Impact case study database

When Prof. Loke’s 2007 AE framework was first published, there were just under 80 systematic reviews in 2007 that focused on evaluating AE. By the year 2014, this had seen a more than four-fold jump with 348 systematic reviews focusing on AE. Since publication of the PRISMA-Harms checklist in 2016, more than 75 systematic reviews have cited PRISMA-Harms as an underlying basis for the methods in their review. This includes a very recent review on COVID-19-related adverse events (e.g., miscarriage, foetal mortality) in pregnant mothers.

Methodological advances in the process of evidence synthesis for detailed assessment of harms: New technology or process has been adopted by the US Government Agency for Healthcare Research and Quality (AHRQ) [Source A]

Professor Loke’s work led to new AHRQ methodological guidance to prioritize and select harms in their evidence-based reviews of healthcare interventions. This ensures that balanced assessments are available for those who commission and use information from systematic reviews in the US and internationally.

The AHRQ is part of the Department of Health and Human Services and is the lead US Federal department charged with improving the safety and quality of America's health care system. It has a USD451,000,000 budget to develop the knowledge, tools, and data needed to improve the health care system and help patients, clinicians and policymakers make informed health decisions. The AHRQ’s overarching objectives are to produce evidence to make health care safer and of higher quality and they have produced more than 700 systematic evidence-based reviews in the past 20 years. Notable current examples in progress include masks for prevention of COVID-19, and no-touch disinfection modalities.

In Feb 2016, the AHRQ contacted Prof. Loke to arrange an interview and provide written expert advice into their methodological guidance for assessing adverse effects. The AHRQ emphasised that the selection and prioritization of harms:

“was identified as an important area given the potentially large number of harms that could be assessed in many reviews.”

[Source A page 23]

Here, the AHRQ had recognized the incomplete benefit:harm coverage in their evidence-based reviews, particularly when they became aware of Prof. Loke’s published data regarding selective and incomplete reporting on harms (2,4). Hence the AHRQ set up interviews with key experts/informants by invitation and incorporated Prof. Loke’s expertise into their Methods guide to explicitly identify harms, and to select specific harms for evaluation in AHRQ evidence-based reviews.

This led to the publication in Feb 2018 of the updated AHRQ Methods Guide for Comparative Effectiveness Reviews: Prioritization and Selection of Harms for Inclusion in Systematic Reviews [Source A].

Methodological recommendations on best way to search for and identify reports of adverse effects (European Medicines Agency, Australian National Health and Medical Research Council) [Sources B and C]

The European Medicine Agency (EMA) set up the European Network of Centres of Pharmacoepidemiology and Pharmacovigilance (ENCEPP) in 2007. This network gives methodological guidance to public institutions and commercial research organisations across all of Europe on the standards they should adhere to when conducting pharmacoepidemiology studies with safety outcomes. Prof. Loke’s systematic framework and terms used in the search (5) are explicitly cited and form the basis for ENCEPP Methodological Standards on how to conduct comprehensive reviews of safety [Source B]. Similarly, the Australian National Health and Medical Research Council has drawn up methodological standards on identification of evidence [Source C], and they cite Prof. Loke’s research (4) into missing adverse effects data as the basis for explicit recommendations to search for and include data from grey literature.

Empirical use of this new benefit:harm methodology has led to policy changes in recommendations of treatment by the World Health Organization [Source D]

