INTERSTITIAL LUNG DISEASE WORKING GROUP MEETING

CHAIR: Luca Richeldi

DATE: Tuesday September 6th

TIME: 10-11.30am

VENUE: Hotel Novotel London Excel, Western Gateway, London

ROOM: Board Room

–  Global Characterisation of ILD Diagnostic practice

–  Missed Diagnostic Opportunities in IPF

Agenda

•  Global Characterisation of ILD Diagnostic Practice o Identifying Participant Sites

•  Missed diagnostic opportunities in IPF: retrospective cohort study: o Results Summary

Attendees (RSVPs) Confirmed •  Carole Youakim •  Claudia Valenzuela •  Keertan Dheda (now meeting at 4pm) •  Luca Richeldi •  Maria Molina Molina •  Lurdes Planas •  Pilar Ortega •  Simon Walsh •  Steven Nathan (changed to tentantive) •  Toby Maher (changed to tenatntive) •  Ggiovanni Ferrara •  Vincent Cottin •  Aileen Wang •  Camilo Roa •  Paolo Spagnolo •  David Price •  Paola Rottoli •  Sergey Adveev •  Zuo Jun Xu •  Klaus-Uwe Kirchgaessler (supporter) •  Demosthenes Bouros

•  Arata Azuma •  Mariano Maezzi •  Antonio Morais •  Andrew Worsfold •  Alison Chisholm •  Thao Le

Dial ins •  Camera Corte (yes) •  Ivan Rosas (possibly) •  Kevin Brown (improbable - time zone issue) •  Andrew Wilson (probable) •  Mike Rosenblyth (supporter) (improbable -

timezone issue)

Tentative •  Fernando Martinez •  Kevin Flaherty •  Mark Jones •  Martin Kolb •  Ulrich Costabel

GLOBAL ILD DIAGNOSTIC CHARACTERIZATION STUDY

Background (I)

•  REG’s focus is real-life research

o  Raising the quality and profile of real-life research methodologies

o  Using real-life research to address unmet research needs and

address gaps in the evidence base

•  Efficacious IPF therapies resulted interest in a need to better understand the reality of ILD diagnostic practice to optimise

treatment outcomes

•  Initial concept – utilise the REG ILD Working Group network to conduct a diagnostic agreement study:

o  Discussion around variability in diagnostic agreement within ILD.

o  Would a range of MDTs within this network agree on the diagnoses if given the same set of “test cases”

Background (II)

•  Questions when designing the agreement study:

o What would be appropriate definition of an MDT?

o What would be the right case mix for inclusion?

o What does real-life diagnostic practice look like?

•  There is limited knowledge of how diagnosis takes place outside specialist centres

•  As a precursor to evaluating agreement, it’s necessary to understand how ILDs (in particular IPF) are diagnosed in routine care

Agreement Study: Phase I Outputs

•  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 Phsae II and future research: o  The Phase II diagnostic agreement/accuracy study

o  Future ILD and IPF research (RCT and real-life studies)

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.

Timeline & Status

ATS 2015: first working group meeting, Denver (developed proposal June–Aug)

ATS 2016: reviewed draft questionnaire (Updated June; ethics secured June; Global leads invited July/August)

ERS, Sept 2015: shared study protocol with working group and potential supporters

(Funding secured Oct–Dec 2015)

Timeline & Status

ATS 2015: first working group meeting, Denver (developed proposal June–Aug)

ATS 2016: reviewed draft questionnaire (Updated June; ethics secured June; Global leads invited July/August)

ERS, Sept 2015: shared study protocol with working group and potential supporters

(Funding secured Oct–Dec 2015)

Application prepared June

Approval secured July 24th

Obline questionnaire

Timeline & Status

ATS 2015: first working group meeting, Denver (developed proposal June–Aug)

ATS 2016: reviewed draft questionnaire (Updated June; ethics secured June; Global leads invited July/August)

ERS, Sept 2015: shared study protocol with working group and potential supporters

(Funding secured Oct–Dec 2015)

ERS, Sept 2016: utilise the working group network to identify participant sites & support language translation

Centre Recruitment: principles (I)

•  Centre Inclusion: Not restricted to expert / specialist centres; a broad a range of different diagnostic settings will be included

•  Objective: The study will help to characterise and describe range and variation in diagnostic practice

