Slides from meeting held at ERS 2016 in London, UK with Biomarkers and Severe Asthma REG Working Groups

1. SEVERE ASTHMA /
BIOMARKERS JOINT
WORKING GROUP
MEETING
DATE: Saturday September 3RD
TIME: 14.45 –16.00
VENUE: Royal College of General Practitioners;
30 Euston Square, London, UK
Co-chairs: Leif Bjermer & Rohit Katail

2. Agenda
14.45-14.50 Welcome / Introduction Leif Bjermer, Rohit Katail
(Biomakers & Severe Asthma WG Leads)
14.50–14.55 On-going Biomarkers Project
– GINA / NICE FeNO Editorial Kjell Alving
14.55–15.05 Severe Asthma Working Group Walter Canonica, Nikos
– Motivation; Addressing a Need Papadopoulos, Rohit Katail
15.05–15.50 A Global Severe Asthma Registry
a joint Biomarkers / Severe Asthma project
15.05–15.10 • REG’s potential role David Price
15.10–15.25 • What currently exists…?
– Example 1: Italy (SANI) Walter Canonica
– Example 2: UK Andrew Menzies-Gow
15.25–13.35 • A Global ‘Blue Print’ Victoria Carter
15.35–15.50 • Group Discussion All
15.50–16.00 Any Other Business / Open Discussion / Project Brainstorm

3. WELCOME INTRODUCTION
FIRST BIOMARKERS / SEVERE ASTHMA
WORKING JOINT WORKING GROUP MEETING
LEIF BJERMER & ROHIT KATAIL
14.45–14.50PM

4. BIOMARKERS WORKING GROUP PROJECTS
GINA/NICE FENO COMMENTARY
KJELL ALVING
14.50–14.55PM

5. Differences between NICE & GINA statements
on FeNO (focus on inflammometry)
• Draft developed & circulated August 2015
o Adaptation of a letter to the Editor of ECRJ (in 2014)
• Reviewed at Biomarkers’ Working Group Meeting at the ERS (Sept
2016)
• Originally targeted at npj Primary Care Medicine
o ERS Meeting – decision to “aim higher”
o New target = Lancet Respiratory Medicine
• Formatted as a Commentary and submitted to LRM February 2016;
o Rejected: "Many thanks for submitting your manuscript to The Lancet Respiratory
Medicine. Several editors here have discussed the manuscript, but their decision was
that it would be better placed elsewhere.”

6. Differences between NICE & GINA statements
on FeNO (focus on inflammometry)
• Formatted as Correspondence to the ERJ; submitted March 2016
• Rejected: This letter has been assessed by external reviewers and the editorial
board. Although it raises some interesting points, it was considered to add little
to the debate while some other important aspects of this topic were missing.
• Reviewer 1:
– This is a very well written Letter on a timely topic in asthma
– Reads as though FeNo and blood eosinophilic counts are the only biomarkers which should be included in
the guidelines for asthma management. Suggest
§ Change the title in the current form, being more specific, or
§ Add a table with the most promising (serum) biomarkers for asthma management, to give an idea of
the complex panorama in this field.
• Reviewer 2:
– The authors initially complain that guidelines are driven by RCTs and should be driven by more real world
studies. This argument does not really advance their hypothesis as we lack real world studies for the use of
this technique
– There is an additional consideration of cost and availability in terms of real world implementation
– Spirometry is a poor method for assessing asthma but at least it brings well developed standards and
reproducibility
– Agree with the need for more refined biomarkers for management of all airways disease but the practical
aspect is the challenge of showing efficacy in RCTs and then bringing it into clinical practice.
– Refer to the most recent Cochrane review on this topic

7. Differences between NICE & GINA statements
on FeNO (focus on inflammometry)
• Next…?
o Incorporate a table of promising biomarkers (as per ERJ
Reviewer 1’s suggestion)
– “Reads as though FeNo and blood eosinophilic counts are the only
biomarkers which should be included in the guidelines for asthma
management. Suggest adding a table with the most promising (serum)
biomarkers for asthma management, to give an idea of the complex
panorama in this field.”
o Reformat for Respiratory Medicine

8. Developing a table of promising biomarkers
• What biomarkers should be listed in a Table – 6-8 markers?
• Any other changes / suggestions?
# Biomarker Comment / Key Reference
1 ?
2 ?
3 ?
4 ?
5 ?
6 ?
7 ?
8 ?

