiatives, which were implemented by all Scottish pharmacies to embed safe working practices and reduce risk concerning HRM. The initiatives have also been adopted by 55 New Zealand pharmacies. The Strathclyde research also informed a service review by the Scottish Government, which included new HRM measures in its 2018 National Therapeutic Indicator report, influencing Prescribing Action Plans within all 944 General Practices in Scotland. As a result, 30% fewer patients ≥65 years were exposed to HRM combinations since 2018.
2. Underpinning research
Context
Medicines can reduce mortality and morbidity, but are not without potentially harmful side effects. UK studies show 6.5% of hospital admissions are attributed to adverse effects of high-risk medicines (HRMs), which in Scotland equates to an estimated 61,000 admissions each year. HRMs, including anticoagulants and non-steroidal anti-inflammatory drugs (NSAIDs), carry a risk of harming patients, most commonly due to gastric irritation and bleeding. Risks are greater for older patients who are more likely to be suffering from multiple conditions and using multiple medicines – factors which can exacerbate the adverse effects of HRMs. To reduce the harm from HRMs, patients and healthcare practitioners must be informed about their safe use.
Key research insights
Since 2010, research led by Professor Bennie has informed national Scottish policies by focussing on two key areas: i) gathering and curating real world data intelligence on use of HRM, and ii) designing and testing new quality improvement (QI) programmes for General Practitioners and community pharmacists to enhance the safe and effective use of medicines.
NHS Scotland invested in a new integrated clinical system enabling a nation-wide prescribing dataset to capture all individual-level prescribing and dispensing of medicines in primary care. This enabled Bennie’s team, for the first time in Scotland, to investigate individual patient-level HRM prescribing over a 10-year period across the entire Scottish population of 5.5 million and to use this to improve prescribing practice [ R1]. The Strathclyde team led the preparation and presentation of the data to permit effective messaging to clinicians and to allow varied stakeholders to use the data for healthcare studies [ R1, R2]. Before this research, those seeking to quantify individual drug exposure across populations spent significant time transforming data into a usable format, often with variable and poorly documented methods. Now, using the natural language processing algorithm [ R2] which takes a zero assumptions approach, structured output from free-text dose instructions (estimated at 100 million items annually) is generated efficiently to allow users maximum flexibility to derive drug exposure information appropriate to their area(s) of study. Since 2018, researchers can request details on dose instruction translation through the eDRIS service run by NHS Public Health Scotland.
The real world data referred to above were used to provide feedback to frontline clinicians in General Practices and community pharmacies. This enabled them to make better informed decisions about HRM prescribing and advice to patients on their use.
General practice setting: In 2010, Bennie’s team, in collaboration with Prof Guthrie’s team at the University of Dundee, brought together a group of Scottish clinicians to derive consensus on which HRMs to target, resulting in the selection of NSAIDs and anticoagulants [ R3]. Using an established ‘feedback intervention’ model for encouraging behavioural change, the team designed an intervention protocol with the aim of providing tailored information to General Practitioners to help them make more knowledgeable decisions about HRM prescribing [ R3]. The resulting ‘Effective Feedback to Improve Primary Care Prescribing Safety’ (EFIPPS) trial tested the intervention protocol in 262 General Practices within a pragmatic three-arm cluster randomised trial [ R3]. The trial featured an educational intervention (in all 3 arms), feedback of performance for targeted indicators (arms 2 & 3), and a theory-informed behaviour change intervention (arm 3 only). The findings identified a 12-14% reduction in HRM prescribing among practices that received feedback (arm 2&3) compared to a simple educational intervention (arm 1) [ R4]. This demonstrated that a relatively simple, easy-to-deliver and nationally scalable provision of feedback performance on prescribing safety could effectively reduce usage of HRM.
Community pharmacy setting: Strathclyde’s research on HRM use in community pharmacies [ R5, R6] was undertaken as part of the ‘Scottish Patient Safety Programme – Pharmacy in Primary Care’ (SPSP-PPC) initiative, established in 2014. Recruiting 29 community pharmacies from across Scotland, the SPSP-PPC explored the use of:
An iterative learning model, the Breakthrough Series Collaborative model, and the capacity for a QI approach in community pharmacies.
A safety climate questionnaire (SafeQuest-CP), designed at Strathclyde, to measure staff perceptions of the safety of the pharmacy setting.
