CF AMR Syndicate | Virtual Symposium

Virtual symposium for lung infections and exacerbations on diagnostics

Meeting report

Executive Summary

The CF AMR Syndicate aims to accelerate the translation of CF antimicrobials and diagnostics to the clinic, bringing better treatment options to people with CF, faster To this end we worked with the community to develop a suite of draft diagnostic target product profiles (TPPs) describing new diagnostics needed to better manage lung infections and exacerbations. The TPPs were developed through extensive stakeholder engagement, including a survey whose results showed good consensus across the TPP characteristics and focus outlined. Several key areas for further discussion were identified to inform the final TPP guidance document (due out 2024) and shape the research agenda.

On the 6th of December 2023, the CF AMR Syndicate held a virtual symposium on diagnostics. Convening diverse expertise from the clinic, academia, industry, alongside people with CF, the event provided a platform to discuss the critical issues facing the CF community and how they can be addressed. Discussions focused on the three areas of unmet need addressed by the TPPs (exacerbation management, pathogen detection/ identification and antimicrobial susceptibility testing), as well as challenges with current practice and future research and opportunities. The main key challenges and opportunities identified for consideration in diagnostic research and development were:

1 Current clinical practice is informed by legacy data pre-dating Highly Effective Modulator Therapy (HEMT) and needs to adapt alongside an evolving CF population. Most notably, there’s an urgent need for technologies utilising novel sample types, reducing the reliance on sputum.

2 Current diagnostic tests for infections in CF only provide part of the clinical picture. New tests are needed to inform clinicians when and what intervention is required in the context of an infection and/or exacerbation.

3 The collection and storage of a range of CF relevant biospecimens, and associated metadata, is needed to help drive research and development efforts.

4 There is a call for a more personalised approach to care, transforming current clinical practice to enable more agency, joint decision-making and the delivery of personalised solutions on a case-by-case basis.

5 Interdisciplinary collaboration between researchers, clinicians, and industry partners, integrating perspectives of people with lived experience of CF throughout the development process, will help ensure that new diagnostics address the needs and priorities of those with the condition.

Target Product Profile development process

The CF AMR syndicate has engaged a broad range of experts across the CF field, including people with lived experience, and industry experts, to understand the unmet diagnostic needs for managing lung infections and exacerbations, and develop target product profiles (TPPs) addressing these needs.

High level TPPs were drafted, and characteristics refined through extensive stakeholder engagement and a survey to drive consensus. Survey results demonstrated consensus across the key considerations, value propositions and characteristics for each TPP. Discussion outputs from the symposium have helped further refine the TPP guidance document, which will be published and disseminated widely in 2024.

Needs and priorities of people with CF

At the symposium, Simon Bell described his experiences of lung infections as a person living with CF. Alongside discussions held across the different break out rooms at the symposium, the following themes for consideration emerged around the needs and priorities of people living with CF:

• The introduction of HEMT has increased diversity within the CF population. Researchers and innovators need to ensure that representation in both clinical trials and research considers the variation in the population with respect to treatment regime, health status, comorbidities, polypharmacy and age.

• The significant number of people with CF who are unable to take HEMT continue to require complex treatment on a daily basis. This treatment regime escalates in response to exacerbations, adding lengthy courses of additional treatment which may be undertaken at home or under a hospital admission. It is important that the needs of this group are considered alongside those benefitting from HEMT who may still experience this acute response, but less frequently.

• The diversity within the CF population demands a personalised approach to care. People with CF are experts in their own condition through continuous self-monitoring, self-management and self-care. Their tolerance and acceptance of diagnostic procedures will be determined by their health status i.e. people experiencing stability of health on HEMT may be less accepting of diagnostic procedures that are unpleasant, burdensome or hard to tolerate during periods of ‘good’ health.

• The familiar symptoms of lung infections and exacerbations have changed, or become absent, for many individuals taking HEMT, but there is concern and anecdotal evidence that infections are persisting and going undetected. For everyone with CF, whether on HEMT or not, the lack of confidence in current diagnostic approaches highlights the demand for accurate, repeatable diagnostic methods that would inform timely treatment decisions, reducing the impact and damage of persistent infection and treatment side effects.

Pulmonary Exacerbations

Current practice and challenges

There is no agreed definition of a pulmonary exacerbation. The CF population can be divided into frequent or infrequent exacerbators, on a stable or progressive disease trajectory, with lung function not always a determinant of exacerbation frequency. Within a heterogenous CF population differing exacerbator subtypes exist, with multifactorial drivers of exacerbations including disease trajectory, infective and inflammatory change, adherence to treatment, and psycho-social factors all contributing to variable presentations.

