Key points from the REG IPF/ILD Working Group meeting held in Amsterdam in September 2015

1. DATE: FRIDAY SEPTEMBER 25TH
VENUE: Wyndham Apollo Hotel, Amsterdam
ROOM: Boardroom
TIME: 2:00-3.30PM
CHAIR: Luca Richeldi, Professor of Respiratory
Medicine, Chair of Interstitial Lung Disease,
University of Southampton, UK
IPF/ILD WORKING
GROUP MEETING

2. Agenda

3. Working Group Members
Lead: Luca Richeldi
• Fernando J Martinez
• Simon Walsh
• Kevin Flaherty*
• Bruno Crestani
• Martin Kolb
• Toby Maher
• Francesco Bonella
• Ganesh Raghu
• Ian Glaspole
• Katerina M. Antoniou
• Paola Rottolli
• Juergen Behr
• Ganesh Raghu
• Tamera Corte
• Chris Ryerson
• Harold Collard
• Ulrich Costabel
• Moises Selman
• Thomas Geiser
• Manuela Funke-Chambour
• Kevin Brown
• Giovanni Ferrara
• Nathan Steven
• Mariano Mazzei
• Vincent Cottin
• Demosthenes Bouros
• Carlo Vancheri
Participation key: Blue=confirmed; italic = tentative; *dial-in attendance

4. Luca Richeldi
Southampton Respiratory Biomedical Research Unit,
University of Southampton, Southampton, UK
Welcome & Introduction:
Portfolio of Diagnostic Work

5. Diagnostic Initiatives
Database Characterisation of the Primary Care Path to Diagnosis
• Using the UK’s primary care Optimum Patient Care Research Database
(OPCRD), the study will characterise patterns of primary care healthcare
resource utilisation (HRU) in the years leading up to a diagnosis of IPF.
Global Characterisation of the diagnostic pathway in ILD
• Characterise diagnostic practice in previously little-studied regions across a
wide range of resource and healthcare settings;
• Inform the optimum design of a subsequent ILD MDT agreement study.
Global ILD MDT agreement study
• Evaluate the association between ILD diagnostic pathway and diagnostic
agreement and accuracy relative to other centres.
• Establish best practice recommendations for ILD (specifically IPF) diagnosis.
Future research
• Diagnostic characterisation work (above) will develop a characterised network
of global centres for future research.

6. David Price
REG Chairman and Professor of Primary Care Respiratory Medicine,
University of Aberdeen, UK
Primary Care Pathway to Diagnosis:
a UK historical records study

7. Background Rationale
• Knowledge is limited of the pathway to a diagnosis of IPF.
• Clinicians working in general practice may only come across one or
two cases in their medical careers.
• It is hypothesized that patients presenting in primary care with
symptoms of IPF may be:
o Misdiagnosed, and/or
o Delayed in receiving an IPF diagnosis.
• In the UK, all/most patients with IPF will first present in primary care
• A historical review of the primary care records for patient in the years
preceding their IPF diagnosis, should identify common patterns
(trends) in healthcare resource utilization (HRU) and identify potential
“red flags” to support decision support tools to aid earlier diagnosis.

8. Reference COPD Study
Consults for LR
symptoms
Chest radiography
Chest X-rayOutpatient Consults
Mean frequency of missed opportunities to diagnose COPDConsort Diagram
Jones RCM, et al on behalf of REG. Opportunities to diagnose chronic obstructive pulmonary disease
in routine care in the UK: a retrospective study of a clinical cohort. LRM. 2014; 2:267-76

9. Aims & Design
Aim
• With a view to identifying potential opportunities for earlier referral to
specialists and (ultimately) earlier diagnosis of IPF, this study aims to:
o Evaluate patients’ patterns of HRU in the years preceding their IPF
diagnosis.
o Characterise the clinical features of patients at the time of their IPF
diagnosis.
Design
• Historical follow-up study using electronic medical records and linked
questionnaire data from the Optimum Patient Care Research Database
(OPCRD).