•  Local Expertise: Local experts will guide participation in their country to

ensure a range of relevant healthcare settings / centres are included

•  Descriptive study: No conclusions about practice approach prevalence

(e.g. what is ‘usual practice’) will be made, i.e.:

o  A range of centers in each country is required to reflect the variation in practice within each country

o  The selection of participating centers does not need to be representative of practice in that country, overall

Cascade Approach

•  Regional Leads will be asked to: o Provide country lead names

•  Country leads will be asked to to: o Advise as to translation requirements

o Support translation(s) (personally, or nominate colleague) o  Forward to a number of ILD Centres known to them

•  Participating centres will be asked to: o Complete the questionnaire

o Send it to other centres in their network

We are here

Cascade Recruitment

STEP 1 ACTIONS: CO-PIs Actions Identify Regional Leads / Experts in key global areas: (i) Continental Regions (ii) BRIC Countries

STEP 2 ACTIONS: Regional & BRIC Country Leads Identify National Leads or (BRIC) sub-country leads

STEP 3 ACTIONS: National & Area Leads (i)Confirm & support language translations (ii) Complete the questionnaire (iii) Send the questionnaire to (e.g.) 10 national ILD centres

STEP 4 ACTIONS: ILD Centre Leads (invited at Step 3) (i) Complete the questionnaire (ii) Send the questionnaire to members of their community network

International Roll Out •  Regional/Continent & National (BRIC) Leads:

o  Contacted (July);

o  Briefed & Confirmed (August)

To guide participant centre engagement around the world

REGIONAL LEADS GLOBAL REGION CONTACT NAME BRAZIL IVAN ROSAS

RUSSIA SERGEY ADVEEV

INDIA ZARIR UDWADIA

CHINA ZUO JUN XU

NORTH AMERICA FERNANDO MARTINEZ

KEVIN FLAHERTY

EUROPE LUCA RICHELDI

SIMON WALSH

SOUTH & CENTRAL AMERICA IVAN ROSAS

MIDDLE EAST CAROLE YOUAKIM

AFRICA KEERTAN DHEDA

ASIA-PACIFIC ARATA AZUMA (JAPAN / ASIA)

TAMERA CORTE (AUSTRALIA / NEW ZEALAND)

Example approach – Latin America

•  Registry efforts in recent years have identified lead contacts for most countries in Latin American (except Bolivia) and Central American

•  Each national lead can be contacted and asked how they would envisage contacting their national peers e.g.: o  What resources would they use to identify participants and email addresses,

o  How many contacts they have o  How they would recommend we contact those centres)

•  Invitations can then be sent to a number (e.g. 20-50) of centres in each country along with the questionnaire link and a cover note outlining the broad objectives of the study

•  Turnaround should be relatively rapid and feasible within the proposed 2-month data collection period

•  Translation will be important, especially in Brazil, but should be a minor effort to implement

Identification of Country Leads & Participants

Help us to: – Identify National Leads – Translate the questionnaire

Translations •  Local language translations will be offered as:

o  Necessary in some countries

o  Desire standardization of approach across all countries (i.e. translate for all not some)

•  Translation support required:

o  Preliminary translations can be provided for the following languages, but review and

tailoring will be required by a native speaker: –  English – UK; Esperanto; Estonian; Finnish; French; German; Greek; Gujarati; Hebrew; Hindi; Hungarian; Italian;

Japanese; Khmer; Korean; Latvian; Lithuanian; Macedonian; Mongolian; Myanmar; Norwegian; Persian; Polish;

Portuguese; Romanian; Russian; Serbian; Slovak; Slovenian; Spanish (Latin America); Spanish (Spain); Swahili;

Swedish; Tamil; Thai; Turkish; Ukrainian; Urdu; Vietnamese; Welsh

–  Test (in Italian) suggests preliminary translation is ~80% accurate

–  Text will be provided in a Word Document that can be edited / corrected

o  Where a preliminary translation is not possible; a native speaker must be identified to

support

•  Questions are clear and straight forward, so forward translation only will be sufficient

IDENTIFYING OPPORTUNITIES FOR EARLIER DIAGNOSIS OF

IDIOPATHIC PULMONARY FIBROSIS IN ROUTINE CARE IN THE UK:

A HISTORICAL CLINICAL COHORT STUDY

A STUDY BY THE RESPIRATORY EFFECTIVNESS GROUP’S INTERSTITIAL LUNG DISEASE WORKING GROUP

PRINCIPAL INVESTIGATOR: Prof. Luca Richeldi

STUDY REFERENCE: REG-RES1510

Realities of Current IPF Diagnosis

1 2

1. British Lung Foundation: https://www.blf.org.uk/Page/IPF-Patient-differential-diagnosis-of-COPD. (Last accessed February 2016); 2. NHS Choices Pulmonary Fibrosis (idiopathic) (http://www.nhs.uk/conditions/pulmonary-fibrosis/pages/introduction.aspx) (Last accessed February 2016)

Figure reproduced from the Inspiration: Idiopathic Pulmonary Fibrosis (IPF) Report February 2016; produced by Action for Pulmonary Fibrosis, BLF and Boehringer Ingelheim (BI)

Look back to move forwards •  Time to look upstream…:

o  What happens to patients in the lead up to their diagnosis

o  Are opportunities for earlier diagnosis being missed in primary care

o  How can non-specialists be supported to help identify potential IPF and earlier referral to specialist care…?

•  Identify common patterns (trends) in healthcare resource utilization (HRU) and identify potential “red flags” to to aid earlier diagnosis

Diagnosis & potential treatment

IPF Management

Pre-diagnosis

REG ILD WG Study Aims

•  With a view to identifying potential opportunities for earlier referral to specialists and (ultimately) earlier diagnosis of

IPF, the study aims to:

1.  Characterise the clinical features of patients at the time of their IPF diagnosis

2.  Evaluate patients’ patterns of HRU in the years preceding their IPF diagnosis

3.  Develop optimum code lists for IPF database research, i.e. variation in 1 & 2 for sensitive versus specific code lists

Collaborators Steering Committee •  Luca Richeldi: University of Southampton, Southampton, UK •  David Price: University of Aberdeen, Aberdeen, UK •  Carlo Vancheri: University of Catania, Catania, Italy •  Christopher Ryerson: University of British Columbia, Vancouver Canada •  Ian Glaspole: Alfred Hospital, Melbourne, Australia •  Ganesh Ragu: University of Washington, Washington, USA •  Kevin Flaherty: University of Michigan Medical School, Ann Arbor, MI, USA

•  Vincent Cottin: Claude Bernard Lyon University, Lyon, France •  Toby Maher: National Institute for Health Research (NIHR) Clinician Scientist and Physician on

the Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK

•  Andrew Wilson: Norwich Medical School, University of East Anglia, Norwich, UK •  Alan Kaplan: Family Physician Airways Group of Canada, Ontario, Canada •  Martin Kolb: McMaster University, Hamilton, Ontario, Canada •  Simon Walsh: ‎Consultant Thoracic Radiologist at Kings College Hospital, London, UK

REG Research Leads •  Alison Chisholm: Chief Scientific Officer, REG, UK

•  Anjan Nibber: Researcher, REG, UK •  David Price: REG Founder

Design & data source

Design •  Historical follow-up study using electronic medical records and

linked questionnaire data from the Optimum Patient Care Research Database (OPCRD)

Data source •  The Optimum Patient Care Research

Database (OPCRD) is a UK primary care database available to REG: o  Quality-controlled, longitudinal, primary-care database o  Contains anonymous data from ≥550 UK general practices

& ~2.5 million patients

o  Captured via the OPC asthma and COPD clinical review service –  Respiratory “enriched” database

o  Ethical approval for medical research

Study duration & design Study Period: 10-year period (2005–2015)

Evaluation Period: will consist of:

•  An index date at which patients receive their IPF diagnosis

•  Characterisation period: 2-10 years continuous EMR pre diagnosis

•  Where available, exploratory outcome period to evaluate time to death

Historical evaluation of healthcare resource utilisation

Period 2-10 years

Index date, i.e. date of: •  Primary analysis: specific IPF diagnosis •  Secondary analysis: broad IPF diagnosis

(exploratory analysis of time to death)

Evaluation of clinical characteristics at time of diagnosis

Post IPF diagnosis

Patient eligibility: inclusion criteria

•  A diagnostic (Read) code for IPF

o Specific* IPF Read code

o Broad* IPF Read code

•  Diagnosed with IPF between 2005 and 2015

•  ≥2 years’ continuous clinical records in the years immediately preceding their index diagnosis

•  Aged ≥40 years or older at index date

* Code lists defined on next slide

IPF Read Codes

Reviewed by working group members from primary & secondary care and prior experience of IPF research within UK EMRs:

Read Code Read Term

H563.00 Idiopathic fibrosing alveolitis

H563.12 (including: H563.11)

Cryptogenic fibrosing alveolitis (Hamman - Rich syndrome)

H563z00 Idiopathic fibrosing alveolitis NOS

H563300 Usual interstitial pneumonitis

H563.13 Idiopathic pulmonary fibrosis

XE0Yb Idiopathic pulmonary fibrosis

X102v Usual interstitial pneumonitis

H563z Idiopathic fibrosing alveolitis NOS

H563100 Diffuse pulmonary fibrosis

H563200 Pulmonary fibrosis

Bro

ad

primary

analysis S

pecific

prim

ary analysis

Patient eligibility: exclusion criteria

•  Comorbid*: o  Connective tissue disorder (CTDs)

o  Allergic alveolitis

o  Sarcoidosis

o  Pneumoconiosis

o  Asbestosis

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

*Read Code ever during the observation period

Characterization at IPF Diagnosis Patients will be stratified by broad vs specific IPF code and characterized in terms of:

•  Demographics

•  Lifestyle factors

•  Comorbidities: Respiratory, Other

•  Obstructive lung disease (OLD) pharmacotherapy in the year

preceding index date

•  Symptom severity (mMRC)

•  Lung function (FVC, FVC %pred, FEV1, FEV1/FVC)

•  Obstructive lung disease characteristics:

o  COPD GOLD status

o  Blood eosinophilia (≥0.5 x 109/ L)

Outcomes: trends in HRU

•  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  LR complaint on the same day o  LR complaint within 14 days

•  Chest X-ray / radiology

•  Cough

•  Therapies o  Prescriptions for antibiotics

o  Prescriptions for oral steroids: –  Acute –  Maintenance

•  Emergency Room / Accident & Emergency (A&E) attendances coded for a: o  LR complaint on the same day

Longitudinal trends in HRU preceding IPF diagnosis:

•  10-year annual trends

•  2-year quarterly trends (last 2 years before diagnosis)

RESULTS (SUMMARY / ANALYSIS ON-GOING)

Flow Diagram

Clinical features of patients at the time of their IPF diagnosis

In this routine care IPF population from the UK:

•  Demographics

o  Mean age: 72-73 years

o  Men accounted for 62-65% of the population

o  Approximately 1/3 were never smokers; 2/3 current or ex-smokers

•  Comorbidities

o  13-25% had obstructive lung disease (13-15% asthma; 19-25% COPD)

o  Approximately 50% of patients:

–  Had cardiovascular disease (46-53%)

–  Consulted for cough (40-52%; ~10% in the 2 years preceding IPF diagnosis)

•  Respiratory therapies

o  18-26% of patients received ≥1 prescription for SABA in the year preceding IPF diagnosis

o  Prescribing of all other obstructive lung disease therapies (ICS, LABA,

LAMA, combinations) was low (<10%)

Patterns of HRU in the years preceding their IPF diagnosis

•  All markers of respiratory HRU increased annually over the 10-years and quarterly within the last 2 years leading up to patient’s IPF diagnosis:

o Primary care events –  LR consultations, LR antibiotics and oral steroids (acute and

maintenance)

o Secondary care attendances –  Hospital admissions, Out patient department attendances,

Accident & emergency attendances

o Other: –  Cough events, Chest X-rays, Incidence of pneumonia

Code lists: specific vs broad

•  Compared with patients with a “specific” IPF diagnostic code, those with a “broad” diagnostic label were similar in terms of their:

o  Demographic presentation at the time of diagnosis

o  Escalating trends in HRU in the years preceding IPF diagnosis

o  Lung function: Similar mean(SD) FVC: 3.1(6.8) vs. 2.5(0.9) (p=0.405)

•  Comorbidities broad IPF patients had:

o  Similar burden of:

–  Chronic respiratory conditions (incl. asthma; excl COPD); heart failure,

rhinitis, bronchiectasis, eczema, osteoporosis, cerebrovascular disease, sleep apnoea, depression and anxiety

o  Higher burden of :

–  COPD, cardiovascular disease, ischaemic heart disease, Hypertension,

diabetes, myocardial infraction, GERD,CKD, lung cancer, cough

•  Drug usage: broad IPF patients had higher use of short-acting bronchodilator therapy

in the year preceding IPF diagnosis (26 vs 18%)