International Severe Asthma Registry

Journal Pre-proof International Severe Asthma Registry: Mission Statement ISAR Study Group PII:

S0012-3692(19)34287-4

DOI:

https://doi.org/10.1016/j.chest.2019.10.051

Reference:

CHEST 2741

To appear in:

CHEST

Received Date: 13 June 2019 Revised Date:

23 August 2019

Accepted Date: 4 October 2019

Please cite this article as: ISAR Study Group, International Severe Asthma Registry: Mission Statement, CHEST (2019), doi: https://doi.org/10.1016/j.chest.2019.10.051. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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Word counts Abstract: 250 Main text: 3543

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International Severe Asthma Registry: Mission Statement

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The ISAR Study Group

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ISAR Study Group

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G. Walter Canonica MD,1 Marianna Alacqua MD PhD,2 Alan Altraja MD, PhD,3 Vibeke Backer

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MD DMSci,4 Elisabeth Bel MD PhD,5 Leif Bjermer Prof MD PhD,6 Unnur S. Bjornsdottir MD,7

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Arnaud Bourdin MD PhD,8 Guy G. Brusselle MD PhD,9 George C. Christoff MD PhD MPH,10

9

Borja G. Cosio MD PhD,11 Richard W. Costello MB MD FRCPI,12 J. Mark FitzGerald FRCPC,13

10

Peter G. Gibson MBBS,14,15 Liam G. Heaney MD,16 Enrico Heffler MD PhD,1 Mark Hew PhD,17

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Takashi Iwanaga MD PhD,18 Rupert C. Jones MD,19 Mariko S. Koh MRCP,20 Chin Kook Rhee

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MD PhD,21 Sverre Lehmann MD PhD,22 Lauri A. Lehtimäki MD PhD,23 Dora Ludviksdottir MD

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PhD,24 Anke-Hilse Maitland-van der Zee PhD,25 Andrew N. Menzies-Gow PhD,26 Nikolaos G.

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Papadopoulos MD PhD,27,28 Vicente Plaza MD PhD,29-31 Luis Perez de Llano MD PhD,32

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Matthew Peters MD,33 Celeste M. Porsbjerg MD PhD,4 Mohsen Sadatsafavi MD PhD,34 You

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Sook Cho MD PhD,35 Yuji Tohda MD PhD,18 Trung N. Tran MD PhD,36 Eileen Wang MD

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MPH,37 James Zangrilli MD,36 Lakmini Bulathsinhala MPH,38 Victoria A. Carter BSc,38 Isha

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Chaudhry MSc,38 Neva Eleangovan BSc,38 Naeimeh Hosseini MD,38 Thao L. Le BCom,38 Ruth

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B. Murray PhD,38 Chris A. Price LLB,38 David B. Price MD FRCGP38-40

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1

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Milan, Italy, & SANI-Severe Asthma Network Italy; 2AstraZeneca, Cambridge, UK; 3Dept of

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Pulmonary Medicine, University of Tartu & Lung Clinic, Tartu University Hospital, Tartu,

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Estonia; 4Respiratory Research Unit, Dept of Respiratory Medicine, Bispebjerg Hospital,

Personalized Medicine Asthma & Allergy Clinic, Humanitas University & Research Hospital,

1|Page

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Copenhagen University, Copenhagen, Denmark; 5Dept of Respiratory Medicine, Academic

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Medical Centre, University of Amsterdam, The Netherlands; 6Dept of Respiratory Medicine

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& Allergology, Skane University Hospital, Lund, Sweden; 7Faculty of Medicine, University of

27

Iceland, Reykjavik, Iceland; 8Dept of Respiratory Diseases, Montpellier University Hospitals,

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Hopital Arnaud de Villeneuve and PhyMed Exp (INSERM U 1046, CNRS UMR9214),

29

Universite de Montpellier, Montpellier, France; 9Dept of Respiratory Medicine, Ghent

30

University Hospital, Ghent, Belgium and Depts. of Epidemiology and Respiratory Medicine,

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Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands; 10Faculty of Public Health,

32

Medical University, Sofia, Bulgaria;

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Mallorca, Spain; 12Clinical Research Centre, Smurfit Building Beaumont Hospital and Dept of

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Respiratory Medicine, RCSI, Dublin, Ireland;

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Vancouver, Canada;

36

Healthy Lungs, University of Newcastle, Newcastle, Australia;

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Institute, Department of Respiratory and Sleep Medicine, John Hunter Hospital, New

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Lambton Heights, Australia;

39

Belfast, Northern Ireland;

40

Medicine & Allergology, Kindai University Faculty of Medicine, Osakasayama, Japan;

41

19

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Respiratory & Critical Care Medicine, Singapore General Hospital and Duke-National

43

University, Singapore Medical School, Singapore;

44

Critical Care Medicine, Department of Internal Medicine, St. Mary’s Hospital, College of

45

Medicine, The Catholic University of Korea, Seoul, South Korea;

46

University of Bergen, and Dept. of Thoracic Medicine, Haukeland University Hospital,

47

Bergen, Norway; 23Allergy Centre, Tampere University Hospital and University of Tampere,