• Current treatment approaches for managing exacerbations are based on old pre-HEMT data. With the increasing recognition that varied exacerbator subtypes exits, there is a growing concern on the overuse of antibiotics which are commonly prescribed without full understanding of cause.

• A more nuanced approach to managing exacerbations is needed. Reframing exacerbations to consider them as deviations from baseline clinical stability could lead to earlier detection and intervention, subsequently reducing the likelihood of irreversible lung damage.

• The lack of a definition on what an exacerbation is and the variability in criteria and presentation poses a challenge for identifying ideal biomarkers to aid detection.

Future research and opportunities

• Characterisation of exacerbation subtypes based on cause and disease trajectory will help to identify biomarkers of prognosis. In addition, large scale, high quality, interventional studies to identify optimal treatment strategies based on exacerbation subtypes are needed.

• The field needs predictive tools which collate an array of clinical, inflammatory, and microbiological information onto a single platform working in a synchronised, holistic way to deliver real time information to enable more timely diagnosis of exacerbations and better management.

• People with CF would like to see a move to passive methods of monitoring which do not add to their existing burden of care. Digital tools that collect data such as heart rate, temperature, changes in exercise performance, and integrate algorithms that identify patterns and deviations from ‘norms’ could prove useful. Not only could they support individuals with CF to understand their own baseline, such tools could also have utility in triaging individuals to seek assistance when deviations do occur.

Pathogen Detection and Identification

Current practice and challenges

Current practise for pathogen identification involves positive culture from sputum. The availability of expectorated sputum has largely decreased with widespread HEMT use among people with CF. There is now a greater reliance on induced sputum sampling and/or other sampling methods in those unable to expectorate sputum on demand.

• There is a need for education on what constitutes a ‘good’ sputum sample, due to changes in volume, appearance, colour and consistency for many on HEMT.

• There is no standardised protocol on performing sputum induction, and the length of time it takes to perform in a clinic setting is a barrier to collection.

• A large proportion of currently stored clinical samples and data date back to the pre-HEMT era, reflecting airways chronically infected with high loads of pathogens such as Burkholderia spp. and Pseudomonas aeruginosa. There is uncertainty on how reflective these samples are of the airways post HEMT, meaning samples representative of the current clinical situation are unavailable for research and development.

• There is a limited understanding of when detection of problematic CF pathogens requires clinical intervention. Also lacking is an understanding on the ideal frequency of sampling necessary for surveillance.

Future research and opportunities

• Identifying biomarkers of active infection, such as host inflammatory markers or pathogen biomarkers, could allow discrimination of infections requiring clinical intervention from colonisation. Studies measuring a broad range of potential biomarkers could enable the selection of the best biomarkers for infection state. These biomarkers could be used in research to track the course of infection and to better understand prognosis.

• Longitudinal studies investigating the optimal sample types for detecting both pathogens and biomarkers of host response will facilitate the development of new tests that can improve clinical decision-making without a need for sputum.

• Quantitative pathogen identification molecular tests could be more widely used in research to investigate clinically relevant thresholds in pathogen load for starting and stopping treatment. Additionally, greater use of quantitative tests to support monitoring of treatment response in the context of long, arduous treatment regimens such as for Non-Tuberculous Mycobacteria (NTM) related infections.

• Alternative, and non-invasive sample types to detect pathogen presence and host markers of infection will need to be determined and validated across all CF populations. Tests that detect infection biomarkers at relevant concentrations using accessible, non-sputum samples, should be prioritised.

• As circulating pathogens evolve over time across the CF population and within an individual, diagnostic tests will need to evolve in parallel to remain relevant and accurate.

Antimicrobial Susceptibility Testing

Current practice and challenges

There is a lack of confidence in AST reliability and uncertainty around the clinical utility of the data, with many studies having shown little association between AST data and clinical outcomes.

• Limitations on the use of AST include poor reproducibility, slow time for real-time clinical decision making and failure to predict clinical outcomes due to potential mismatches between the in-vitro testing environment and the CF airway environment.

• In current clinical settings, AST has a role in the management of NTM infection via genetic testing to determine macrolide sensitivity and guide treatment selection.

• AST data are required to evaluate the rationale for accessing third- and fourth-line antimicrobials as they become available.

• AST should not be considered in isolation but as part of the wider clinical picture.