Surgical site infections are a major burden internationally affecting up to 300 000 patients per year in the USA, costing between USD3,500,000,000 and USD10,000,000,000. Previous WHO 2016 guidelines made a Strong Recommendation for high inspired oxygen to reduce wound infections. However, this was widely challenged and publicly debated by the clinical community who had major reservations about safety of oxygen and incomplete evaluation of benefit:harm balance. Prof. Loke was invited by the WHO to take part in the conduct of two new systematic reviews (one on benefit, the other focusing on harm). The two reviews yielded a far more complete understanding of the clinical effects of oxygen and the limitations of the underlying data in terms of bias and inadequate measurement of outcomes. Both reviews (with Professor Loke as co-author) generated new and more comprehensive benefit:harm evaluations for the December 2019 re-written WHO Global Guidelines for the Prevention of Surgical Site Infection. The two reviews are specifically listed as the evidence-base for the more carefully nuanced updated recommendations. Here, incorporation of Prof. Loke’s new methodologies for assessing benefit and harm led to the WHO down-grading the recommendations for high oxygen delivery in surgical patients, particularly in developing countries where oxygen is scarce [Source D]. Now that WHO is no longer making a strong recommendation for high oxygen concentrations in surgical patients, the clinicians in developing countries are able to prioritize scarce supplies oxygen for use in COVID-19 patients.

UK government reviewed and revised their definition of COVID-19-mortality in August 2020 following publication of Prof. Loke’s evaluation [Sources E, F and G]

Prof. Loke’s analysis of COVID-19 -deaths triggered a review of PHE’s method of data collection which was ordered by the Secretary of State for Health on that very same day [Source E]. The review of PHE's method of data collection was reported globally thousands of times in just two days between 17-19th July [Source F]. The review reported its findings on 12 Aug 2020, with PHE revising its method of measurement to report both: (i) deaths within 60 days or if the death occurred after 60 days, COVID-19 is listed on the death registration and (ii) deaths in laboratory-confirmed positive individuals where the death occurred within 28 days. The four Chief Medical Officers across the UK also agreed on the standardised measurement of COVID-19-related deaths to a defined time-period of 28 days within a positive test allowing direct comparisons of mortality rates. The death toll in England was revised down by 5,377 to 41,329 [Source G]. The greatest impact of Prof. Loke’s recommendation was seen for mid-July, where the death toll for England was drastically revised down by 75% from 442 to 111 [Source H, table 2]. The standardised definition of COVID-19 deaths also allows compatibility with WHO international datasets: England is no longer an outlier (the WHO definition specifies “There should be no period of complete recovery from COVID-19 between illness and death”). A quote from the Director of Health Improvement at PHE emphasises the importance of the revised method:

“Our analysis of the long-term impact of the infection now allows us to move to new methods, which will give us crucial information about both recent trends and overall mortality burden due to Covid-19”

[Source G]

Livermore's research has led to both the generation of new antibiotics and treatment options, as well as the adoption of measures to prevent the spread of AMR infections in secondary care settings. This has been of benefit to pharmaceutical companies, medical practitioners treating patients with life threatening infections, hospital management who manage the treatment of patients with life threatening infections in secondary care settings, as well as the patients with antibiotic resistance infections.

Discovering New Antibiotics and Treatment Options

Impact on Industry Practice

Two drug candidates, for which Livermore performed and published in vitro analysis ( 3.2, 3.3) have recently been approved for clinical use (Fetroja (Cefiderocol - Shionogi ltd) and Recarbio (MK7655 with imipenem - Merck & Co. Inc)). These two drugs represent a significant breakthrough for previously untreatable urinary tract and hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia caused by highly resistant gram-negative pathogens. Both drugs are considered as drugs of last resort ( 5.1, 5.2). Fetroja (Shionogi ltd) is the first new treatment which provides coverage against all Gram-negative pathogens considered of critical priority by the World Health Organization. It was given FDA approval in the US in 2019 (> USD10,000 treatment course) and European Union Approval for use in 2020 ( 5.2). Recarbrio (Merck & Co. Inc) (> USD7,000 treatment course) has been designed for use in patients aged 18 and above with limited or no alternative therapies ( 5.2). The Committee for Medicinal Products for Human Use – part of the European Medicine Agency- that grants approval to new drugs stated that for the drugs Recarbrio and Fetroja ( 5.2) :

“Based on the CHMP review of data on quality, safety and efficacy, the CHMP considers by consensus that the benefit-risk balance of […] is favourable in the following indication; Treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options.” European Agency Assessment report for Recarbrio (pg. 277) and Fetroja (pg. 155) ( 5.2).