NSAID and warfarin HRM care bundles. The NSAID care bundle comprised two elements: the ‘NSAIDs’ Communication Care bundle’ focussed on patient education, and the ‘NSAIDs’ Safer Care bundle’ focused on the pharmacists’ clinical assessment.
The Strathclyde team provided leadership in the design, validation and testing of all interventions, led the programme evaluation, and informed the national implementation strategy [ R5, R6]. SafeQuest-CP was developed based on responses from 250 pharmacy staff, resulting in a 30 item questionnaire exploring the safety climate factors of ‘leadership’, ‘teamwork’, ‘safety systems’, ‘communication’, and ‘working conditions’ [ R5]. SafeQuest-CP raises awareness of the importance of safety and facilitates action plans for improvement in Scottish community pharmacies [ R5]. Additional research explored the scope to successfully integrate HRM care bundles within Scottish community pharmacies. Quality improvement process mapping techniques were used within participating pharmacies, supplemented by a case study validation exercise [ R6]. The findings highlighted the core steps to delivering the HRM care bundles and positively identified that they can be successfully integrated into routine pharmacy practice. The findings of both studies [ R5, R6] demonstrated the capacity for community pharmacies to deliver safety-focussed initiatives.
3. References to the research
(Strathclyde affiliated authors in bold; FWCI as at 02/02/2021)
Bennie M, Malcolm W, McTaggart S, Mueller T. (2020) Improving prescribing through big data approaches – Ten years of the Scottish Prescribing Information System, British Journal of Clinical Pharmacology, 86: 250– 257. DOI: 10.1111/bcp.14184
McTaggart S, Nangle C, Caldwell J, Alvarez-Madrazo S, Colhoun H, Bennie M. (2018). Use of text-mining methods to improve efficiency in the calculation of drug exposure to support pharmacoepidemiology studies. International Journal of Epidemiology, 47(2):617-624. DOI: 10.1093/ije/dyx264 [REF2; FWCI: 1.65]
Barnett KN, Bennie M, Treweek S, Robertson C, Petrie DJ, Ritchie LD et al. (2014) Effective feedback to improve primary care prescribing safety (EFIPPS) a pragmatic three-arm cluster randomised trial: designing the intervention (ClinicalTrials.gov registration NCT01602705), Implementation Science,11;9:133. DOI: 10.1186/s13012-014-0133-9
Guthrie B, Kavanagh K, Robertson C, Barnett K, Treweek S, Petrie D, Ritchie L, Bennie M. (2016) Data feedback and behavioural change intervention to improve primary care prescribing safety (EFIPPS): multicentre, three arm, cluster randomised controlled trial, The British Medical Journal, 354:i4709. DOI: 10.1136/bmj.i4079 [REF2; FWCI: 4.17]
Newham R, Bennie M, Maxwell D, Watson A, de Wet C, Bowie P. (2014) Development and psychometric testing of an instrument to measure safety climate perceptions in community pharmacy. Journal of Evaluation in Clinical Practice, 20(6):1144-52. DOI: 10.1111/jep.12273
Weir NM, Newham R, Dunlop Corcoran E, Ali Atallah Al-Gethami A, Mohammed Abd Alridha A, Bowie P, Watson A, Bennie M. (2017) Application of process mapping to understand integration of high risk medicine care bundles within community pharmacy practice. Research in Social and Administrative Pharmacy, 14(10):944-950. DOI: 10.1016/j.sapharm.2017.11.009
Notes on the quality of research: All articles are published in peer-reviewed journals. This research was supported with competitively-won funding:
- Bennie M. Community Pharmacy Safety Culture Application, NHS Education for Scotland, 01/03/2012-30/09/2013, GBP27,900.
- Guthrie B, Bennie M, Robertson C. et al. Efficient feedback to improve Primary Care Prescribing Safety (EFIPPS) Application, Chief Scientist's Office, 01/08/2011-30/11/2014, GBP224,512 (Strathclyde GBP56,343).
- Bowie P Bennie M, Newham R, Watson A. Scottish Patient Safety Programme – Pharmacy in Primary Care, Greater Glasgow NHS, 01/04/2014-31/03/2021 (Strathclyde GBP68,400).
- Morris A, Pell J, Ford I, Sutherland F, Colhoun H, Bennie M, et al. The Scottish eHealth Informatics Research Consortium, MRC, 01/03/2013-30/09/2018, GBP4,032,595 (Strathclyde GBP255,477).