9. REG SEVERE ASTHMA WORKING GROUP:
FULFILLING AN UNMET NEED
ROHIT KATAIL, NIKOS PAPADOPOULOS
& WALTER CANONICA
14.55–15.05PM

10. UK News Article: Telegraph 1 Sept 2016
Asthma deaths reach highest level for decade
Deaths from asthma have risen 21 per cent in a year to reach
their highest figure in a decade, a charity has warned.
Asthma UK said 1,468 people died from asthma attacks in the
UK last year. The charity called for better implementation of
digital health technology to help sufferers manage their illness.
“The alarming increase in asthma deaths over the last decade is
an urgent wake-up call to the Government to take action to
improve standards of asthma care now,” said Kay Boycott, chief
executive of Asthma UK.

11. DEVELOPING A GLOBAL
SEVERE ASTHMA REGISTRY
15.05–15.50PM

12. EFPIA-EBE-VE Position
on Patient Registries
• Background & Context:
o European Commission (EC) and European Medicines Agency (EMA)
have supported initiatives to enhance the utility of registries.
o Recent completion of the PARENT JA, revision of Good
Pharmacovigilance Practices Module VIII on PASS
o Guidance on the scientific aspects of PAES in draft
o Launch of EMA’s Patient Registries Initiative
• Principles:
o Timely to define a vision and principles regarding the development of
the registry infrastructure and use of registry data to address
research questions.
o There are other fundamental challenges to the successful conduct of
all methods of real world evidence generation that need to be
addressed.

13. EFPIA-EBE-VE Position on
Patient Registries: Vision (I)
• Patient registries should be maintained as a core part of the health
information infrastructure:
o Supporting healthcare systems to deliver quality care
o Providing a high quality research platform for the life science sector
• Long-term registries and networks should be established for priority
diseases independently of specific product approval and
reimbursement processes.
• When new medicines are launched, these patient registries, linked
through international networks, should be used to address
outstanding research questions of Regulators, HTA bodies, Payers
and Clinicians.
• Increasing consistency, quality and therefore confidence in the
evidence derived from such registries and networks should lead to
greater use of registries in support of innovative, adaptive pathways
of drug development, assessment, managed entry and lifecycle
monitoring of benefit and risk.

14. EFPIA-EBE-VE Position on
Patient Registries: Vision (II)
• The regulatory framework for the creation and maintenance of a
patient registry should be defined separately from that for studies
• The creation and maintenance of a health service or disease
based patient registry should not be considered a study.
• Registries that require primary data collection from patients should
be classified as interventional or non-interventional consistently; if
considered to be interventional, they should be designed as fixed
studies rather than on-going registries.
• Clear rules for ethics approval, data privacy and consent regarding
registries must be established and applied consistently across
Member States.

15. EFPIA-EBE-VE Position on
Patient Registries: Vision (III)
• National level patient registries should ideally be funded by
healthcare systems. Industry … should be made via Public Private
Partnerships wherever possible.
• Distributed health data networks should be used to connect
individual registries; individual registries should be incentivised to
join such networks.
• Wherever possible, individual registries should apply common
standards and definitions for disease outcome data.
• There should be a clear process for researchers to access registry
networks.
• The cost of research access should provide sustainable funding but
not create a barrier to research.
• Specific stakeholders should define clear quality standards expected
of a registry/ registry network for it to be considered suitable to
address the research objectives of that stakeholder.

16. REG’s potential role: “steerage”
• Identification of
• Current registries around the world (and gaps)
• Potential national leads for a global collaboration
• Review:
• Data fields / variables within existing registries for completeness
• Develop:
• Develop a list of registry variables:
• Core: must be common to all;
• Supplementary variables: beneficial in addition to core
variables, where feasible
• Algorithms to identify “Severe Asthma” patients from within
existing clinical records

17. Existing registries: some examples
• Severe Asthma Network in Italy (SANI)
o G. Walter Canonica
• British Thoracic Society Severe Asthma Registry, UK
o Andrew Menzies-Gow

19. – Observatory/Registry
with a unique informa7c Pla;orm (previously tested in a Regional Network)
Severe Asthma Pts in the Reference Centers Network
working with the same criteria and data collec7on
& possible interac7ons with similar ini7a7ves ( i.s.RASP-
UK)
– Monitoring Adherence to Treatment
– Unmet Needs
Scopes

20. Step 1
Recruitement
GINA, SIAAIC & SIP/IRS
Network of Severe Asthma
Reference Centers
Criteria
derived from the
Interna7onal Excellence Center Network
(es. )