Two other candidates analysed by Livermore are in Phase 2 trials including WCK4282 ( 3.5) (a high dose combination of cefepime-tazobactam) and WCK6777 (ertapenem-zidebactam) produced by Wockhardt. Emphasising Livermore’s role, The Chief Scientific Officer of Wockhardt states:

“Dr Livermore’s work has provided independent, valuable scientific evidence for substantiating the unmet need addressed by Wockhardt’s three antibiotics [WCK4282 ( 3.2) , WCK6777, WCK5222 ( 3.4) ] that target Gram-negative pathogens” and “ we recognise that Prof Livermore is a world-renowned expert in this area and our collaborations have been extremely fruitful and together we have made great progress in our hunt for new antibiotic drugs to tackle the unmet need of antimicrobial resistance and the growing need for new drugs” ( 5.3).

Wockhardt’s investment in AMR is the largest program anywhere in the world. 'Wockhardt's' CEO commented on their drug portfolio which contains the three drugs analysed by Livermore:

“In 2019-20 our sales were $440 m [USD440,000,000] (Rs 3325 Crore). It is a matter of great pride that we are now the only company in the world to hold QIDP (Qualified infectious disease product) status for six antibiotics, three of which target Gram Negative pathogens while the other three target Gram Positive difficult-to-treat ‘Superbugs’” ( 5.3).

Global Phase 3 studies for WCK4282 and WCK6777 have been held back by the COVID pandemic but hope to be re-established in 2021. WCK6777 has received the Qualified Infectious Disease Product (‘QIDP’) from the United States Food and Drug Administration indicating. The QIDP status provides fast track approval to drugs that are effective against a set of multi-drug resistant pathogens, which have a high degree of unmet need in the treatment of infected patients. ( 5.3) The Chief Scientific Officer of Wockhardt ( 5.3) states that:

“Livermore’s studies of one of these drugs WCK4282 reaffirmed the clinically interesting aspects of this antibiotic as a work horse antibiotic used against hard-to-treat Gram negative pathogens”

He also describes the potential benefit of the third Wockhardt drug WCK5222 (cefepime-zidebactam) ( 3.4) as “ WC 5222 meets the urgent threat of Carbapenem-Resistant Enterobacteriaceae and serious threats like multidrug-resistant Acinetobacter and multidrug-resistant Pseudomonas aeruginosa. It is positioned as a novel MOA-based, high-efficacy destination therapy for XDR pathogens beyond the treatment scope of existing products in the US and Europe. The investigational product is manufactured for Phase III trials at FDA-approved contract manufacturing sites in Europe. An abridged Phase III global study protocol has been finalised in consultation with US FDA, European Medicine Agency (EMA) and Chinese regulator, National Medical Products Administration (NMPA)” ( 5.3).

Impact on Patient care: Saving lives of Patients with Hard-to-Treat Life Threatening Infections

Livermore’s expertise in identifying and interpreting resistance mechanisms of pathogenic bacteria was invaluable in guiding treatment of specific patients, some with life-threatening infections ( 3.1). During Livermore’s part-time secondment to PHE (1.5 days per week from 2011-18) he was frequently (often on a weekly basis) consulted by clinicians to use his expertise and knowledge to advise on unconventional regimens for infection caused by multidrug-resistant pathogens, where standard treatment options had been exhausted. It sometimes included compassionate use of developmental agents prior to licensing. Three such examples ( 5.4a-c), have been published as patient case notes where bespoke antibiotic drug regime led to successful patient outcomes. The Director for the Centre for Clinical Infections and Diagnostics Research, a consultant microbiologist at Guy’s & St Thomas’ Hospital states that “ one such case study was a 78-year-old woman who was admitted to the intensive care unit at London Bridge Hospital with aortic valve endocarditis that was not controlled by all currently available antibiotics and therefore life-saving surgery to replace the heart valve could not proceed. Blood cultures grew an extremely drug-resistant (XDR) Pseudomonas aeruginosa due [..]that we rarely see in the UK. The patients was colonised with other resistance bacteria that complicated the situation (Klebsiella pneumoniae with OXA-48 carbapenemase and Acinetobacter baumannii with OXA-23/OXA-51 A). Discussion led to a decision to make a successful, formal request for compassionate use of cefiderocol (subsequently licensed under the trade name Fetroja) after David [Livermore] had arranged urgent susceptibility testing of cefiderocol to confirm its activity against the isolate. Two days after starting cefiderocol treatment the septicaemia was stopped and aortic valve replacement could proceed with a successful outcome. It is highly likely that without this successful treatment plan this patient would not have survived. This was a particularly successful case which illustrates the path we have to follow, that David [Livermore] has helped with over the years at multiple stages” ( 5.4a).