48

Tampere, Finland;

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University of Iceland, Reykjavik, Iceland; 25Dept of Respiratory Medicine, Amsterdam UMC,

50

University of Amsterdam, Amsterdam, The Netherlands;

51

Royal Brompton & Harefield NHS Foundation Trust, London, UK;

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Athens, Greece; 28University of Manchester, UK; 29Dept of Respiratory Medicine, Hospital de

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la Santa Creu y Sant Pau, Barcelona, Spain; 30Institut d'Investigació Biomédica Sant Pau, IIB

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Sant Pau, Barcelona, Spain;

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11

Son Espases University Hospita-IdISBa-Ciberes,

13

The Institute for Heart Lung Health,

Australasian Severe Asthma Network, Priority Research Centre for

17

16

15

Hunter Medical Research

UK Severe Asthma Registry, Queen’s University Belfast,

Alfred Health, Melbourne, Australia;

18

Dept of Respiratory

Faculty of Medicine & Dentistry, University of Plymouth, Plymouth, UK;

24

21

20

Dept of

Division of Pulmonary, Allergy and

22

Dept of Clinical Science,

Dept of Respiratory Medicine, Landspitali University Hospital and

26

UK Severe Asthma Network, 27

University of Athens,

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Dept of Medicine, Universitat Autònoma de Barcelona, 2|Page

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Barcelona, Spain; 32Dept of Respiratory Medicine, Hospital Universitario Lucus Augusti, Lugo,

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Spain; 33University of Sydney Medical School, Sydney, Australia; 34Faculty of Pharmaceutical

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Sciences, University of British Columbia, Vancouver, Canada;

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Division of Allergy & Clinical Immunology, Asan Medical Center, University of Ulsan College

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of Medicine, Seoul, South Korea; 36AstraZeneca, Gaithersburg, MD, USA; 37Division of Allergy

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& Clinical Immunology, Dept. of Medicine, National Jewish Health, and Division of Allergy &

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Clinical Immunology, Dept. of Internal Medicine, University of Colorado Hospital, CO, USA;

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38

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Singapore; 40Academic Primary Care, University of Aberdeen, Aberdeen, UK

35

Dept of Internal Medicine,

Optimum Patient Care, Cambridge, UK; 39Observational and Pragmatic Research Institute,

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3|Page

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Corresponding author

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Prof David B Price

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Academic Primary Care

69

Division of Applied Health Sciences

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University of Aberdeen

71

Polwarth Building

72

Foresterhill

73

Aberdeen AB25 2ZD

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UK

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E-mail: [email protected]

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ISAR is conducted by Optimum Patient Care Global Limited, and co-funded by OPC Global

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and AstraZeneca.

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Running head: ISAR mission statement

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Key words: ISAR, severe asthma

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Abbreviations: ADEPT: Anonymized Data Ethics & Protocol; ATS: American Thoracic Society;

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EDC:

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Pharmacoepidemiology & Pharmacovigilance asthma; ERS: European Respiratory Society;

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GINA: Global Initiative for Asthma; ICS: inhaled corticosteroid; ISAR: International Severe

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Asthma Registry; ISC: ISAR Steering Committee; OCS: oral corticosteroid; OPC: Optimum

85

Patient Care; RCT: randomized controlled trial; REG: Respiratory Effectiveness Group;

86

SAWD: Severe Asthma Web-based Database

Electronic

Data

Capture;

ENCEPP:

European

Network

of

Centres

for

87

4|Page

88

Conflict of Interest

89

G. Walter Canonica has received research grants, as well as lecture or advisory board fees

90

from A. Menarini, Alk-Abello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune,

91

Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti-

92

Malesci, GlaxoSmithKline, Hal Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi-

93

Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva,

94

Thermo Fisher, and Valeas.

95

Marianna Alacqua, Trung N. Tran and James Zangrilli are employees of AstraZeneca, a co-

96

funder of the International Severe Asthma Registry.

97

Alan Altraja has received lecture fees from AstraZeneca, Boehringer Ingelheim, Chiesi,

98

GlaxoSmithKline, MSD, Norameda, Novartis, and Orion; sponsorships from AstraZeneca,

99

Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MSD, Norameda, and Novartis; and has been

100

a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline,

101

Novartis, and Teva.

102

Vibeke Backer, Unnur Bjornsdottir, George Christoff, J. Mark FitzGerald, Enrico Heffler,

103

Marikoh Koh, Dora Ludviksdottir, Celeste Porsbjerg, Mohsen Sadatsafavi, You Sook Cho,

104

and Ruth Murray declare no relevant conflicts of interest concerning this paper.

105

Elizabeth Bel has received lecture or advisory board fees from AstraZeneca, Boehringer

106

Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron, and Teva, and research grants to

107

her institution from AstraZeneca, GlaxoSmithKline, Novartis, and Teva.

108

Leif Bjermer has (in the last three years) received lecture or advisory board fees from Alk-

109

Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma,

110

Novartis, Sanofi, Genzyme/Regeneron, and Teva. 5|Page

111

Arnaud Bourdin has received speaker fees and grants to his institution from AstraZeneca,

112

Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Novartis for unrelated projects.

