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