Implementing a New Tool; Acute trust toolkit for early detection, management and control of carbapenemase-producing Enterobacterales; Impact on infection prevention and management

Livermore’s research highlighted the scale, mechanism and global spread, of rapidly emerging multi-drug resistant carbapenemase-producing organisms ( 3.1). Livermore’s research expertise in this area and his secondment role with PHE informed 1) the updated screening criteria for suspected cases of carbapenem resistant infections including travel from abroad including Indian subcontinent 2) guidance on the therapies to be prescribed to treat carbapenem resistant infections, 3) advice on monitoring infection trends in trusts and robust diagnostic plans using laboratory services. In 2013, Livermore was invited to join a British Working Group commissioned by PHE. This group outlined AMR concerns and developed a toolkit (published 2014) ( 5.5 designed to prevent and reduce the spread of carbapenemase-producing Enterobacterales (CPE) infections in health and residential care settings. This was a key pathway to raising awareness of CPE infection and prevention methods in Trusts across England as evidenced by widespread uptake of the toolkit into local trust guidelines ( 5.5). The Director for the Centre for Clinical Infections and Diagnostics Research, a consultant microbiologist at Guy’s & St Thomas’ Hospital states “ the toolkit they published in 2014 to reduce the spread of carbapenemase-producing Enterobacteriaceae […]is a landmark reference document on which the framework for infection control of CPEs is based at probably all NHS hospitals including our own” ( 5.4). The toolkit advised front line staff about the 1) early detection of these infections through early recognition of individuals who may be colonised 2) improved laboratory screening methods for these infections 3) prevention and control of infections through enhanced cleaning and decontamination protocols 4) isolation procedures for patients with infections. It also provided a series of checklists for the Trust Boards, Executive and IP&C teams to ensure effective infection prevention practices are in place within Trusts and information sheets on CPE infections for patients and families. An accompanying letter to the toolkit from the Chief Executive of PHE sent to all Trusts in England stated that: “ The toolkit is intended to provide a framework to support local risk assessment, providing the minimum interventions required to safeguard patient safety and prevent an escalation of the problem” ( 5.5).

A 2019 PHE commissioned quantitative evaluation of the toolkit in all English trusts ( 5.8) showed;

• 92% of Trusts, implemented or wrote new local prevention plans based on this toolkit;

• 75% reported consistent compliance with screening and isolation of CPE risk patients outlined in the toolkit.

A qualitative evaluation was undertaken on the implementation of the toolkits in 2017 based on 44 interviews with staff from 12 Acute Trusts. This report includes a statement that one Trust used the toolkit ‘to inform and check their own CPE prevention, management and control plans in particular in the event of an outbreak’ ( 5.7 pg. 18). In addition, the toolkit has been used as a catalyst for change and influenced individual trusts to change their funding priorities.