21. REFERENCE CENTERS

22. ERJ 2014
Defini7on ERS /ATS

23. MASS TARGET
ASTHMA
THERAPY
GINA
GUIDELINES
TH2 HIGH
TH2 LOW
STRATIFIED
ASTHMA
PHATOGENESYs
PERSONALIZED
ASTHMA
THERAPY
Omalizumab
Mepolizumab
Reslizumab
Dupilumab
Lebrikizumab
Tralokinumab
Pitrakinra
Brodalumab
α TSLP (AMG 157)
α CRTH2
PREDICTIVE
BIOMARKERS
of RESPONSE
AIT-Allergen ImmunoTherapy ICS
SABA
LABA
LAMA
AnHLTRs
OCS
Chromones
Macrolides
Biomarkers
Anrukizumab
Benralizumab
Ligelizumab
Quilizumab
Bagnasco et al. Exp.Rev.Resp.Med. 2016

24. – DATA Collec7on for interac7on with
Regulatory Authori7es & Payers
– DATA Collec7on for pharmacoeconomic
evalua7ons
– DATA Collec7on & elabora7on for scien7fic
pubblica7ons
Scopes

25. A GLOBAL ‘BLUE PRINT’
SUPPORTING THE DELIVERY
VICTORIA CARTER

26. BTS Severe Asthma Registries

27. iHARP: 5,000 pa7ents over 8 countries
Chief Inves7gator: David Price
UK: Henry Chrystyn, John Haughney, Dermot Ryan, Kevin Gruffydd-Jones
France: Nicolas Roche, David Costa
Italy: Federico Lavorini, Alberto Papi, Antonio InfanQno
Spain: Miguel Román Rodríguez
Sweden: Karin Lisspers, Björn Ställberg
Australia: Sinthia Bosnic-AnQcevich
Norway: Svein Henrichsen
Netherlands: Thys van der Molen
5,000 moderate-severe asthma patients over 8 countries

28. Linking to OPCRD in the UK
Clinical Trial
Registries GP Demographics
Questionnaire
Hospital Data
PrescriptionsGP Diagnostics
Linking Multiple Data Sources : OPCRD
Clinical Trials
Registries
Hasehed ID:
Practice:
Data::
Visit:
12345
Z0001
Inhaler
Technique
05/2005
General Practitioner
Patient Reported
Hospital Referrals
Diagnostics
National Prescribing
Prescriptions
National
Prescribing
OPC Health Record
10/2010
01/2010
05/1991
04/2008
04/2008
07/2006
05/1972
05/2005
12345
Z0001
12345
12345
12345
12345
12345
12345
FeNO Reading
Spiromax Prescriptions
Asthma Diagnosis
Ventolin 100mcg
LRTI Referral
RCP Symptoms High
Practice Registration
Poor Inhaler Technique
Hashed NHS Number: 12345 Practice Code: Z0001
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Visit Date: Identifier Treatment / Prescription: Consent:
Hasehed ID:
Practice:
Data::
Visit:
12345
Z0001
Practice
Details
05/1972
Hasehed ID:
Practice:
Data::
Visit:
12345
Z0001
Inhaler
Technique
10/2010
Z0001
Spiromax
Prescriptions
Started
01/2010
Hasehed ID:
Practice:
Data::
Visit:
12345
Z0001
Asthma
Diagnosis
05/1991
Hasehed ID:
Practice:
Data::
Visit:
12345
Z0001
Ventolin
100mcg
04/2008
Hasehed ID:
Practice:
Data::
Visit:
12345
Z0001
LRTI
Referral
04/2008
Practice:
Data::
Visit:
12345
Z0001
RCP
Questions
07/2006
Hashed ID:
Practice:
Data::
Visit:
Finding a unique iden7fier to allow linkage to various longitudinal data sources

29. Lessons from iHARP
• Strong core delivery team
• Committed specialists
• Ethics set-up: country specific
• User friendly IT interface
• Data collection & feedback
• Do not limit to cross-sectional data
• Do not re-invent the wheel

30. REG Proposal for a Global Severe Asthma Registry
Key deliverables:
1) Establishment of a global registry & standardised coding
• Containing key data (common to all contribuQng naQonal databases) on
severe asthma paQents
2) Registry set up and data collec7on
• PotenQally building on exisQng naQonal registries (such as the BTS Difficult
Asthma Registry in the UK)
3) Long-term management & oversight of the global registry
• Data pre-populaQon and linking to primary care data systems to
automate/facilitate data entry