• The inadequate pharmacokinetic (PK) and pharmacodynamic (PD) characterisation of antimicrobials in CF may be limiting optimal dosing of currently available treatments. There is also a lack of PK/PD data for nebulised antibiotics in the CF lung.

Future research and opportunities

• Repeat studies on the utility of AST are required as there may be changes in the CF airway following HEMT that allow better drug exposure at the target site. Research is also needed to understand, which infections which would benefit from AST data to steer treatment decisions.

• PK/PD studies are needed to understand how different antibiotics behave in a CF lung. In addition, a personalised approach to optimising dosing strategies paired with AST data and linked to relevant markers of response to infection may improve treatment outcomes.

• The development of PK/PD models that mimic the CF lung environment can help determine suitable breakpoints and better predict clinical outcomes.

• AST needs to evolve with advances in treatment, including the development of companion diagnostics to support emerging novel therapeutics such as phage and anti-virulence programmes.

Key Considerations for the Field

Cross-sector engagement to enhance diagnostic development

• Engaging and involving people with CF in the development of diagnostics is critical to ensure acceptability and tolerability. Where possible engagement and involvement activities should not be disruptive to activities of daily life. Through CF networks, including organisations like Cystic Fibrosis Trust, innovators can access insights from people with CF, connect with clinicians and other relevant stakeholders to engage in further discussions about the clinical care pathway and diagnostic needs. It is important to ensure broad representation when engaging with an increasingly diverse CF population, as described earlier.

• Innovators have an opportunity to access some well-established CF academic and clinical networks. Via these networks, innovators can access expertise to support with trial design and delivery of studies that are sufficiently powered, and more likely to be successful.

• There is an opportunity for researchers and innovators to collaborate with those working on other chronic respiratory conditions to share knowledge and advance the translation of diagnostics. Although many solutions developed for use in CF will have applications in related conditions, e.g. bronchiectasis, there are key differences in these patient groups. Engagement exercises should involve patients affected by the disease being targeted.

• There is an opportunity for collaborating with biomedical engineers who come uniquely positioned to employ creative problem-solving skills to address challenges in healthcare and medical technology.

• Engaging with regulatory agencies, clinical trial support teams, clinical statisticians, and methodologists throughout the diagnostic development process will help guide appropriate and methodologically sound research and development steps to generate the best quality evidence for assessment or adoption.

Biobanking

• Going forward, opportunities to build and strengthen prospective collections of CF relevant bio-samples and associated metadata should not be missed. To minimise burden to individuals, sample collection can be undertaken as part of annual assessment clinics, ensuring any excess samples are stored for research and not discarded. These biomaterials and data can be used for defined, or as yet undefined research priorities by researchers in academia and industry, be it for longitudinal studies, clinical trials and more.

• CF clinicians are encouraged to proactively engage people with CF in discussions about the benefits of biobanking and future research studies to benefit the CF community.

Sampling

• Sputum volume and appearance has changed for many individuals on HEMT. Education and clear messaging on what constitutes a good sputum sample in the post HEMT era would help manage expectations for people with CF and their clinical teams.

• There is a call for a clear, simple protocol for sputum induction for individuals unable to expectorate sputum on demand. The protocol could be made widely available and potentially incorporated into the CF standard of care guidelines.

• Given the uninterrupted mucociliary clearance overnight, the first cough/clear of the day may be enriched with lower airway pathogens and could offer a value sample type for collection.

Diagnostics in other disease areas: lessons from CF

• Diagnostics developed for CF lung infection could be deployed to other disease areas. Biomarkers developed for the detection of active P. aeruginosa in CF for example could be useful in other patient groups with clinical vulnerability to the same pathogen such as bronchiectasis, primary ciliary dyskinesia, chronic obstructive pulmonary disease and cerebral palsy.

• Attracting commercial interest in diagnostic development can be challenging. Small companies in particular face multiple challenges related to funding and market uptake. This can limit innovation in the rare disease space. CF is a well characterised condition, with strong clinical, research, and charity support available. Harnessing this support can help drive advances in diagnostics that can be deployed across other indications with larger populations.

Concluding remark

There is a growing drive to move healthcare from managing illness to maintaining health. This paradigm shift requires a holistic approach to healthcare and novel methods to monitor changes in health measures. This approach is already underway in CF care, providing learnings that can be applied across other disease indications.

The CF AMR Syndicate will continue to bring the community together to identify ongoing promising research and drive impactful collaborations to address the areas of need identified.