4. Details of the impact
From its inception, the research described in section 2 was designed and conducted with real world impact in mind. The Strathclyde researchers worked closely with Scottish health policy makers to inform current strategy on prescribing HRM, and with NHS Healthcare Improvement Scotland, which supports national quality improvement (QI) initiatives and sponsored the SPSP-PPC initiative. The research has been directly incorporated into national strategy, service delivery and system monitoring, improving how clinicians prescribe and review their use of HRMs and how patients are informed about HRMs as they engage with clinicians in the primary care setting.
Influencing Scottish healthcare policy
As members of the SPSP-PPC Programme Board, the Strathclyde team informed the design of the programme and evaluated its findings [ R5, R6]. The Programme Board outputs were shared with the Scottish Government Medicines Policy Division, with the Strathclyde team presenting findings and evidence-based proposals to inform Scottish Government negotiations with the community pharmacy representative body. In this way, the Strathclyde research contributed to an expanding QI programme across all 1,257 community pharmacies in Scotland, including a Quality Improvement Methodology Payment to all Scottish community pharmacy contractors (annualised non-recurring pool of GBP2,000,000) and significant changes to the community pharmacy contract, which serves as the agreement of services between community pharmacies and the Scottish Government [ S1a]. These changes included the requirement for all community pharmacies in Scotland to participate in SafeQuest-CP (developed by the Strathclyde team) and the implementation of the NSAIDs Communication Care and NSAIDs Safer Care bundles [ S1a], as informed by the research [ R5, R6]. Attesting to this, Scotland’s Chief Pharmaceutical Officer stated: ‘the national implementation strategy of quality improvement measures within the community pharmacy setting was directly informed by Strathclyde’s research findings.’ [ S1b]
The work of the SPSP-PPC, together with the key results of the Strathclyde team’s evaluation, featured in ‘ Achieving Excellence in Pharmaceutical Care, 2017’ [ S2, p.26], as an approach to improve the safety and reliability of health care. This document contains a Scottish Government commitment to ‘provide the focus, resources and tools to support the safer use of medicines’ in part by ‘making quality improvement an integral component of community pharmacy funding’ and by introducing ‘a programme of continuous improvement’ [ S2, p.52], as advocated by Bennie’s team [ R5, R6].
Improving healthcare practice in Scotland and internationally
As a direct result of the Strathclyde team’s evaluation of the SPSP-PPC, in 2016 the Scottish Government announced continuous Quality Improvement (QI) as an ongoing element within the community pharmacy contract and made significant changes in line with this [ S1a]. The requirement for all community pharmacies to participate in SafeQuest-CP, a tool designed and validated by the Strathclyde team [ R5], ensures pharmacy staff reflect on and discuss how prescriptions can be dispensed safely to minimise errors and potential patient harm. Similarly, the inclusion of the NSAIDs Safer Care bundle prompts pharmacists to conduct patient needs assessments and identify ‘high risk’ patients along with potential interventions when processing a prescription for NSAIDs, and the NSAIDs Communication Care bundle supports the pharmacy team to deliver key messages to patients being dispensed or purchasing NSAIDs [ S3]. As the underpinning research had demonstrated the core steps to delivering the HRM care bundles [ R6], the Strathclyde research team collaborated with NHS Education for Scotland to inform their implementation strategy, including co-designing a webinar [ S4, S5] and hard copy resources, such as a guidance booklet and an awareness poster [ S3]. Early adopters who participated in the SPSP-PPC pilot work encouraged new adopter pharmacies and facilitated nationally coordinated ‘training-the-trainers’ events [ S1a]. The NSAIDs Communication Care bundle has since been implemented in all dispensing general practices and all community pharmacies in NHS Scotland [ S1a]. National implementation of the NSAIDs Safer Care bundle began formally in March 2019 [ S1a], supported by the NHS Education for Scotland webinar [ S4] which was well received. As commented by the PG Pharmacy Dean, NHS Education for Scotland, the webinar was ‘essential to support the pharmacy teams’ effective implementation of the NSAIDs care bundle in community pharmacies across the whole of Scotland’ and was ‘ made available to all community pharmacy staff and accessible at any time’ [ S5]. The care bundle is now widely used by pharmacists to improve the clinical care of patients who take NSAIDs in addition to other medication. Highlighting the significance and novelty of these changes, Scotland’s Chief Pharmaceutical Officer stated: ‘national training resources co-designed with the Strathclyde team were developed… to include a focus on QI activities for the first time in Scotland.’ [ S1b]
The SPSP-PPC programme has now been used as the basis of an evolving programme in Auckland, New Zealand. As stated by the Pharmacist and Project Manager, Quality Use of Medicines Team, ’ The University of Strathclyde’s involvement in the development and evaluation of the care bundles and a Safety Climate Survey … informed various decisions and influenced the community pharmacy service delivery within Auckland from 2017 onwards’ [ S6]. By 2020, 55 community pharmacy teams in Auckland had adopted the NSAIDs care bundle [ S6], demonstrating its international relevance and adaptability to suit various healthcare systems.