31. Dendrite Clinical Systems: Web based
• The system must be user friendly prevent duplication of data

32. Summary of Variables in the BTS Difficult Asthma Registry
Follow up: Annual Review
Pa7ent Details
Gender, Age, Ethnicity, BMI
etc
Medical History
ExacerbaQons, Episodes of invasive
venQlaQon, Atopic disease
Inves7ga7ons
Eosinophils, IgE, CT Scan, Bone
densitometry
Lung Func7on
FEV1, FVC, KCO, FENO, PC20
methacholine/histamine
Allergen Tes7ng
RAST posiQve, SPT posiQve, Perennial
allergen etc
Ques7onnaires
Asthma Control QuesQonnaire (ACQ7)
Euro-QOL-5D
Asthma Medica7on
Inhaled/oral steroids, LAMA, SABA,
adherence, corQsol & prednisolone
Systemic Assessment
Adherence, other contribuQng factors,
biologic therapy details

33. What currently exists globally?

34. Linking Primary & Secondary Care: A pilot in UK
• Using unique idenQfiers to link primary care data from OPCRD
• IdenQficaQon of severe asthma paQents managed in primary
care
• Expert algorithm from REG - encouraging appropriate referrals
to severe asthma clinics
• Pilot the linked data potenQal in Northern Ireland or interested
UK locality (Liverpool)

35. Our Collaborative Network
Observational & Pragmatic
Research Institute
• 600+ GP Prac7ces
• 2.7 million pa,ents
• 500,000 ques,onnaires
• 5,000 clinical reviews
• GP research network
• OPCSD: service database
Optimum Patient Care
Social Enterprise
Respiratory Effectiveness Group
Academic Partners
• 50+ Projects Delivered
• Opera,onal research
capabili,es
• Commercial access to OPCRD
• Clinical trial delivery support
• Bespoke data collec,on
• Primary care specialists
OPC Global
Research Solutions
• 140+ Publica7ons
• Interna,onal impact
• Observa,onal
research
• Pragma,c clinical trials
• Sta,s,cal exper,se
• Medical writers
• Interna7onal KOL’s
• 300 members
• 40 countries worldwide
• 14 working groups
• ADEPT ethics commiRee
• Academic access to
OPCRD
A group of independent companies collabora7ng together with the shared
goal to improve pa7ent management and overcome unmet medical needs

36. Severe Asthma Registries
Background: 5% of paQents have severe refractory asthma that
responds poorly or not at all to high-dose inhaled or systemic
glucocorQcosteroid treatment
Aim: Define and characterise clinical phenotypes in severe asthma
to facilitate research into the assessment and clinical
management
• Phenotyping of paQents
• EvaluaQon and opQmizaQon of treatment
• EvaluaQon of heterogeneity in diagnosis
• IdenQficaQon of comorbidiQes
• Understanding of underlying mechanisms of airway inflammaQon &
structural changes
• Development of effecQve and efficient diagnosQc rouQnes and
therapeuQc principles
• Development of novel and effecQve biologic-based therapies
• GeneQc profiling of paQents with asthma

37. REG Proposal for a Global Severe Asthma Registry
Key deliverables:
1) Establishment of a global registry containing key data (common to
all contribuQng naQonal databases) on severe asthma paQents
• PotenQally building on exisQng naQonal registries (such as the BTS Difficult
Asthma Registry in the UK)?
2) Registry set up and data collecQon support over Qme:
• Data pre-populaQon and linking to primary care data systems to
automate/facilitate data entry
3) Long-term management of the registry and making data available
to researchers

38. OPEN TO ALL COUNTRIES: REG TO UNDERSTAND GLOBAL
INTEREST
A LEAD AND PILOT IN EACH COUNTRY OF AZ INTEREST:
• USA: Rohit KaQal & NJH – Severe Asthma Working Group Lead
• GERMANY : Roland Buhl – German Severe Asthma Registry
(n= 463)
• UK: Liam Heaney, Andrew Menzies-Gow – UK Severe Asthma
Registry (n=770)
• FRANCE: Nicolas Roche?
• ITALY: Walter Cononica – SANI
• SPAIN: Marc Miravitlles, Joan Soriano
• AUSTRALIA: Sinthia Bosnic-AnQcevich & Woolcock InsQtute
REG Proposal for a Global Severe Asthma Registry