10. Data source
Cohort Patients
"Prevalence" within
database population
Total Patient Population 2,414,621
Asthma Population 755,693 31.30%
COPD Population 134,281 5.56%
Pulmonary fibrosis
(idiopathic)
2,955 0.12%
Interstitial lung disease 5,299 0.22%
• The Optimum Patient Care Research Database (OPCRD) is UK primary
care database available to REG:
o Quality-controlled, longitudinal, primary-care database
o Contains anonymous data from ≥525 UK general practices
& ~2.5 million patients
o Ethical approval for medical research.

11. Study duration & design
Study Period: 45-year period (1970–2015) coincident with the migration of UK patient records
from paper to electronic format.
Evaluation Period: will consist of:
• An index date at which patients receive their IPF diagnosis
• Characterisation period: ≥2 years continuous EMR immediately preceding the index date
• Where available, exploratory outcome period to evaluate time to death
Historical evaluation of healthcare
resource utilisation
period ≥2 years
Index date, i.e. date of:
• Primary analysis: IPF diagnosis
• Secondary analysis: ILD diagnosis
Post IPF diagnosis
(exploratory analysis of time to death)
Post ILD diagnosis
(exploratory analysis of time to death)
Secondary analysis
Primary analysis
Evaluation of clinical
characteristics at
time of diagnosis

12. Eligibility Criteria
Inclusion criteria
• A diagnostic (Read code) for IPF
• Diagnosed with IPF between 1990 and 2015.
• Have a minimum of 2 years continuous clinical records in the
years immediately preceding their index diagnosis
• Aged 40 years or older at index date
Exclusion Criteria
• No additional exclusion criteria will be applied to ensure the
study population includes the broadly heterogeneous patient
population treated in routine primary care in the UK.

13. Outcomes
• Consultations:
o Lower respiratory (LR) consultations
o LR Consultation resulting in a course of
antibiotic drugs (on the same day)
o LR Consultation resulting in a course of
oral steroids (on the same day)
• Hospitalisations (in-patient attendances)
with a code for a:
o All
o LR complaint on the same day
o LR complaint within the following
7 days
• Out patient visits with a code for a:
o LR complaint on the same day
o LR complaint within the following 7 days
• Accident & Emergency (A&E)
attendances coded for a:
o LR complaint on the same day
o LR complaint within the following 7 days
• Chest X-ray / radiology
• Prior Diagnoses
o Presence of diagnosis
o Duration of diagnosis (esp. COPD)
To evaluate trends in HRU in patients diagnosed with IPF, outcomes will be
evaluated over the 25 years preceding their diagnosis and in 5-year categories:
0–5 years; 6–10 years, 11–15 years, 16–20 years and 21–25 years.

14. Characterization at Diagnosis
Patients will be characterized as follows in order to:
• Evaluate whether patients diagnosed with IPF within the OPCRD are
representative
• Identify potential differential diagnoses
• Identify common traits and potential triggers for earlier specialist referral.
• Patients will be characterized in terms of:
o Demographic & lifestyle factors
o Comorbidities:
– Respiratory
– Other
o Respiratory pharmacotherapy in the year preceding index date:
o Symptom severity (mMRC, CAT, COPD exacerbations)
o Spirometry / lung function
o Blood eosinophilia (≥0.5 x 109/ L).

15. Status & timelines
• Funding:
o Under internal review by Boehringer Ingelheim UK
• Timeline:
o ~4 months following funding confirmation &
contract

16. Luca Richeldi (Southampton, UK)
Fernando Martinez (New York, USA)
Kevin Flaherty (Ann Arbor, USA)
Simon Walsh (London, UK)
Jeff Myers (Ann Arbor, USA)
Global evaluation of MDT
diagnosis in the real-world

17. Background
1. Flaherty KR, et al. Am J Respir Crit Care Med 2004;170:904–910
• There has been little evaluation of the MDT approach to ILD
diagnosis since the MDT was established as the diagnostic gold
standard.1
• There is substantial discussion around variability in diagnostic
agreement within ILD.
• Very little is know about how the MDT is "rendered" in routine practice
outside a limited number of well-characterised specialist tertiary centres
(e.g. format, governance; specialty involvement).
• A critical step to evaluating agreement is the need to understand common
diagnostic practice around the world, particularly areas / regions that are
under represented in previous research.