113

Guy Brusselle has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim,

114

Chiesi, GlaxoSmithKline, Novartis, and Teva. He is a member of advisory boards for

115

AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron, and Teva.

116

Borja G Cosio declares grants from Chiesi; personal fees for advisory board activities from

117

Chiesi and AstraZeneca; and payment for lectures/speaking engagements from Chiesi,

118

Novartis, Menarini, and AstraZeneca, outside the submitted work.

119

Richard Costello has received honoraria for lectures from Aerogen, AstraZeneca, Boehringer

120

Ingelheim, GlaxoSmithKline, Novartis, and Teva. He is a member of advisory boards for

121

GlaxoSmithKline and Novartis, has received grant support from GlaxoSmithKline and

122

Aerogen and has patents in the use of acoustics in the diagnosis of lung disease, assessment

123

of adherence and prediction of exacerbations.

124

Peter Gibson declares speaker fees and grants to his institution from AstraZeneca,

125

GlaxoSmithKline, and Novartis for unrelated projects.

126

Liam Heaney declares he has received grant funding, participated in advisory boards and

127

given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim,

128

Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, and Teva; he has taken part in

129

asthma clinical trials sponsored by Boehringer Ingelheim, Hoffmann la Roche, and

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GlaxoSmithKline for which his institution received remuneration; he is the Academic Lead

131

for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma

132

which involves industrial partnerships with a number of pharmaceutical companies

6|Page

133

including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche,

134

and Janssen.

135

Mark Hew declares grants and other advisory board fees (made to his institutional

136

employer) from AstraZeneca, GlaxoSmithKline, Novartis, and Seqirus, for unrelated projects.

137

Takashi Iwanaga declares grants from Astellas, Boehringer Ingelheim, Daiichi-Sankyo,

138

Kyorin, MeijiSeika Pharma, Teijin Pharma, and lecture fees from Kyorin.

139

Rupert Jones declares grants from AstraZeneca, GlaxoSmithKline, and Novartis; and

140

personal fees for consultancy, speakers fees, or travel support from AstraZeneca,

141

Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Nutricia, OPRI, and Pfizer.

142

Chin Kook Rhee declares consultancy and lecture fees from AstraZeneca, Boehringer

143

Ingelheim, GlaxoSmithKline, Mundipharma, MSD, Novartis, Sandoz, Takeda, and Teva-

144

Handok.

145

Sverre Lehmann declares receipt of lecture (personal) and advisory board (to employer)

146

fees from AstraZeneca, Boehringer Ingelheim, and Novartis.

147

Lauri Lehtimäki declares personal fees for consultancy and lectures from AstraZeneca,

148

Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, Novartis, Orion Pharma, and

149

Teva; and personal fees for consultancy from ALK.

150

Anke-Hilse Maitland-van der Zee declares unrestricted grants from Boehringer Ingelheim,

151

GlaxoSmithKline, and Novartis; and personal fees for advisory board activities from

152

AstraZeneca and a travel grant from Chiesi.

153

Andrew N. Menzies-Gow declares grants from AstraZeneca, Boehringer Ingelheim,

154

GlaxoSmithKline, and Hoffmann La Roche; consultancy agreements with AstraZeneca,

155

Sanofi, and Vectura; attendance at advisory boards for AstraZeneca, Boehringer Ingelheim,

7|Page

156

GlaxoSmithKline, Novartis, Sanofi, and Teva; received speaker fees from AstraZeneca,

157

Boehringer Ingelheim, Novartis, Teva, and Vectura; and attended international conferences

158

for Boehringer Ingelheim and Teva.

159

Nikolaos G. Papadopoulos declares research support from Gerolymatos, Menarini, Nutricia,

160

and Vian; and consultancy/speaker fees from ASIT, Boehringer Ingelheim, HAL Allergy,

161

Menarini, MSD, Mylan, Novartis, and Nutricia.

162

Vicente Plaza declares (in the last three years) honoraria for speaking at sponsored

163

meetings from AstraZeneca, Chiesi, GlaxoSmithKline, and Novartis; travel grants from Chiesi

164

and

165

Mundipharma, and Sanofi; funding/grant support for research projects from a variety of

166

Government agencies and not-for-profit foundations, as well as AstraZeneca, Chiesi, and

167

Menarini.

168

Luis Perez de Llano declares non-financial support, personal fees, and grants from Teva;

169

non-financial

170

GlaxoSmithKline, Mundipharma, and Novartis; personal fees and grants from AstraZeneca

171

and Chiesi; personal fees from Sanofi; and non-financial support from Menairi outside the

172

submitted work.

173

Matthew Peters declares personal fees and non-financial support from AstraZeneca and

174

GlaxoSmithKline.

175

Yuji Tohda: declares honoraria from Kyorin Pharma and Teijin Pharma and research funding

176

from Kyorin Pharma and Meiji Seika Pharma.

Novartis;

consultancy

support

and

fees from

personal

ALK,

fees

AstraZeneca,

from

Boehringer

Boehringer

Ingelheim,

Ingelheim,

Esteve,

8|Page

177

Eileen Wang has been an investigator on clinical trials sponsored by AstraZeneca,

178

GlaxoSmithKline, Novartis, Teva, and National Institute of Allergy and Infectious Diseases

179

(NIAID) for which her institution has received funding.