39. Apps
• PROs
• PEF etc.
Medical
History
Severe Asthma
Registry
Baseline
Assessment
Prospec7ve Data
Collec7on
Smart Inhalers
• Adherence
Asthma Reviews at Clinic
• Clinical assessment
• Biomarkers etc.
Primary Care Records
• MedicaQon
• ExacerbaQons
• ComorbidiQes
• Healthcare resource
uQlisaQon etc.
Secondary Care Records
• HospitalisaQons
• Healthcare resource
uQlisaQon
• QuesQonnaires
• Lung funcQon
• Biomarkers
• Allergen tesQng
• Op#onal blood
sample for
future gene#c
tes#ng?
Primary Care
Records
• MedicaQon
• ExacerbaQon
history
• ComorbidiQes
Secondary Care
Records
• HospitalisaQons
• Healthcare
resource
uQlisaQon
REG Proposal for a Global Severe Asthma Registry

40. BENEFITS TO…
Pa7ents
• PotenQal to improve paQent outcomes in short-term (through biomarker
profiling and smart technologies)
• Increase understanding of severe asthma to improve paQent care in long-term
Clinicians
• PaQent care:
• Improve characterisaQon (and over Qme, understanding of) severe asthma
to help guide clinical decision making
• Introduce smart technologies to facilitate paQent management in clinic
• Asthma registry pre-populated from exisQng clinical systems via anonymised
paQent idenQfiers
(in countries where feasible)
Researchers
• Access to a global registry of well-characterised severe asthma paQents
• Comprehensive retrospecQve medical history data combined with conQnued
prospecQve follow-up (in countries where feasible)
REG Proposal for a Global Severe Asthma Registry

41. A Working Example in the UK
BTS Difficult Asthma Registry: Web Based Registry: Dendrite
Clinical Systems
• 770 severe asthma paQents
• Maintaining paQent anonymity and confidenQality (safe and
secure)
• Time saving compared to paper-based systems
• PaQents consent to collecQon of data
• Data Controller is local hospital and Dendrite Clinical Services
UK Ltd.
• UK Severe Asthma Steering Group
• REG to review UK severe asthma registry fields for global use
• Limited by cross-secQonal nature – possibility to link in with
longitudinal primary care data: OPCRD

42. Linking Primary & Secondary Care: A pilot in UK
• Using pseudoanonymised unique idenQfiers (hashed NHS) to
link longitudinal primary care data from OPCRD with cross-
secQonal UK severe asthma registry.
• IdenQficaQon of severe asthma paQents in primary care
records, using expert algorithm from REG - encouraging
appropriate referral to severe asthma clinics
• Pilot the iniQaQve in Northern Ireland or interested UK
locality (Liverpool)

43. Summary of Variables in the BTS Difficult Asthma Registry
BASELINE
Pa7ent Details
• Gender, Age, Ethnicity, BMI, etc.
Medical History
• ExacerbaQons, Episodes of invasive venQlaQon, Atopic disease, etc.
Inves7ga7ons
• EOS, IgE, CT scan, bone densitometry, etc.
Lung Func7on
• FEV1, FVC, KCO, FeNO, PC20 methacholine/histamine, etc.
Allergen Tes7ng
• RAST posiQve, SPT posiQve, PosiQve to perennial allergen, etc.
Ques7onnaires
• Asthma Control QuesQonnaire (ACQ7), Euro-QoL-5D
Asthma Medica7on
• Inhaled/oral steroids, LAMA, SABA, Evidence of poor adherence, CorQsol and prednisolone levels, FeNO
suppression test, etc.
Systema7c Assessment
• Adherence, Other factors contribuQng to symptoms, Biologic therapy details, etc.
FOLLOW-UP
Annual Review
Bronchial Thermoplasty

44. REG Working Group Inputs
• Iden7fica7on of
• Current registries around the world (and gaps)
• PotenQal naQonal leads for a global collaboraQon
• Review:
• Data fields / variables within exisQng registries for
completeness
• Develop:
• Develop a list of variables for the registries
• Core: must be common to all;
• Supplementary variables: beneficial in addiQon to core
variables, where feasible
• An algorithm to idenQfy “Severe Asthma” paQents from
within exisQng UK primary care clinical records

45. Timelines
• Q4 2016
• Define core and opQmal variables
• Q1-Q2 2017
• Set up registry within the selected sotware system
• IniQate development of infrastructure to link with other
data sources, where feasible (paQent records, apps etc.)
• Q3 2017
• Release of registry
• First paQents in pilot countries/areas
• From Q1 2018
• Data access to researchers

46. GROUP DISCUSSION / FEEDBACK

47. ANY OTHER BUSINESS
– OTHER IDEAS FOR THE GROUP(S)
15.50–16.00PM