18. Background (continued)
• A broad survey is required to establish a picture of routine
diagnostic practice.
• A two-phase study is proposed:
o Phase I: First characterise diagnostic practice in different
geographical areas (in terms of composition, functionality,
etc.).
o Phase II: Design a diagnostic agreement and accuracy
study involving centres that reflect real-world practice (with
particular interest in agreement of IPF diagnosis).

19. Outputs: Phase I
• Characterise the ILD diagnostic process globally,
especially in countries/territories where little is currently
known.
• Provide valuable insight as to current diagnostic
practices to inform the robust design of Phase II.
• Develop a characterised global network of ILD centres
for engagement in:
o The Phase II diagnostic agreement/accuracy study
o Future ILD and IPF research (RCT and real-life studies)

20. Outputs: Phase II
• Evaluate agreement and accuracy of ILD MDT
diagnosis across a range of global sites and healthcare
settings
• Identify features of current MDT diagnostic practice
associated with accurate diagnosis (including the
effect of bronchoscopic sampling for diagnosis)
• Produce a series of best practice recommendations to
optimise the pathway to accurate ILD diagnosis for future
practice.

21. Link with REG
• Characterising real-world clinical practice and
evaluating effectiveness (not drug efficacy)
• REG has a proven track record in delivering real-
world research on behalf of international stakeholder
groups (to date primarily in asthma and COPD)
• REG is a not-for-profit organisation; all research
funding is used in the most cost-effective way
possible.

22. Pause for discussion…
• Clarifications…?
• Comments…?

23. Geographical Scope
• Building on prior work,1-2 the study will include:
o Dedicated and non-dedicated ILD centres
o Countries within both mature and expanding
economies
o All continents and key global regions.
• Of particular interest will be features of practice
in Brazil, Russia, India and China (the “BRIC”
countries) owing to their limited representation in
previous studies and large population size.
1. Flaherty KR, et al. Am J Respir Crit Care Med 2004;170:904–910;
2. Kevin R. et al. Am J Respir Crit Care Med. 2007; 175: 1054–1060.

24. Design: country selection
• Inclusive approach
• All countries and
participants involved in
the diagnosis of ILD
eligible for inclusion
• For operational
feasibility the following
continents, countries
will be prioritised for
inclusion.
Continent /
Region
Country Proposed Lead Collaborator
Europe
UK Luca Richeldi (Southampton)
Italy Carlo Vancheri (Catania)
France Vincent Cottin (Lyon)
Germany Jürgen Behr (Munich)
Greece Demosthenes Bouros (Athens)
Russia Sergey Avdeev (Moscow)
Scandinavia
Elisabeth Bendstrup (Aarhus,
Denmark)
Belgium Wim Wuyts (Leuven)
Netherlands Jan Grutters (Utrecht)
Spain / Portugal Ferran Morell (Barcelona, Spain)
North America
USA
Kevin Flaherty (Ann Arbor) & Fernando
Martinez (New York)
Canada
Charlene Fell (Calgary) ± Chris
Ryerson (Vancouver) ± Martin Kolb
(Ontario)
South America
Brazil
Ivan Rosas (Colombia)Argentina
Chile
Asia
Japan Arata Azuma
China Zuo Jun Xu (Beijing)
India Zarir Udwadia (Bombay)
Middle East Carole Youakim (Beirut, Lebanon)
Australasia Australia Tamara Corte (Sydney)
Africa South Africa Keertan Dheda (Cape Town)

25. Design: site selection (I)
• Lead collaborators within the prioritised
countries/regions will provide local expertise on:
o Geographical distribution of diagnostic centres
o Weighting of diagnostic case load across centres.
• Through local consortia, networks and professional
links, these data collection “nodes” will distribute the
survey (and curate responses) within their assigned
territory.*
*Industry links and the REG network will be used to engaged appropriate national leads
in areas currently “unknown” to the Investigators

26. Design: site selection (II)
• Pragmatic - “strategic-opportunistic” - site
inclusion combining:
o Scalable electronic data capture
o Local expertise & broad participation invitation
o Representative range of (ultimately self-selecting)
Participants.

