severe asthma and biomarkers working group meeting
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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
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
WELCOME INTRODUCTION FIRST BIOMARKERS / SEVERE ASTHMA
WORKING JOINT WORKING GROUP MEETING LEIF BJERMER & ROHIT KATAIL
14.45–14.50PM
BIOMARKERS WORKING GROUP PROJECTS GINA/NICE FENO COMMENTARY
KJELL ALVING 14.50–14.55PM
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.”
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
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
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 ?
REG SEVERE ASTHMA WORKING GROUP: FULFILLING AN UNMET NEED
ROHIT KATAIL, NIKOS PAPADOPOULOS & WALTER CANONICA
14.55–15.05PM
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.
DEVELOPING A GLOBAL SEVERE ASTHMA REGISTRY
15.05–15.50PM
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.
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.
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.
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.
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
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
– Observatory/Registrywithauniqueinforma7cPla;orm(previouslytestedinaRegionalNetwork)SevereAsthmaPtsintheReferenceCentersNetworkworkingwiththesamecriteriaanddatacollec7on&possibleinterac7onswithsimilarini7a7ves(i.s.RASP-UK)– MonitoringAdherencetoTreatment– UnmetNeeds
Scopes
Step1Recruitement
GINA,SIAAIC&SIP/IRSNetworkofSevereAsthma
ReferenceCenters
Criteriaderivedfromthe
Interna7onalExcellenceCenterNetwork(es.)
REFERENCE CENTERS
ERJ2014
Defini7onERS/ATS
MASSTARGETASTHMATHERAPY
GINAGUIDELINES
TH2HIGH
TH2LOW
STRATIFIEDASTHMA
PHATOGENESYs
PERSONALIZEDASTHMATHERAPY
Omalizumab
MepolizumabReslizumab
Dupilumab
LebrikizumabTralokinumab
Pitrakinra
BrodalumabαTSLP(AMG157)
αCRTH2
PREDICTIVEBIOMARKERSofRESPONSE
AIT-AllergenImmunoTherapyICSSABALABALAMAAnHLTRsOCSChromones
Macrolides
BiomarkersAnrukizumab
Benralizumab
LigelizumabQuilizumab
Bagnascoetal.Exp.Rev.Resp.Med.2016
– DATACollec7onforinterac7onwithRegulatoryAuthori7es&Payers
– DATACollec7onforpharmacoeconomicevalua7ons
– DATACollec7on&elabora7onforscien7ficpubblica7ons
Scopes
A GLOBAL ‘BLUE PRINT’ SUPPORTING THE DELIVERY
VICTORIA CARTER
BTSSevereAsthmaRegistries
iHARP:5,000pa7entsover8countries
ChiefInves7gator:DavidPrice
UK:HenryChrystyn,JohnHaughney,DermotRyan,KevinGruffydd-JonesFrance:NicolasRoche,DavidCostaItaly:FedericoLavorini,AlbertoPapi,AntonioInfanQnoSpain:MiguelRománRodríguezSweden:KarinLisspers,BjörnStällbergAustralia:SinthiaBosnic-AnQcevichNorway:SveinHenrichsenNetherlands:ThysvanderMolen
5,000 moderate-severe asthma patients over 8 countries
LinkingtoOPCRDintheUK
Clinical Trial
Registries GP Demographics
Questionnaire
Hospital Data
Prescriptions GP 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:
Findingauniqueiden7fiertoallowlinkagetovariouslongitudinaldatasources
LessonsfromiHARP
• 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
REGProposalforaGlobalSevereAsthmaRegistry
Keydeliverables:
1) Establishmentofaglobalregistry&standardisedcoding• Containingkeydata(commontoallcontribuQngnaQonaldatabases)on
severeasthmapaQents
2) Registrysetupanddatacollec7on• PotenQallybuildingonexisQngnaQonalregistries(suchastheBTSDifficult
AsthmaRegistryintheUK)
3) Long-termmanagement&oversightoftheglobalregistry• Datapre-populaQonandlinkingtoprimarycaredatasystemsto
automate/facilitatedataentry
DendriteClinicalSystems:Webbased
• The system must be user friendly prevent duplication of data
SummaryofVariablesintheBTSDifficultAsthmaRegistry
Followup:AnnualReview
Pa7entDetailsGender,Age,Ethnicity,BMI
etc
MedicalHistoryExacerbaQons,Episodesofinvasive
venQlaQon,Atopicdisease
Inves7ga7onsEosinophils,IgE,CTScan,Bone
densitometry
LungFunc7onFEV1,FVC,KCO,FENO,PC20methacholine/histamine
AllergenTes7ngRASTposiQve,SPTposiQve,Perennial
allergenetc
Ques7onnairesAsthmaControlQuesQonnaire(ACQ7)
Euro-QOL-5D
AsthmaMedica7onInhaled/oralsteroids,LAMA,SABA,adherence,corQsol&prednisolone
SystemicAssessmentAdherence,othercontribuQngfactors,
biologictherapydetails
Whatcurrentlyexistsglobally?