In 2016, the results of the ‘ Effective Feedback to Improve Primary Care Prescribing Safety’ (EFIPPS) trial [ R4] were presented to the policy leaders of NHS Scotland’s Effective Prescribing and Therapeutics Branch to explore national adoption of the researchers’ proposals within the National Therapeutic Indicators (NTI) report [ S8]. The NTI report measures prescribing activity in specified therapeutic areas and compares these measurements across NHS Boards and General Practices, with results published annually. The report is applied by all Scottish NHS Boards as a tool to promote safe, effective and more consistent prescribing, and to identify potential areas requiring attention through their Prescribing Action Plans. In 2018, the HRM measures established and tested within EFIPPS were adopted by NHS Scotland as NTIs [ S7] and applied to all 944 General Practices in Scotland [ S8]. The 2018 annual report [ S7], together with the addition in 2019 of an interactive visualisation tool [ S9], allows NHS Boards and Scotland’s General Practices to monitor changes in these measures over time [ S8]. Furthermore, the HRM measures were incorporated into the Scottish Government’s ‘Polypharmacy Guidance Realistic Prescribing 2018’ as part of the Scottish response to Medication Without Harm, the WHO’s third Global Patient Safety Challenge [ S8, S10].
Improving patient wellbeing
As a result of these quality improvement initiatives, patient welfare has been improved due to fewer HRMs being prescribed to patients. For example, the HRM measure ‘Acute Kidney Injury’ (i.e. percentage of people aged ≥65 years co-prescribed a NSAID and an Angiotensin-converting-enzyme (ACE) inhibitor/angiotensin receptor blocker and a diuretic) shows that over the period April 2018 to June 2020, there was a 30% reduction in those patients exposed to this HRM combination across Scotland [ S8]. Similarly, there has been a reduction of 16% in the volume of NSAIDs prescribed in Scottish General Practices for the period April 2018 to June 2020 [ S8]. As summarised by the PG Pharmacy Dean, NHS Education for Scotland, ‘ robust research led by Professor Bennie had a key influence in driving forward pharmacy services ….ultimately improving patient safety’ [ S5].
5. Sources to corroborate the impact
- (a) Factual statement from Chief Pharmaceutical Officer and Deputy Director, Pharmacy and Medicines Division, Chief Medical Officer Directorate, Scottish Government, dated 2/9/2020.
(b) Supplementary e-mail statement from Chief Pharmaceutical Officer, dated 14/2/2021.
Scottish Government (2017) Achieving Excellence in Pharmaceutical Care, pp.24,52. https://bit.ly/3byF5ix
Health Improvement Scotland, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) ‘Communication Care Bundle’ toolkit. https://bit.ly/3qa1Gan
NES Education for Scotland. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) ‘Safer Care Bundle’ Webinar. Available from: https://vimeo.com/323773001/884511cca8.
Factual statement from PG Pharmacy Dean, NHS Education for Scotland, dated 15/2/2021.
Factual statement from Pharmacist and Programme Manager, Quality use of Medicines Team, Waitemata and Auckland District Health Boards, dated 2/12/2020.
NHS Scotland (2018) National Therapeutic Indicators and Additional Prescribing Measures 2017/18, pp.54-57. https://bit.ly/3dCyExe
Factual statement from Head of Effective Prescribing and Therapeutics Branch, Scottish Government, dated 07/03/2021.
National Therapeutics Indicator (NTI) programme visualisation tool. https://bit.ly/3aIhzjJ
Scottish Government (2018) Polypharmacy Guidance Realistic Prescribing, pp 71-76. https://bit.ly/2ZGnSy4
- Submitting institution
- University of Strathclyde
- Unit of assessment
- 3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
- Summary impact type
- Technological
- Is this case study continued from a case study submitted in 2014?