27. Design: data capture & quality
Collection approach
• Electronic data capture
• Standardised survey questionnaires
• Electronic case report form (eCRF) technology, data will be:
o Captured digitally; Stored centrally; Monitored at an item,
participant, national and regional level, as required.
• Scalable at minimal additional cost
Quality assurance
• Edit checks and quality assurance monitoring will be implemented
throughout: Data within logical ranges; Completion of mandatory fields;
Measurement of survey completion time; Data pattern recognition;
Logic flow, etc
• Data cleaning will be conducted and monitored on an on-going basis

28. Pause for discussion…
• Missing countries?
• Feasibility of approach?
• Key considerations?
• Additional comments?

29. Methodology
• Expertise of survey respondent: (clinical; pathology; radiology)
• Demographics of respondent site: Geographical territory (continent,
country); Practice setting: Diagnostic techniques used in practice
• Patient demographics of respondent site: Number of (IPF and ILD)
patients (i) managing and (ii) diagnosing; Referral pattern of patients
• ILD patient management: self- / referred; # physicians seen during
diagnostic pathway
• Approach to diagnosis employed by respondent site: specialists
involved; diagnostic tools used
• Differential diagnosis: distribution of ILD by specific disease; diagnostic
confidence
• Use of available therapeutics at respondent site
• Process of diagnosis: use of MDT; method of seeking specialist input

30. Methodology (continued…)
• Process of diagnosis:
o If not using MDT: Confidence in diagnostic process; Frequency of
interactions between specialists; Types of specialists consulting;
Consistency of specialists
o If using MDTs: Confidence in diagnostic process; Fraction of cases that go
to MDT; Frequency of MDT diagnostic meetings; Structure & Format of
MDT; Attending specialists; Time per case; Diagnostic evaluations available;
format of case presentation; decision pathway; assignation of diagnostic
confidence; resolution approaches in the absence of consensus; # of
differential diagnoses documented; non-diagnostic information documented
by MDT; Common diagnostic or management dilemmas discussed.
• Optional
o New technologies, e.g. likelihood of use of molecular diagnostic test
o Case evaluations: series of cases presented to understand concordance
between physicians in study in diagnostic evaluation of ILDs.

31. Pause for discussion…
• Obvious omissions?
• Opportunities for first steering
committee review of methodology
• Comments/expectations re local
adaptions?

32. Study Design Summary
Global Steering Committee
Local specialist input:
(i) Regional
survey adaptions
(ii) Geographical
distribution of
diagnostic centres
(iii) Case load / mix
distribution by centres
Approval / adaption of
global methodology
Pragmatic
recruitment:
strategic, inclusive
approach
Continent / Regional Lead Continent / Regional LeadContinent Lead
X
X
X
X
X
X
X
X
X
X
X
National
Leads
Engagement of
local / regional
diagnostic
teams
(dedicated
ILD centres
& community
based)
local consortia,
network and
professional links
Continent Lead
National
Leads
Engagement of
local / regional
diagnostic
teams
(dedicated
ILD centres
& community
based)
local consortia,
network and
professional links
National
Leads
Engagement of
local / regional
diagnostic
teams
(dedicated
ILD centres
& community
based)
local consortia,
network and
professional links
National
Leads
Engagement of
local / regional
diagnostic
teams
(dedicated
ILD centres
& community
based)
local consortia,
network and
professional links
National
Leads
Engagement of
local / regional
diagnostic
teams
(dedicated
ILD centres
& community
based)
local consortia,
network and
professional links
National
Leads
Engagement of
local / regional
diagnostic
teams
(dedicated
ILD centres
& community
based)
local consortia,
network and
professional links

33. Key phases & timelines
Study Component
Indicative
Timeline
Contracts &
Funding
Signing of all contracts & necessary agreements with
supporting organisations and study sponsor
Q4 2015
Signing of all contracts & necessary agreements with national
vendors (as required)
Q1 2016
Review /
Adaption of
Methodology
Steering Committee review & adaption of screening
methodology
Q1 2016
National/regional validation and/or adaptation (including
translation) of screening methodology
Q2 2016
Systematic
Data
Collection
Commence Q3 2016
Conclude Q4 2016
Analysis
Data Cleaning & master file generation Q1 2017
Analysis: full population and stratified by region Q1 2017
Publication
Draft Development Q2 2017
Final manuscript submitted Q2/3 2017
Study Phase II
Protocol development for Phase II analysis* Q1-Q2 2017
Commencement of Phase II Q3 2017
~6-months to agree
methodology &
implement regional
adaptions
~6-months data
collection
~3-months analysis
Publication 3-6 months
post analysis sign off
Phase II to commence
≤3 months of Phase I
completion