180

Lakmini Bulathsinhala, Victoria Carter, Isha Chaudhry, Nevaashni Eleangovan, Naeimeh

181

Hosseini, and Chris Price are employees of Optimum Patient Care, a co-funder of the

182

International Severe Asthma Registry.

183

Thao L. Le declares educational grants from AstraZeneca, Bayer, Boehringer Ingelheim, Care

184

Pharmaceuticals, GlaxoSmithKline, Mylan, Novartis, Mylan, and Teva.

185

David Price declares advisory board membership with Aerocrine, Amgen, AstraZeneca,

186

Boehringer Ingelheim, Chiesi, Mylan, Mundipharma, Napp Pharmaceuticals, Novartis, and

187

Teva; consultancy agreements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim,

188

Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp Pharmaceuticals, Novartis, Pfizer,

189

Teva, and Theravance; grants and unrestricted funding for investigator-initiated studies

190

(conducted through Observational and Pragmatic Research Institute Pte Ltd) from

191

Aerocrine, AKL Research and Development Ltd, AstraZeneca, Boehringer Ingelheim, British

192

Lung Foundation, Chiesi, Mylan, Mundipharma, Napp Pharmaceuticals, Novartis, Pfizer,

193

Respiratory Effectiveness Group, Teva, Theravance, UK National Health Service, and Zentiva;

194

payment for lectures/speaking engagements from Almirall, AstraZeneca, Boehringer

195

Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Merck, Mundipharma, Novartis,

196

Pfizer, Skyepharma, and Teva; payment for manuscript preparation from Mundipharma and

197

Teva; payment for the development of educational materials from Mundipharma and

198

Novartis;

199

AstraZeneca, Boehringer Ingelheim, Mundipharma, Napp Pharmaceuticals, Novartis, and

payment

for

travel/accommodation/meeting

expenses

from

Aerocrine,

9|Page

200

Teva; funding for patient enrolment or completion of research from Chiesi, Novartis, Teva,

201

and Zentiva; stock/stock options from AKL Research and Development Ltd which produces

202

phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd

203

(Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd

204

(Singapore); and is a peer reviewer for grant committees of the Efficacy and Mechanism

205

Evaluation programme and Health Technology Assessment.

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Summary

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Regional and/or national severe asthma registries provide valuable country-specific

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information. However, they are often limited in scope within the broader definitions of

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severe asthma, have insufficient statistical power to answer many research questions, lack

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intra-operability to share lessons learned, and have fundamental differences in data

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collected, making cross comparisons difficult. What is missing is a worldwide registry which

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brings all severe asthma data together in a cohesive way, under a single umbrella, based on

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standardized data collection protocols, permitting data to be shared seamlessly. The

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International Severe Asthma Registry (ISAR; http://isaregistries.org/) is the first global adult

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severe asthma registry. It is a joint initiative where national registries (both newly created

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and pre-existing) retain ownership of their own data but open their borders and share data

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with ISAR for ethically approved research purposes. Its strength comes from collection of

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patient level, anonymous, longitudinal, real-life, standardized, high-quality data (using a

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core set of variables) from countries across the world, combined with organizational

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structure, database experience, inclusivity/openness, and clinical, academic, and database

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expertise. This gives ISAR sufficient statistical power to answer important research

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questions, sufficient data standardization to compare across countries and regions, and the

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structure and expertise necessary to ensure its continuance as well as the scientific integrity

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and clinical applicability of its research. ISAR offers a unique opportunity to implement

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existing knowledge, generate new knowledge, and identify the unknown, therefore

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promoting new research. The aim of this commentary is to fully describe how ISAR may

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improve our understanding of severe asthma.

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Introduction

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Optimum treatment of severe asthma represents a major unmet need. Although it affects a

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relatively small proportion of the asthma population (approximately 5-10%), and even less

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(<1%) for severe uncontrolled eosinophilic asthma,1,2,3,4 it accounts for over 50% of the costs

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attributed to the disease.5 Those with severe disease incur on average 3-times the asthma

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medication costs as those with persistent disease.6 Despite improvement in outcomes,

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severe asthma is still a cause of mortality.7 There is, therefore, an unmet need to

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characterize and classify these patients with a view to improving therapy and reducing costs

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on a global scale. The World Health Organization describes severe asthma as ‘uncontrolled

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asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse

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reactions to medications and/or chronic morbidity’.8 However, in clinical practice other

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terms are often used such as ‘difficult-to-treat’, ‘refractory’, ‘unresponsive’ or ‘brittle’,

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‘steroid-dependent’ and ‘treatment-resistant’.8,9,10 This language is reflected in the ERS/ATS

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task force definition of severe disease as ‘asthma which requires treatment with high-dose

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inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to

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prevent it from becoming uncontrolled or which remains uncontrolled despite this therapy’.2

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Confirmation of good adherence to therapy, proper inhalation technique, appropriate

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management of exposures and co-morbidities, and accurate patient education are further