- No
1. Summary of the impact
Strathclyde research has been crucial in creating new methods and technologies for industrial pharmaceutical process development associated with continuous manufacturing and crystallisation (CMAC) generating impacts across the UK and international technology and pharmaceutical sectors. This has led to new product lines being developed (Alconbury Weston Ltd), and documented savings in development studies (Lilly) that have gone on to inform commercial manufacturing (AstraZeneca). Since August 2013, approximately GBP45,000,000 of savings and improvements have been realised by the 22 multinational and Small and Medium-sized Enterprises (SMEs) who have invested directly in proprietary analytical and process improvement projects.
2. Underpinning research
The EPSRC Centre for Innovative Manufacturing (CIM) in Continuous Manufacturing and Crystallisation (CMAC) was established at the University of Strathclyde in 2011, based on the joint research and expertise of Florence (A3) and Sefcik (B12). Now an EPSRC Future Manufacturing Research Hub, CMAC undertakes demand-led manufacturing research in partnership with six universities, eight multinational pharmaceutical companies (AstraZeneca (AZ), Bayer, Eli Lilly, GlaxoSmithKline (GSK), Novartis, Pfizer, Roche, Takeda) and 18 equipment, analytical, software and consultancy companies.
CMAC research is conducted by a multi-disciplinary team from Strathclyde’s Science and Engineering Faculties to generate a critical-mass ecosystem for advanced pharmaceutical manufacturing research. The development of small scale, modular, agile and flexible continuous manufacturing processes for medicines is essential to meet the rapidly changing demands of modern healthcare. This has never been more evident than in the essential medicines shortages resulting from international supply chain disruption in the ongoing COVID-19 pandemic.
The underpinning research spans understanding of particle formation, continuous processes, advanced technology and innovative digital solutions. Important contributions from Florence, Brown, Ter Horst, Halbert and Johnston among others in the Strathclyde Institute of Pharmacy and Biomedical Sciences have been made to research on:
Particles - Exquisite control of particle quality attributes: Controlling the formation of particles is crucial to realising improved manufacturability, performance and stability demanded by robust, sustainable and cost effective medicines manufacture. Understanding how key particle attributes can be better controlled using advanced process technologies and exploiting this knowledge to streamline the final production of formulated products is vital to ensure medicines can be made with greater control and lower cost. Examples include the development of an advanced process control system jointly developed with CMAC, an SME (Perceptive Engineering) and AZ. This project delivered methods to directly control particle size, size distribution and significantly improve process yield (26% higher than corresponding batch process), improving productivity and reducing off-spec product and waste [ R1]. In addition, extensive characterisation of plug flow reactors coupled with supersaturation and seeding control enabled control over polymorphic form and unwanted nucleation and encrustation during continuous crystallisation [ R2].
Processes - Smart workflows for accelerated development of particle formation processes: CMAC research has focussed extensively on the development of robust, scalable workflow processes for continuous crystallisation and drug product processes to enhance process understanding, avoid common failure modes and deliver consistent, high quality products. Several examples have been developed building a comprehensive and rigorous framework for advanced process development that support regulatory requirements such as the US Food and Drug Administration’s Quality by Design guidance. An extensive multidisciplinary project developed the first major comprehensive workflow for continuous cooling crystallisation as a key outcome from the EPSRC CIM [ R3]. This system-wide view of the crystallisation process coupled scaled down experiments, prediction and multi-scale modelling to deliver robust process design and operation to achieve exquisite control of product attributes and quality. Workflows have also been published for anti-solvent crystallisation, impurity rejection in crystallisation [ R4], spherical agglomeration, wash solvent selection in filtration washing and drying, determination of solubility of materials in polymeric systems and manufacturability of formulated products.
Technologies - Advanced continuous platform technology development: CMAC has provided fundamental science to design and develop novel processing equipment, or microfactories, to broaden the applicability and benefits of continuous processing. These platforms include: Novel Nucleator Platform; mixed suspension mixer product removal crystalliser with Digital Twin; meso-scale, moving liquid Continuous Oscillatory Baffled Crystalliser [ R1, R2], in line mixers for rapid antisolvent crystallisation and a moving baffle oscillatory baffled reactor cascade.