34. Costs
Phase I
• £240k
• FYs:
o 2015/16
o 2016/17
Phase II
• Circa £300k
o FYs: 2016/17 & 2017/18
• Smaller number of sites (site selection informed by
phase I); more involved data provision (case selection) &
capture & final analysis
Project Management
PI / Steering Committee Meetings
Full protocol development
Methodology adaptions
Data capture & dataset creation
Data Analysis
Study Registration
Regional Management
Dissemination

35. Grant Requests: co-operative approach
£47,725.00
£47,725.00
£47,725.00£47,725.00
£47,725.00
£47,725.00
Supporter # 1 Supporter # 2 Supporter # 3
Supporter # 4 Supporter # 5 Supporter # 6• Global project
• Global benefits
o Clinical insights
o Centre / site characterisation
o Diagnostic pathway
characterisation
• Maximum global benefit for
respective investment
• Equivalent support
required for Phase II

36. Pause for discussion…
• Feasibility of:
o Proposed timelines
o Co-operative funding approach?
–Alternatives options (if required)
• Next steps…

37. Phase II: agreement & accuracy

38. Phase II Agreement Study Planning (I)
Study Design
• Informed by the Phase I global characterisation of MDT processes.
• A balance will be sought between study power (in terms of participating
centres and cases included) and feasibility. Considerations will include:
MDT definition
• It is recognised that the structure of MDTs differ within and between
countries and Phase I will inform the definition of “MDT” used in the Phase II
MDT diagnostic agreement/accuracy evaluation.
Participating Collaborators and Centres
• Phase I will establish the contacts and national practices necessary to
inform:
o Relative structure (face-to-face vs virtual) and composition (team members) of
participating centres.
o The “weighting” of participant centres across each country to reflect current practice

39. Phase II Agreement Study Planning (II)
Defining “Accuracy”
• Accurate diagnosis cannot be defined in absolute terms; however, for the purposes of the
study diagnostic “accuracy” may be defined in three ways.
• The Tier 1 definition (below) would be used as the primary definition of accuracy with Tiers
2 & 3 being used for sensitivity evaluations only.
o Tier 1 “gold standard” (principle definition): the correct diagnosis will be that assigned by the
source/providing MDT for each case, i.e. the diagnosis as assigned by the local MDT
o Tier 2: A second level of “correct diagnosis” will be defined as those Tier 1 diagnoses that are
confirmed in a blinded review by the “Study MDT” (i.e. an artificial MDT comprising an expert
clinician; radiologist and pathologist from the study steering committee). This MDT arrangement will
provide a source of external validation of the Tier 1 diagnosis, but will be limited as it will constitute
a “quasi” MDT where the members do not work together routinely as a team and will have no direct
contact with the patient to inform diagnostic decision making
o Tier 3: A third level of “correct diagnosis” will be applied by using available follow-up date to confirm
the diagnosis. Only cases meeting the Tier 2 definition for accurate diagnosis will be considered for
Tier 3.

40. Phase II Agreement Study Planning (III)
Potential Outcomes
• Descriptive analysis of participating MDTs
o Organisation & structure of MDT
o Governance of MDT
o Information generated by MDT
• Descriptive analysis of MDT accuracy, against:
o Tier 1 diagnosis
o Tier 2 diagnosis
o Tier 3 diagnosis
• Concordance / measure of agreement across centres
o Total
o Within-country
o Within-continent
o Stratified by MDT composition
o Stratified by case diagnosis
• Independent MDT features associated with diagnostic accuracy.

41. Pause for discussion…
• Overall comments?
• Suggestions?
• Next steps?
• Additional projects?

42. DATE: FRIDAY SEPTEMBER 25TH
VENUE: Wyndham Apollo Hotel, Amsterdam
ROOM: Boardroom
TIME: 2:00-3.30PM
CHAIR: Luca Richeldi, Professor of Respiratory
Medicine, Chair of Interstitial Lung Disease,
University of Southampton, UK
IPF/ILD WORKING
GROUP MEETING