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required to distinguish severe asthma from asthma that is uncontrolled due to other causes,

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such as poor adherence or co-morbidities.11,12

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Prevalence estimates of severe asthma vary widely from country to country (ranging from

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3.6% in the Netherlands to 8.1% in Denmark);13,14,15,16 a reflection of different definitions

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employed and difficulties associated with obtaining reliable figures as a consequence of

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differences in access to healthcare. Reliability of the data is further confounded by the

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possibility that severe asthma patients may be ‘hidden’ due to a variety of factors including

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a patient’s willingness to live with, or tolerate, their symptoms and lifestyle

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limitations,17,18,19 an acceptance of the need for frequent courses of oral corticosteroids

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(OCSs) as usual rather than exceptional care, pressure on primary care providers not to refer

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to specialist clinics, and/or lack of awareness that the condition needs specialist attention

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and intensive therapy, as well as newer treatment options. Therefore, the true prevalence

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of severe asthma may be higher than that reported in the literature.

262 263

Many countries have developed regional and/or national severe asthma registries in order

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to gather information on severe asthma, to better understand the disease history,

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progression, impact, and response to treatment.14,20,21,22,23,24,25,26 These registries have

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provided valuable information on country-specific epidemiological patterns, risks, treatment

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benefits, and enabled safety monitoring of therapies. However, due to the relatively small

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size of the severe asthma population, and their spread over a wide geographical area2,3 such

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registries often have limited power to answer important research and clinical questions, and

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differ in their inclusion criteria and/or focus. Furthermore, since these registries were set up

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independently, it is hardly surprising that they reflect country-specific variability in patient

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selection, healthcare access, and referral patterns and incorporate different data fields, so

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ultimately collecting data of variable quality and completeness. This makes cross

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comparisons difficult and large-scale epidemiological studies challenging. The discrete and

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segregated nature of these local registries means that there is no capacity for intra-

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operability with no linkage between them, so valuable information is not shared in real time

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and cannot be contextualized within a global severe asthma framework until individual

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registry data are published.

279 280

What is missing is a worldwide registry, which brings all severe asthma data together in a

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cohesive way, under a single umbrella. Pooling our resources to generate a centralized

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severe asthma dataset would permit data to be shared seamlessly between countries and

283

institutions, to ultimately gain better insight into severe asthma on a global scale, covering

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response to therapies across all genetic backgrounds. This can be done by opening our

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severe asthma registry borders to share information gathered at the national and regional

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levels. The process may be further optimized by standardizing the variables collected,

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producing one over-arching registry. The International Severe Asthma Registry (ISAR;

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http://isaregistries.org/) is the first global adult severe asthma registry. It gathers patient-

289

level, anonymized, longitudinal, real-life data from pre-existing national registries (and

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newly established national registries, for which ISAR provides set-up support) for adults with

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severe asthma, from countries all over the world. Severe asthma is defined by ISAR as those

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patients on Global Initiative for Asthma (GINA) Step 5, or those with uncontrolled asthma on

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GINA Step 4.27,28 Pooling data in this way provides important information for all

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stakeholders. With such a large dataset, clinicians gain information not only on patient

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presentation, but also knowledge of predictors of treatment success in the era of

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personalized medicine and predicted outcomes of personalized therapies; patients gain a

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better understanding of the natural history of their disease, with their collective data used

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to inform treatment guidelines; payers get evidence on how treatments are used and their

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effectiveness (both clinical and economic) in different patient populations; and the

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pharmaceutical industry can assess the effectiveness and long-term safety of therapeutic

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agents in real-life, fulfilling post-marketing surveillance commitments and identifying

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patients for future clinical trials.29

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What does ISAR bring to our understanding of severe asthma?

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ISAR contributes to our understanding of severe asthma in 6 key areas (Figure 1). It is the

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first global severe adult asthma registry, which ultimately will be large enough to ensure

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sufficient power to answer numerous important clinical questions. A pediatric registry is

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currently in the planning stages. The data collected by ISAR are standardized, individualized,

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and comprehensive. ISAR has scientific, academic, and ethical oversight providing

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confidence in data collection, analysis and dissemination, and extensive experience in large

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data collection and management. It operates on the principle of inclusivity and

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collaboration, continually seeking new partners and prioritizing relevant research pertinent

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to severe asthma. Finally, ISAR is a cross-disciplinary initiative, holding within it the

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combined experience of key thought leaders in severe asthma (clinicians & epidemiologists)

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as well as basic scientists, data analysts, and experts in database management and

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communication. Each of these 6 attributes contribute to ISAR’s overall aim of improving the

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care of adults with severe asthma globally (both in primary and secondary care). This aim

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will be achieved via provision of a rich source of real-life data for scientific research to better

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understand the epidemiology, burden, clinical evolution, real-world safety of new treatment

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and management patterns of severe asthma (exploring differences across healthcare

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systems), and to assess treatments (in the absence of comparative randomized controlled

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trials (RCTs)) and patient outcomes for severe asthma.