Digital Design: Manufacturing research spans many length scales from molecular to process and bulk materials. CMAC research has included the development of Machine Learning models to predict the formation of novel solvates and crystallisability thereby creating novel predictive tools to inform and accelerate development. Molecular dynamics and atomic force microscopy (AFM) has informed new understanding of the fundamental mechanisms of crystal formation [ R5]. In addition, digital design tools for formulated product manufacture via direct compression provide new tools to accelerate development using predictive modelling approaches [ R6]. The role of data science is key and CMAC has developed a database of common excipients to support rapid screening of formulation options in-silico, saving time as well as associated material use.
3. References to the research
(Strathclyde affiliated authors in bold; FWCI at 02/02/2021)
- F. Tahir, K. Krzemieniewska-Nandwani, J. Mack, D. Lovett, H. Siddique, F. Mabbott, V. Raval, I. Houson, A. Florence (2017) Advanced control of a continuous oscillatory flow crystalliser, Control Engineering Practice, 67: 64-75
https://doi.org/10.1016/j.conengprac.2017.07.008
- N.E.B Briggs, U. Schacht, V. Raval, T. McGlone, J. Sefcik, A.J. Florence (2015) Seeded crystallization of ß-l-glutamic acid in a continuous oscillatory baffled crystallizer, Organic Process Research & Development, 19(12): 1903-1911
https://doi.org/10.1021/acs.oprd.5b00206 [FWCI: 2.15]
- C. Brown, T. McGlone, S. Yerdelen, V. Srirambhatla, F. Mabbott, R. Gurung, M.L. Briuglia, B. Ahmed, H. Polyzois, J. McGinty, F. Perciballi, D. Fysikopoulos, P. MacFhionnghaile, H. Siddique, V. Raval, T.S. Harrington, A. Vassileiou, M. Robertson, E. Prasad, A. Johnston, B. Johnston, A. Nordon, J.S. Srai, G. Halbert, J.H. ter Horst, C.J. Price, C.D. Rielly, J. Sefcik, A.J. Florence (2018) Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations, Molecular Systems Design & Engineering, 3: 518-549
https://doi.org/10.1039/C7ME00096K [FWCI: 3.24; REF2]
S.J. Urwin, G. Levilain, I. Marziano, J.M. Merritt, I. Houson, J.H. Ter Horst (2020) A structured approach to cope with impurities during industrial crystallization development. Organic Process Research & Development, 24(8): 1443-1456.
M. Warzecha, L. Verma, B. Johnston, J. Palmer, A.J. Florence, P. Vekilov (2020) Olanzapine crystal symmetry originates in preformed centrosymmetric solute dimers, Nature Chemistry, 12: 914-920 https://doi.org/10.1038/s41557-020-0542-0 [FWCI: 2.15]
H.G. Jolliffe, F. Papathanasiou, E. Prasad, G. Halbert, J. Robertson, C.J. Brown, A.J. Florence, (2019) Improving the prediction of multi-component tablet properties from pure component parameters, Computer Aided Chemical Engineering, 46: 883-888
https://doi.org/10.1016/B978-0-12-818634-3.50148-X
Notes on the quality of research: This research has been supported with competitively awarded core funding from EPSRC totalling GBP26,059,706, including:
- Florence (PI), ter Horst, Johnston (CIs), EPSRC Centre for Innovative Manufacturing for Continuous Manufacturing and Crystallisation, 01/10/11-31/12/2016, GBP5,990,295;
- Halbert (PI), Florence (CI), Doctoral Training Centre in Continuous Manufacturing and Crystallisation, 01/07/2012-01/01/2021, GBP4,645,116;
- Florence (CI): Computationally Designed Templates for Exquisite Control of Polymorphic Form, 01/10/13-30/6/18, GBP1,248,345;
- Johnston (PI), Florence (CI): ARTICULAR: ARtificial inTelligence for Integrated ICT-enabled pharmaceUticaL mAnufactuRing, 01/07/18-31/06/22, GBP1,956,119.