“The CPE toolkit was seen as a credible source of information, which could help to secure management support for financial investments to address resource challenges such as a shortage of isolation facilities or funding for additional training’ ( 5.7 pg 6) Individual hospital trusts have also provided accounts of how they have implemented the toolkit. The Royal Wolverhampton Trust UK, reported to its Trustee’s that “ So far there have been 12 patients identified as having CPE-producing organisms in the New Cross Microbiology Laboratory [..] So far during 2014 there have been two incidents during which the toolkit has had to be actioned and these account for four of the twelve patients. Local application of the toolkit has been successful in these instances, and there is no evidence of widespread dissemination of these resistant organisms’ ( 5.9).

In October 2020, this toolkit was updated and published as a new document ‘ Framework of actions to contain carbapenemase-producing Enterobacterales that also draws on Livermore’s research ( 3.6) . This update was in response to the published evaluation reports ( 5.7, 5.8) and feedback from key stakeholders requesting one document in a simplified format that provides a framework of actions for all health and social care providers in acute and non-acute settings. The objectives of the new framework are the same namely 1) to provide a framework of actions and tools to support health and social care providers 2) support development of local guidance and tools for the early detection of CPE with the aim of preventing transmission and containing their spread for the safety of patients and the wider population 3) direct health and care professionals to the relevant guidelines for laboratory methods, including reporting of results to PHE. The original Acute trust toolkit for the early detection, management and control of carbapenemase-producing Enterobacteriaceae has also been used to develop similar, specific toolkits for Scotland in 2017, Wales in 2018 and for non-acute and community settings in England 2019 ( 5.6). Finally, in 2020 the Department of Health and Social Care changed its policy on notifiable diseases stating ‘ Acquired carbapenemase-producing Gram-negative bacteria to the list of causative agents which, when identified in a human sample, must be notified by the operator of a diagnostic laboratory to Public Health England (PHE)’ ( 5.10).

The results of the UEA led CONCEPTT trial, published in 2017, have been translated into new national and international policy and practice that are having positive impacts on the care of pregnant women with type 1 diabetes, delivering substantial health benefits for those mothers and their babies. In the UK, the NHS anticipates significant cost savings, with reduced pressure on antenatal services, maternity wards, and neonatal intensive care units as well as improved patient experiences.

Changes to National Policy and Guidelines

The NHS accelerated CGM implementation pathway [A, B, C]

Based on the CONCEPTT results, National Health Service England (NHSE) have, in their Long Term Plan [Source A (i)], incorporated an accelerated implementation pathway, with funding for CGM (GBP2,000 per pregnancy) allocated to local maternity services starting from 01 November 2020. Local maternity services must now make CGM available to all pregnant women with type 1 diabetes by March 2021:

“...all pregnant women with type 1 diabetes will be offered continuous glucose monitoring, helping to improve neonatal outcomes.” [Source A (ii) page139]

Among pregnant women with diabetes, the risks of infection and of stillbirth are influenced by the quality of glucose control. CGM improves maternal glucose levels during pregnancy and because live CGM data are remotely shared with healthcare providers, CGM assists patients and healthcare providers in adjusting diabetes treatment during virtual appointments, which is particularly important for safely managing pregnant women during the COVID19 pandemic. The LTP FAQs clearly set out the neonatal health benefits citing the CONCEPTT findings. [Source A (iii) page151]

Similar changes to healthcare policy with ring-fenced CGM funding for all pregnant women with type 1 diabetes to be offered CGM have been introduced in Wales [B] and in Scotland [Source C]. A Technology Evidence Appraisal from NHS Wales reported that CGM use improves glycaemic control and reduces the incidence of pre-eclampsia in the mother, and reduces neonatal hypoglycaemia and the need and duration of neonatal intensive care stay for the baby [Source B (ii)]. NHS Trusts in England and Wales must now adopt this guidance [Sources A, B].

Equality and health inequalities impact assessments to ensure widespread digital inclusion for equitable implementation of CGM for all pregnant women with type 1 diabetes are now underway across all NHS regional maternity networks [Source A (iii)].