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Global reach

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Severe asthma patients are present over a wide geographical area. ISAR already partners

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with 20 national or regional registries in: Europe (Bulgaria, Denmark, Greece, Ireland, Italy,

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Netherlands, Spain, UK), The Americas (USA, Canada, Columbia, Mexico), Asia Pacific (Japan,

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India, South Korea, Taiwan) and the SAWD registry (comprising patient data from Australia,

328

New Zealand, Singapore), and the Middle East (Kuwait, UAE, Saudi Arabia), with planned

329

expansion to other regions of the world – including Africa. Some of these local registries are

330

currently being developed with ISAR involvement. At the time of writing this report

331

agreements were in process with 8 countries (Finland, Germany, Iceland, Norway, Sweden,

332

Singapore, Argentina and Russia). Countries newly engaged include Portugal, Estonia,

333

France, and Brazil giving ISAR a truly global reach. ISAR currently comprises data from 7,948

334

severe asthma patients (individual data: n=7,250; aggregate data: n=698) with new data

335

provided quarterly. The individual data is prospective for 2113 patients and retrospective for

336

5137 patients (Figure 2). ISAR is a joint initiative and would not exist without the data

337

provided by local registries. Importantly, local registries retain ownership of their own data,

338

but benefit from ISAR in terms of the analytical power it provides and cross comparisons

339

with data from other countries. ISAR also supports setting-up of local registries via provision

340

of a standardized variables list, resource support in assessing data quality and/or an

341

electronic data capturing system. The registry acts as a data custodian, collecting, collating,

342

exploring, and analyzing standardized data provided by local registries. Countries participate

343

by either enabling country data to be provided directly into ISAR or by allowing country data 16 | P a g e

344

to be used for any research conducted under the ISAR initiative, and approved by ISAR’s

345

governance body.

346 347

Quality data

348

The value of any global registry derives not only from its geographical scope and the data it

349

collects, but also from the quality of that data. Data collected by ISAR is fully anonymized,

350

and at individual rather than aggregate level, offering the potential to explore additional,

351

more thorough, and appropriate analyses per research question compared to the limited

352

options possible with aggregate data.30 Patient level data provide the opportunity to

353

conduct biostatistical multivariate analyses, to investigate the potential relationship

354

between outcome and risk factors, provide level of risk for a patient rather than for a group

355

(e.g. age group, country etc.), to track patient progress longitudinally over the course of

356

time, and to analyze response to treatment and changes in medical management. ISAR’s

357

centralized analysis model also removes potential for discrepancies in the methodology of

358

data analyses between countries, provides the ability to dig further into individual country

359

data (as part of a multi-national dataset), and is a cost-effective and time-efficient approach.

360

Data collection is standardized across all ISAR-contributing countries, using a core set of

361

variables which all participating countries have agreed to collect. Arriving at the final list of

362

variables to collect involved in-depth analysis of key variables collected by other registries,

363

formulation of a comprehensive list of those variables (747 in total) and a modified Delphi,

364

consensus-driven approach to reduce this list to 95 core variables, all overseen by a panel of

365

27 experts from 16 countries in the field of severe asthma.27 This final list of 95 core

366

variables encompass data on patient demographics, medical history and diagnostics (e.g.

17 | P a g e

367

peripheral blood and sputum eosinophils & neutrophils and fractional exhaled nitric oxide),

368

clinical characteristics, patient-reported outcomes, and treatment management plans.27 The

369

core variable list may also be added to with optional standardized safety and effectiveness

370

bolt-ons, capturing information on severe infection, malignancies, anaphylaxis, additional

371

co-morbidities, time of exacerbation, ICS/OCS dose, and reasons for medication switching.

372

Although, the list is comprehensive, it is also reduced to the minimum necessary to reduce

373

data input time and error, and to provide meaningful information on severe asthma in real-

374

life. This may help to define a link between best practices and improved outcomes and, at

375

the same time, ensure the sustainability of ISAR moving forward.27 Local registries are free

376

to collect country-specific variables.

377

Organizational structure

378

Currently, ISAR benefits from the support of 3 collaborators. It is overseen by 4 governing

379

bodies safeguarding continuance of the registry into the future, and ensuring ISAR research

380

is ethical, clinically appropriate, and continues to bring genuine value to patients, public

381

health,

382

(http://www.encepp.eu/encepp/viewResource.htm?id=24389).

383

currently include: Optimum Patient Care Global (OPC), the Respiratory Effectiveness Group

384

(REG), and AstraZeneca. OPC is an organisation which specialises in delivering medical

385

research and services to improve the diagnosis, treatment, and care of chronic diseases. It

386

has a long-standing record of delivering clinical support services and global research by

387

developing enhanced quality databases, bespoke datasets for academic research and global

388

registries with the aim of improving patient outcomes. REG is an investigator-led, not-for-

389

profit research initiative, promoting the value of real-life research. ISAR’s 4 governing bodies

and

healthcare.

ISAR

is

a

registered

data

source The

core

on

ENCEPP

collaborators

18 | P a g e

390

include the ISAR Steering Committee (ISC; comprising 48 experts in severe asthma research

391

from 29 countries and medical experts from AstraZeneca), REG, the Anonymized Data Ethics

392

& Protocol Transparency (ADEPT) Committee, and the ISAR Operational Committee. The

393

ADEPT Committee is commissioned by REG to review ISAR research protocols for their

394

scientific quality and rigour. The Operational Committee includes participating country

395

representatives (e.g. country lead, deputy, and data managers) and is involved in the day to

396

day running of ISAR.