Acknowledgements

The Diagnostic TPP Project Team

Lorna Allen

Cystic Fibrosis Trust

Paula Sommer

Cystic Fibrosis Trust

Rachel Dakin

LifeArc

Rebecca Holmes LifeArc

Connie Takawira

Medicines Discovery Catapult

Neill Gingles

Medicines Discovery Catapult

Kile Green

Newcastle In-vitro Diagnostics Cooperative

Nicola Howe

Newcastle In-vitro Diagnostics Cooperative

We would like to thank all the CF experts including people with CF, academics, clinicians, specialist nurses, physiotherapists, microbiologists, as well as industry experts who attended the event for their rich contributions.

A special thank you to the speakers and chairs at the event:

Simon Bell

Mark Sutton

Paul McNamara

Julian Forton

Michael Tunney

Jane Davies

Adilia Warris

Charlotte Addy

Katherine Cowan

Burden

The physical, emotional, social and financial problems that can be experienced by people with CF and their carers, which can be caused by demanding treatment, testing, physiotherapy and nutritional regimes.

Highly Effective Modulator Therapy (HEMT)

Medication which improves CF transmembrane conductance regulator (CFTR) protein functioning leading to marked improvements in symptoms. CF disease can be caused by different mutations, and not all pwCF can benefit from modulator therapy.

Pulmonary exacerbation

A temporary worsening of lung function due to infection and/or inflammation.

Expectorated sputum on demand

Type of coughing and other airway clearance techniques that allow mucus to move away from the lungs so that patients may expectorate it.

Target Product Profiles (TPPs)

Outlines the desired ‘profile’ or characteristics of a product that is aimed at a particular disease or diseases. TPPs state intended use, target populations and other desired attributes of products, including safety and efficacy-related characteristics required for a test to add value to the system.

Appendix 2 – Delegates

Name Surname

Role & affiliation

Area of Expertise

Lorna Allen Involvement Manager, CF Trust Advocating and collating lived experience

Lucy Allen

Joy Allen

CF Trust

CF Trust

Health Economics manager, Roche Test evaluation expertise

Stuart Angell Regulatory Affairs Programme Lead, BIVDA

Daniel Beever

Person with CF

Tiffany Burnett Science Director, Cystic Fibrosis Foundation

Miguel Camara Microbiology Scientist University of Nottingham

Elizabeth Crone

Head of Business Development, Europe, Owlstone

Rachel Dakin Clinical Development Manager, LifeArc

James Davis

Person with CF

Jamie Duckers CF physician

Patrick Flume Physician

Jo Fothergill Microbiologist, University of Liverpool

Hannah Gales Person with CF

Naomi Gibson Scientist, Medicines Discovery Catapult

Neill Gingles Lead Scientist

Nick Gompertz CEO Ear-Switch Ltd

Chris Gorini Director Pulmonary GI and Therapeutics, Cystic Fibrosis Foundation

Doreen Grech Staff member Cystic Fibrosis Foundation

Kile Green Newcastle MIC – Senior IVD Methodologist, University of Newcastle

Regulatory Affairs

Lived experience, health research

Anti-Infective, Drug Development Expertise

Biomarkers of infection, antimicrobial discovery and biofilm research

Sales of tools in scientific research, including biomarker and test development (breath) and antibodies for diagnostic use.

Involved in the clinical development of treatments and diagnostics, part of the CFF TPP team from LifeArc

Living with CF each day. Ineligible for Kaftrio

Clinical, trials, infection

Pulmonary exacerbations

Pseudomonas aeruginosa infection

CF patient

Diagnostic Assay Development

Research microbiologist by training

Former NHS doctor for 30 years (MRCP & last 21 years as a GP). MedTech innovator and developer of EarMetrics

Infection

Business Development

Mixed methodology and evidence generation for diagnostic development

Name Surname Role & affiliation

Ruchi Gupta Researcher, University of Birmingham

Abigail Halstead Person with CF

Chris Hodkinson Vice President of Business Development, Clinical Diagnostics company, Owlestone

Alex Horsley Professor of Respiratory Medicine, Manchester NHS Trust

Beverley Isherwood PACE Director & Strategy Leader – Infectious Diseases, Medicines Discovery Catapult

Catherine Kettleborough Translational Challenge Leader LifeArc

Gabriel Lambert Head of Clinical Operations, Tidal sense

Area of Expertise

Biosensors, microfluidics

Lived experience. CF patient with chronic burkholderia gladioli infection

Diagnostic test development and commercialisation

CF clinical academic

Chronic Respiratory Infection portfolio lead

Medical technology (regulations, clinical studies, business development) and an internal medical doctor