4. Details of the impact
Through the establishment, growth and global influence of CMAC, Strathclyde’s demand-led research and expertise in forming particles with controlled attributes, in workflow design, on advanced continuous platform technology and development of digital tools has improved pharmaceutical development and manufacturing processes globally. By demonstrating the viability and benefits of advanced continuous manufacturing techniques, Strathclyde’s innovative approach to integrated development and operating platforms has enabled adoption within the pharmaceutical industry and created business opportunities for technology providers. As evidenced by the following examples, this has resulted in improved processes which have lowered development time and production costs, increased yields, reduced risk and enhanced product quality to the benefit of manufacturers, suppliers and end-users. Upskilling of staff in new techniques and methods has also been achieved. Since August 2013, CMAC’s research has enabled approximately GBP45,000,000 of savings and improvements for the 22 multinational and SMEs who have invested directly in proprietary analytical and process improvement projects.
Contributing more broadly to technology translation for societal and economic benefit, CMAC’s work has generated 54 highly-skilled individuals, 31 of whom have gone on to employment in industry (e.g. AZ, Pfizer, GSK, Lilly, Novartis, Roche, Perceptive Engineering, National Physical Laboratory (NPL), Solid Form Solution, Process Systems Enterprise (PSE) Ltd, Mettler Toledo) and 23 to academia (e.g. Strathclyde, Imperial, Loughborough, Massachusetts Institute of Technology (MIT)).
Improved Industrial Process Development:
CMAC research workflow outcomes [ R3, R5] were applied by AstraZeneca (AZ; 2016-18) to improve a commercial process for a pharmaceutical product delivering GBP10,000,000 saving [ S1]. The improved process understanding led to reduced waste and increased product quality.
In 2014, Novartis adopted CMAC Strathclyde’s novel methodology for introducing seed crystals into a continuous crystallisation [ R2, R3] in their continuous pilot plant in Basel, Switzerland. This approach has been applied to the development of an anti-cancer product and at least 2 other active ingredients in development. As noted by the Novartis Development Engineer, ‘this effective application of CMAC research reduced chemical exposure risk to operators, minimised plant down time and improved product quality’ [ S2].
CMAC doctoral placements (2013-19) installed a novel continuous nucleation and crystallisation platform at AZ which has since been used on 10 live medicinal compounds, 4 of which are in commercial manufacture [ R2, R3, R5]. This led to a 90% time reduction to generate the existing amount and quality of information compared to previous approaches. AZ’s Principal Scientist confirmed that, ‘Without the CMAC collaboration and student placements we would not have had the laboratory continuous crystallisation facilities established in this time frame or have been able to test the feasibility of continuous crystallisation on multiple AZ compounds. Using this new capability AZ scientists are be able to develop continuous crystallisation processes for APIs in-house in a much shorter timescale’ [ S1].
The application of CMAC’s workflow approaches for particle attribute control at Eli Lilly in 2017 resulted in an improved particle size control from the use of high shear wet milling in the continuous crystallisation of the final active pharmaceutical ingredient for an oncology asset which was then in Phase IIb clinical trials [ R3, R6]. According to a Senior Engineering Advisor at Eli Lilly, by enabling the removal of a post processing dry milling step, this work ‘reduced fouling on the crystalliser walls (reducing plant cleaning and down time) and improved the physical product properties improving the product manufacturability. The removal of a milling step has reduced cycle times of each lot of product by 3 days and development time by 3 months. This is now a platform capability embedded at Lilly’ [ S3].
Enhanced workforce understanding and skills:
The benefits of process insights from CMAC’s multivariate analysis (MVA) and data visualisation approaches were demonstrated on plant data at Lilly’s manufacturing plant in Ireland as part of a PhD project. These learnings enhanced process understanding and operations engagement with data analytics tools [ R1, R3, R6]. The project delivered real-time data cleansing, organisation and visualisation enabling a reduction in plant downtime and product losses. The work demonstrated the benefits of MVA to senior management and resulted in investment in digitisation of manufacturing processes. As noted by the Eli Lilly Team Leader for Small Molecule Technical Services/Manufacturing Sciences, in Cork, Ireland, this ‘really raised awareness of the benefits to manufacturing when data and technology are combined with people with the right skillsets…this work was a significant factor in convincing the site to expand the use of these tools’ [ S4].
Working pre-competitively with its 8 large pharma Tier 1 members, CMAC developed an industrially-relevant workflow with 7 case studies providing methods to avoid the incorporation of impurities in crystals [ R4, R5]. Between Jan and Nov 2020, tailored training was provided to over 130 industry staff who subsequently applied the approaches directly into the process development of all their Active Pharmaceuticals Ingredients (APIs) [ S5].