397

Data capture

398

Electronic data capture (EDC) systems improve efficiency, reduce workload, time, and cost,

399

as well as enhance the quality of data collected. ISAR data collection is supported by the use

400

of a dedicated template, and also integrates with existing data capture systems (e.g. Open

401

Clinica, REDCAP, and other country-specific systems). These EDC systems ensure data

402

quality via data validation and editing at the point of data entry. Automatic data validation

403

rules are built into the EDC platforms to minimize errors at data entry. The data are secure

404

and password-protected, and anonymized and encrypted at source. Mandatory variables

405

must be entered, or a ‘no data’ value imputed to confirm genuine missing data, so

406

maximising registry completeness and minimizing bias. Furthermore, where possible, the

407

ISAR data capture process has been streamlined to maximise efficiency. For example,

408

patients may complete patient-reported outcomes remotely in the comfort of their homes

409

or in the waiting room, and in certain countries (e.g. Denmark) the ISAR data capture

410

template has been embedded into Electronic Medical Records, thus avoiding double-entry

411

as much as possible, reducing the administrative burden, and fulfilling a recent call for

19 | P a g e

412

‘greater integration’ between routine healthcare records, research databases, and

413

biosamples.31

414

Inclusivity

415

ISAR operates under the principle of inclusivity and openness. The ISAR doors are open to

416

new collaborators and partners using the ‘join the registry’ and ‘register your interest’

417

functions on the ISAR home page (http://isaregistries.org/). Research ideas may be

418

suggested by ISC members, country leads, and contributors and visitors to the ISAR

419

webpage (which includes third party commercial and academic research organizations), by

420

simply clicking the ‘submit a proposal or research request’ tab. Each year all research ideas

421

are reviewed, selected, assessed for scientific rigour and compliance with ethics standards,

422

and prioritized by the ISC. Other academic and commercial entities can seek ISAR data

423

access for research purposes, with all research proposals requiring approval by both the ISC

424

and ADEPT.

425 426

Experience & deliverables

427

ISAR holds within it the combined experience of 45 key thought leaders, bringing together

428

the severe asthma knowledge from 29 countries. It benefits from the capability of the OPC

429

database management team (which oversees one of the largest respiratory databases in the

430

world (OPCRD)), ensuring the capture of high-quality data, management of the dataset, and

431

robust and ethical scientific analyses. Finally, ISAR incorporates an experienced

432

communications team committed to ensuring timely dissemination of findings in

433

international, peer-reviewed journals and international and regional scientific meetings.

434 20 | P a g e

435

In terms of deliverables, ISAR offers a unique opportunity to observe the real-life severe

436

asthma situation and to assess the effectiveness, safety, and value of new therapeutic

437

agents (and existing ones), providing valuable and complementary data to that obtained in

438

the more rigid and homogenous RCT environment. ISAR is committed to producing a

439

minimum of 6 datasets annually. Core projects already commissioned include a description

440

of demographic and clinical characteristics of severe asthma patients worldwide, and

441

characterization of eosinophilic asthma versus non-eosinophilic phenotype. Other

442

prioritized research for the coming years is shown in Table 1. As may be expected in severe

443

asthma there is a strong research focus on biologics, but other topics are considered just as

444

important such as assessing hidden severe asthma in primary care, the relationship between

445

socioeconomic status and asthma outcomes, and characterization of health disparities

446

across countries.

447

Limitations and advantages of registry data

448

As an unavoidable consequence of their design, data obtained from registries possess lower

449

internal validity than RCTs, limiting the extent to which they can demonstrate a cause-and-

450

effect relationship. A major challenge is the bias inherent in its volume; knowing what to

451

look for and how to assess and analyse large amounts of data.32 Bias can be minimized by

452

identifying eligible populations, by controlling the study design, study outcomes, and

453

potential confounding factors (e.g. missing data) before work commences, and by using

454

rigorous analytical methods.33 Additionally, a database is only as good as its data (i.e. what is

455

measured, in whom, and how is it measured and recorded). A system to routinely validate

456

and verify data integrity is essential to ensure database utility.34 As the patients included in

457

ISAR are those from tertiary centres (rather than from primary care), we expect that they all 21 | P a g e

458

have asthma. There is the possibility, however, that some patients may have asthma COPD

459

overlap (ACO). An ISAR prioritized research project aims to describe the extent of ACO in

460

this severe asthma population. Furthermore, although North, Central and South America, as

461

well as Europe and the Asia-Pacific region are well represented within ISAR, there are still

462

gaps in the global cover (e.g. Africa). We continue to reach out to countries in these regions

463

with existing registries, and are committed to providing assistance to those countries

464

wishing to set up their own registry. The ultimate aim is to make the ISAR software

465

available open source to assist in the endeavour. Finally, merging data from pre-existing

466

registries brings its own challenges, including inter-country variability in the type of patients

467

included in registries, referral patterns, and service access. Understanding the nature of

468

each pre-existent registry is important before drawing conclusions.