LinkingPrimary&SecondaryCare:ApilotinUK
• UsinguniqueidenQfierstolinkprimarycaredatafromOPCRD• IdenQficaQon of severe asthma paQents managed in primarycare
• ExpertalgorithmfromREG-encouragingappropriatereferralstosevereasthmaclinics
• PilotthelinkeddatapotenQalinNorthernIrelandorinterestedUKlocality(Liverpool)
Our Collaborative Network
Observational & Pragmatic Research Institute
• 600+GPPrac7ces• 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+ProjectsDelivered• 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
• Interna7onalKOL’s• 300 members • 40 countries worldwide • 14 working groups • ADEPT ethics commiRee • Academic access to
OPCRD
Agroupofindependentcompaniescollabora7ngtogetherwiththesharedgoaltoimprovepa7entmanagementandovercomeunmetmedicalneeds
Severe Asthma Registries
Background: 5% of paQents have severe refractory asthma thatresponds poorly or not at all to high-dose inhaled or systemicglucocorQcosteroidtreatment
Aim:Defineandcharacteriseclinicalphenotypesinsevereasthmato facilitate research into the assessment and clinicalmanagement
• PhenotypingofpaQents• EvaluaQonandopQmizaQonoftreatment• EvaluaQonofheterogeneityindiagnosis• IdenQficaQonofcomorbidiQes• UnderstandingofunderlyingmechanismsofairwayinflammaQon&
structuralchanges• DevelopmentofeffecQveandefficientdiagnosQcrouQnesand
therapeuQcprinciples• DevelopmentofnovelandeffecQvebiologic-basedtherapies• GeneQcprofilingofpaQentswithasthma
REG Proposal for a Global Severe Asthma Registry
Keydeliverables:
1) Establishmentofaglobalregistrycontainingkeydata(commontoallcontribuQngnaQonaldatabases)onsevereasthmapaQents• PotenQallybuildingonexisQngnaQonalregistries(suchastheBTSDifficult
AsthmaRegistryintheUK)?
2) RegistrysetupanddatacollecQonsupportoverQme:• Datapre-populaQonandlinkingtoprimarycaredatasystemsto
automate/facilitatedataentry
3) Long-termmanagementoftheregistryandmakingdataavailabletoresearchers
OPENTOALLCOUNTRIES:REGTOUNDERSTANDGLOBALINTERESTALEADANDPILOTINEACHCOUNTRYOFAZINTEREST:• USA:RohitKaQal&NJH–SevereAsthmaWorkingGroupLead• GERMANY:RolandBuhl–GermanSevereAsthmaRegistry
(n=463)• UK:LiamHeaney,AndrewMenzies-Gow–UKSevereAsthma
Registry(n=770)• FRANCE:NicolasRoche?• ITALY:WalterCononica–SANI• SPAIN:MarcMiravitlles,JoanSoriano• AUSTRALIA:SinthiaBosnic-AnQcevich&WoolcockInsQtute
REG Proposal for a Global Severe Asthma Registry
Apps• PROs• PEFetc.
MedicalHistory
SevereAsthmaRegistry
BaselineAssessment
Prospec7veDataCollec7on
SmartInhalers• Adherence
AsthmaReviewsatClinic• Clinicalassessment• Biomarkersetc.
PrimaryCareRecords• MedicaQon• ExacerbaQons• ComorbidiQes• Healthcareresource
uQlisaQonetc.
SecondaryCareRecords• HospitalisaQons• Healthcareresource
uQlisaQon
• QuesQonnaires• LungfuncQon• Biomarkers• AllergentesQng• Op#onalblood
sampleforfuturegene#ctes#ng?