Advanced process technology and industry adoption:
An Advanced Process Control (APC) system for continuous reaction and crystallisation was developed and demonstrated in collaboration with Perceptive Engineering, Centre for Process Innovation (CPI) and AstraZeneca [ R1]. The Managing Director of Perceptive Engineering said, ‘The commercialisation of this software directly led to one new client with follow-on sales of GBP207,700, GBP400,000 of related projects, employment of 1 new FTE to support applications on continuous manufacturing and publication of 4 peer-reviewed papers and 2 articles significantly increasing our visibility and reputation’ [ S6].
In collaboration with Alconbury Weston Ltd (AWL), CMAC developed and delivered a platform for continuous isolation (filtration, washing and drying) of APIs bridging from process development to manufacturing and reducing scale up risk [ R3, R6]. The platform is now in commercial production. As confirmed by AWL’s CEO, ‘Continuous isolation systems are rare at this scale and coupled with the demonstrated benefits of rapid processing times of less than 15 minutes, no particle shear or attrition, precise, repeatable dosing and consistent product, the unit has been demonstrated on >10 commercial molecules (including vitamins, pharmaceuticals, Cannabidiol (CBD) and an energetic material) with more than 15 companies. To date, 8 units have been sold with a further 3 on order, including 2 production scale systems for processing CBD and 2 systems are on hire around the world. The success of the new products based on the outstanding direction and input from Prof. Chris Price has allowed us to refine and commercialise a range of lab, pilot and production scale continuous filtration and drying systems for multiple industries’ [ S7].
Enhanced the global manufacturing landscape:
- At the request of Janet Woodcock, Head of the U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research, CMAC collaborated with the Novartis Centre for Continuous Manufacturing at MIT to initiate biennial symposia to advance continuous pharmaceutical manufacturing. Since 2014, the International Symposium for Continuous Manufacturing of Pharmaceuticals (ISCMP) has been held 5 times (2014, 2016, 2018, 2020 and 2021), demonstrating sustained interest in its potential impact on the global medicines manufacturing landscape. Due to the Covid-19 pandemic, the 2020/21 events were delivered as webinars which attracted over 500 delegates and facilitated discussion between key stakeholders: US and UK regulators (FDA, MHRA), industry bodies (Medicines Manufacturing industry Partnership, MMIP) and the UK Government (Office for Life Sciences and Business Enterprise Innovation and Science, BEIS). By bringing the wider international industry, regulatory and academic communities together to share case studies, develop and share practical guidance on continuous manufacturing (further embedded through the publication of a series of whitepapers and reports) CMAC has accelerated the pace of innovation and change in this strategically important industry sector. Attesting to this, the Chair of the Medicines Manufacturing Industry Partnership (MMIP) notes: ‘CMAC, on the basis of its research and recognised expertise, has strengthened international cooperation around continuous pharmaceutical manufacturing through the ISCMP. By facilitating discussion and focusing attention on key developments and issues to be addressed, this initiative has enhanced global relations and positioned the industry well to respond to current and future challenges’ [ S8].
Strengthened UK Research and Innovation:
- CMAC’s critical mass as a collaborative research centre has highlighted the success of the ‘triple helix’, coupling the power of industry, government and academia working together to accelerate change in the form of the adoption of continuous manufacturing. By working together with the Centre for Process Innovation (CPI Ltd), AZ and GSK, Strathclyde University helped to secure investment of GBP56,000,000 to create the Medicines Manufacturing Innovation Centre (MMIC) in 2018. This new facility, owned by CPI, will be built in 2021 and create 80 high value jobs by 2023 [ S9].
5. Sources to corroborate the impact
Factual statement from Principal Scientist Crystal & Particle Science, AstraZeneca (01/03/2021).
Factual statement from Development Engineer, Novartis, Switzerland (18/02/2021).
Factual statement from Senior Engineering Advisor of Eli Lilly, Indiana, USA (02/03/2021).
Factual statement from Team Leader, Small Molecule Technical Services/Manufacturing Science, Eli Lilly, Ireland (22/02/2021).
Factual statement, CMAC Translation manager, University of Strathclyde (22/02/2021).
Factual Statement from Managing Director, Perceptive Engineering Ltd (16/02/2021).
Factual statement from CEO, Alconbury Weston Ltd, UK (16/02/2021).
Factual statement from MMIP Chairman in the UK (04/03/2021.
UK Government, ‘Faster medicine: £56 million innovation centre for Scotland’, 18/06/2018.