Changes to NICE Guidelines [D]

In the wake of the publication of the CONCEPTT findings, multiple professional and patient organisations called for a review of NICE Guidelines. These included the Royal College of Obstetricians and Gynaecologists; the Royal College of Physicians and Surgeons of Glasgow; the Association of British Clinical Diabetologist; the Diabetes Technology Network; Diabetes UK, the Juvenile Diabetes Research Foundation (JDRF) and INPUT Patient Advocacy. NICE issued the following statement:

“There is new evidence on continuous glucose monitoring. In particular, the CONCEPTT trial has published which experts deem to be a landmark trial that provides the best available evidence for the foreseeable future. The CONCEPTT trial found improvements in a range of neonatal outcomes with continuous glucose monitoring… and advocates routine usage in pregnant women with type 1 diabetes.” [Source D(i)]

The NICE guideline review, published December 2020 [Source D (iii)], states that, based on high quality randomised controlled trial data (taken from the CONCEPTT trial), continuous glucose monitoring (CGM) resulted in

• More pregnant women achieving the blood glucose targets

• Fewer caesarean sections

• Fewer neonatal intensive care unit (NICU) admissions

The current NICE guideline now states:

“Offer continuous glucose monitoring (CGM) to all pregnant women with type 1 diabetes to help them meet their pregnancy blood glucose targets and improve neonatal outcomes.” [Source D (ii)]

Patient organisations [E]

These national policy and guideline changes are strongly endorsed by patient organisations including Diabetes UK, who issued a Position Statement recommending that, for pregnant women, “ real-time CGM with alarms should be considered as first-line therapy” [Source E (i)] and the Juvenile Diabetes Research Foundation (JDRF) who stated that:

“The provision of CGM will help keep mothers and their babies healthy, and will help set world standards for the provision of medical technology for pregnant women with type 1 diabetes.” [Source E (ii)]

Cost and Other Resource Benefits to the NHS [B, F]

Initial cost modelling estimates by NHS Wales point to immediate savings of GBP1,029 per pregnancy from the reduction in neonatal intensive care requirements [Source B (i)]. A budget impact model (conducted by the CONCEPTT team and CGM device manufacturers) has estimated that the annual saving to the NHS from managing type 1 diabetes pregnancy using CGM will be in the region of GBP9,500,000 annually (with current costs running at close to GBP24,000,000, and those post implementation at just over GBP14,000,000) [Source F].

Driving Change in Policy and Practice Overseas [G, H, I, J]

Based on the CONCEPTT results, because of the low use of CGM prior to 2019, time-in-range glucose targets for CGM use are being introduced into clinical research and into policy and practice frameworks for managing diabetes during pregnancy internationally [Source G (i)]. CGM time-in-range is the only glucose outcome measure that both reflects patients’ priorities and can be used to quantitatively evaluate treatment efficacy.

Furthermore, research funders now recognize CGM time-in-range as a primary outcome measure in national and international type 1 diabetes pregnancy clinical trials [Source G (ii)].

In the USA, CGM use in type 1 diabetes pregnancy has increased from 17% to 36% [Source H (i)], and was endorsed by the 2020 American Diabetes Association (ADA) standards of care, which stated that CGM can help achieve glucose control targets, reduce macrosomia (excessive birth weight) and neonatal hypoglycaemia [Source H (ii]).

In Australia, eligibility for fully subsidised continuous glucose monitoring was expanded under the National Diabetes Services Scheme in 2019 to include: women with type 1 diabetes who are pregnant, breastfeeding or actively planning pregnancy. On 1^st March 2019, the Hon. Greg Hunt, Minister of Health, stated:

“Funding over the next five years will assist 37,000 eligible Australians with type 1 diabetes through the expansion of the Continuous Glucose Monitoring (CGM) Initiative.” [Source I]

Likewise, in Sweden, the use of CGM is now reimbursed both before pregnancy and as part of routine antenatal care:

“In Sweden, the use of CGM is reimbursed in type 1 diabetes outside of pregnancy if adequate glucose control is not achieved by conventional methods, and for all women in pregnancy.” [Source J]