John LiPuma Professor, CF airway microbiology

Dave Nichols Cystic Fibrosis Foundation

Jerry Nick CF physician, National Jewish Health

Kevan O’Connor Team member Cystic Fibrosis Foundation

CF clinician and researcher

Clinical care and research in CF-related NTM infection, biomarkers and exacerbations

Industry Partnerships and Investments

Alison Parry-Jones Wales Cancer Biobank Biobanking

Joanna Payne Molecular Diagnostics Assay Development for Randox Laboratories

James Preece Fluoretiq

Timothy Rawson Infectious Diseases and Medical Microbiology, Imperial College London

David Ribeiro CEO, ProAxsis Limited

Molecular diagnostics of infectious diseases - respiratory bacterial, viral and fungal arrays

Antimicrobial optimisation, technology solutions to address AMR

Lab diagnostics and point-of-care tests.

Shaun Robertson Innovation Research Fellow, University of Nottingham Microbiology & diagnostics

Paula Sommer Head of Research, CF Trust Patient Organisation Representative

Gemma Stanford Highly Specialist Physiotherapist, Royal Brompton Hospital Physiotherapy

Steven Tait LifeArc Business development

Tehelj Regulatory Affairs Officer, BIVDA Regulatory affairs

Catherine Ward CF Nurse Specialist

CF clinician and researcher

Breakout Discussion Topics

Prediction and management of exacerbations

Chairs: Charlotte Addy and Jane Davies

Diagnostics for pulmonary exacerbation encompasses potentially a varied range of modalities bringing together the aggregate criteria typically used to clinically evaluate whether or not an individual is experiencing an acute exacerbation. This breakout session aims to discuss:

Session 1: Where are we now?

1 What are the markers that diagnostic developers should consider targeting for tests to predict and manage pulmonary exacerbations?

2 What could be the ‘quick wins’ in terms of development of new tests OR integration of pre-existing tests for PEx detection and management?

3 What priority research studies are required to provide better guidance and enable diagnostic development in this area (e.g. better understanding of relevant PEx biomarkers across different patient groups).

Antimicrobial Susceptibility Testing

Chairs: Mark Sutton and Paul McNamara

Session 2: Where are we going?

1 How do we engage the community in the co-design of new diagnostics, from first inception to implementation?

2 Considering new and potential advances in technology, where do we want diagnostics in this area to be 10 years from now?

3 How might some of the diagnostics discussed here be deployed across other disease indications such as bronchiectasis?

There remains a paucity of evidence demonstrating the clinical utility of antimicrobial susceptibly testing in chronic CF infections where the context is a polymicrobial community. This breakout session aims to discuss:

Session 1: Where are we now?

1 What are the key issues with current antimicrobial susceptibility testing that limit its use in the management of CF infections?

2 What improvements to AST would provide meaningful treatment management outcomes moving away from empiric antibiotic prescription?

3 What priority research studies are required to provide better guidance and enable diagnostic development in this area?

Session 2: Where are we going?

1 How do we engage the community in the co-design of new diagnostics, from first inception to implementation?

2 Considering new and potential advances in technology, where do we want diagnostics in this area to be 10 years from now?

3 How might some of the diagnostics discussed here be deployed across other disease indications such as bronchiectasis?

Pathogen Detection and Identification

Chairs: Adilia Warris and Michael Tunney

Rapid detection of key CF pathogens is crucial for enabling prompt and timely initiation of appropriate clinical action (e.g. minimise risk of cross infection, initiation of eradication therapy etc). A key challenge for individuals who are unable to expectorate sputum on demand (some paediatric populations and some individuals on modulators) is finding the most representative non-invasive alternatives. Furthermore, the microbiology of circulating pathogens has been shifting with new strains of pathogens detected whose virulence and transmissibility is yet to be determined. This breakout session aims to discuss:

Session 1: Where are we now?

1 What is missing from current pathogen detection and identification practise that would improve clinical decision making (e.g treatment, surveillance)?

2 What short term advances in pathogen detection and identification would have immediate impact based on current clinical practice?

3 What research questions would you prioritise to guide future diagnostic development in this area (e.g. non-sputum/novel sample types, better understanding of how CF microbiology has changed post-HEMT, biomarkers)?

Session 2: Where are we going?

1 How do we engage the community in the co-design of new diagnostics, from first inception to implementation?

2 Considering new and potential advances in technology, where do we want diagnostics in this area to be 10 years from now?

3 How might some of the diagnostics discussed here be deployed across other disease indications such as bronchiectasis?