PrimaryCareRecords• MedicaQon• ExacerbaQon
history• ComorbidiQes
SecondaryCareRecords• HospitalisaQons• Healthcare
resourceuQlisaQon
REG Proposal for a Global Severe Asthma Registry
BENEFITSTO…
Pa7ents• PotenQaltoimprovepaQentoutcomesinshort-term(throughbiomarker
profilingandsmarttechnologies)• IncreaseunderstandingofsevereasthmatoimprovepaQentcareinlong-term
Clinicians• PaQentcare:
• ImprovecharacterisaQon(andoverQme,understandingof)severeasthmatohelpguideclinicaldecisionmaking
• IntroducesmarttechnologiestofacilitatepaQentmanagementinclinic• Asthmaregistrypre-populatedfromexisQngclinicalsystemsviaanonymised
paQentidenQfiers(incountrieswherefeasible)
Researchers• Accesstoaglobalregistryofwell-characterisedsevereasthmapaQents• ComprehensiveretrospecQvemedicalhistorydatacombinedwithconQnued
prospecQvefollow-up(incountrieswherefeasible)
REG Proposal for a Global Severe Asthma Registry
A Working Example in the UK
BTSDifficultAsthmaRegistry:WebBasedRegistry:DendriteClinicalSystems• 770severeasthmapaQents• MaintainingpaQentanonymityandconfidenQality(safeand
secure)• Timesavingcomparedtopaper-basedsystems• PaQentsconsenttocollecQonofdata• DataControllerislocalhospitalandDendriteClinicalServices
UKLtd.• UKSevereAsthmaSteeringGroup• REGtoreviewUKsevereasthmaregistryfieldsforglobaluse• Limitedbycross-secQonalnature–possibilitytolinkinwith
longitudinalprimarycaredata:OPCRD
Linking Primary & Secondary Care: A pilot in UK
• UsingpseudoanonymiseduniqueidenQfiers(hashedNHS)tolink longitudinalprimary caredata fromOPCRDwith cross-secQonalUKsevereasthmaregistry.
• IdenQficaQon of severe asthma paQents in primary carerecords, using expert algorithm from REG - encouragingappropriatereferraltosevereasthmaclinics
• Pilot the iniQaQve in Northern Ireland or interested UKlocality(Liverpool)
Summary of Variables in the BTS Difficult Asthma Registry
BASELINEPa7entDetails• Gender,Age,Ethnicity,BMI,etc.MedicalHistory• ExacerbaQons,EpisodesofinvasivevenQlaQon,Atopicdisease,etc.Inves7ga7ons• EOS,IgE,CTscan,bonedensitometry,etc.LungFunc7on• FEV1,FVC,KCO,FeNO,PC20methacholine/histamine,etc.AllergenTes7ng• RASTposiQve,SPTposiQve,PosiQvetoperennialallergen,etc.Ques7onnaires• AsthmaControlQuesQonnaire(ACQ7),Euro-QoL-5DAsthmaMedica7on• Inhaled/oralsteroids,LAMA,SABA,Evidenceofpooradherence,CorQsolandprednisolonelevels,FeNO
suppressiontest,etc.Systema7cAssessment• Adherence,OtherfactorscontribuQngtosymptoms,Biologictherapydetails,etc.
FOLLOW-UPAnnualReviewBronchialThermoplasty
REG Working Group Inputs
• Iden7fica7onof• Currentregistriesaroundtheworld(andgaps)• PotenQalnaQonalleadsforaglobalcollaboraQon
• Review:• Datafields/variableswithinexisQngregistriesfor
completeness
• Develop:• Developalistofvariablesfortheregistries
• Core:mustbecommontoall;• Supplementaryvariables:beneficialinaddiQontocore
variables,wherefeasible• AnalgorithmtoidenQfy“SevereAsthma”paQentsfrom
withinexisQngUKprimarycareclinicalrecords
Timelines
• Q42016• DefinecoreandopQmalvariables
• Q1-Q22017• Setupregistrywithintheselectedsotwaresystem• IniQatedevelopmentof infrastructureto linkwithotherdatasources,wherefeasible(paQentrecords,appsetc.)
• Q32017• Releaseofregistry• FirstpaQentsinpilotcountries/areas
• FromQ12018• Dataaccesstoresearchers
GROUP DISCUSSION / FEEDBACK
ANY OTHER BUSINESS – OTHER IDEAS FOR THE GROUP(S)
15.50–16.00PM
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