469

On the other hand, data entered into registries are not subjected to the same rigorous

470

inclusion and exclusion criteria required for RCTs. This results in high patient numbers

471

allowing comparisons between regions, countries, continents, and populations. Registries

472

are population based and not subjected to the same sample size statistical limitations of

473

RCTs. Registry data is also more heterogeneous in nature (than RCTs) and more

474

representative of patients seeking medical advice in real life.33 The data are not biased by

475

changing patient/physician interaction, modification in healthcare access, treatment(s)

476

prescribed, or outcomes assessed in any way. An assessment of effect over a long period of

477

time may also be better answered using registry data, which is precluded in RCTs due to

478

cost. Registry data may be collected prospectively or retrospectively, and as these data are

479

routinely collected, results can often be obtained more quickly and at a lower cost than

480

RCTs.33 22 | P a g e

481

ISAR vision and conclusions

482

ISAR is a real-life registry with lower internal validity than clinical trial populations but

483

extremely high external validity to the severe asthma patient population worldwide, as

484

defined by the ERS/ATS criteria. It permits the implementation of existing knowledge in the

485

severe asthma patient population, generation of new knowledge, and identification of the

486

unknown, promoting new research. As the severe asthma population is relatively small and

487

heterogeneous, large numbers are needed to understand the complexities of cause,

488

biological/clinical features, and outcomes, in order to provide personalized and targeted

489

care. By combining data from small registries into one large standardized registry,

490

comprising the same set of variables with similar data structures, we are able to compare

491

and contrast differences between countries and care systems, something which is not

492

currently possible in the global severe asthma framework. ISAR has the potential to robustly

493

interpret and generally apply observations, but as it continues to grow, the aim is to no

494

longer simply estimate, but rather to describe the population in its entirety. ISAR’s potential

495

lies not so much in its ability to provide insight into asthma mechanisms, but rather in the

496

information it provides for improving diagnosis, disease stratification (endotypes and

497

phenotypes), and, potentially, the identification of new targets for treatment; an approach

498

which is predictive, preventive, personalized, and participatory.35 The challenge remains to

499

harness ISAR’s global data to provide meaningful clinical insight, and to translate this

500

knowledge into better diagnosis and personalized care.32 Generation of new knowledge will

501

enable us to make the best choices for individual patients, providing the best treatment at

502

the individual level (i.e. the right treatment at the right time to the right patient), thus

503

making a meaningful and beneficial difference to the lives of severe asthma patients around

23 | P a g e

504

the world. By identifying the unknown, ISAR provides a fertile ground to do research to

505

understand both the disease and the impact of current and new therapies.

506

Moving beyond ISAR, there is enormous potential to link ISAR with other databases (e.g.

507

with primary care data to find hidden severe asthma), to reduce the burden and cost of

508

regularly scheduled visits in tertiary care centers, and even linking with other specialist

509

databases/registries (e.g. chronic obstructive pulmonary disease) to gain further insight for

510

patients with co-morbidities. Data provided by ISAR may also be helpful in supporting,

511

modifying, and improving current severe asthma guidelines. In the future, ISAR may be

512

more fully linked with electronic health records, to streamline data collection, and may also

513

be linked with patient-reported outcomes, helping patients and physicians to make better

514

personalized decisions. Knowledge gathered by ISAR from severe asthma patients may be

515

used to improve the management of those with moderate disease; for example, to ascertain

516

whether better care earlier may lead to better outcomes later. The ISAR database could also

517

be used to investigate the effectiveness of novel approaches to asthma treatment or indeed

518

the feasibility of new asthma treatment paradigms. For example, the recently proposed

519

paradigm of regular treatment with biologics (in those patients likely to respond),

520

concomitant reduction of ICS dose, and use of dual or triple combination therapy as a

521

reliever on an as-needed basis deserves investigation.36 ISAR could be used, not only to

522

examine asthma outcomes and identify patients likely to benefit, but also to assess the cost-

523

effectiveness of the approach. Potential benefits are many and include improved adherence

524

and asthma control, fewer ICS-related side effects, and provision of a validated simplified

525

asthma management program offering greater convenience for patients.36

526 24 | P a g e

527

Acknowledgements

528

The International Severe Asthma Registry is conducted by Optimum Patient Care Global

529

Limited, and co-funded by Optimum Patient Care Global and AstraZeneca. The following

530

individuals have contributed substantially to ISAR:

531

Bulgaria: Prof Magdalena Alexandrova; Prof Ted Popov; Prof Ztekomir Vodenicharov; A/Prof

532

Alexandrina Vodenicharova .

533

Greece: Prof Stelios Loukides.

534

Italy: Ms. Concetta Sirena for the SANI Registry.

535

SAWD (incorporating Australia, New Zealand & Singapore): Prof Philip Bardin; Dr Belinda

536

Cochrane; A/Prof David Langton; A/Prof Peter Middleton; Prof Paul Reynolds; Prof John

537

Upham.

538

Spain: Dr Rocío Díaz Campos; Dr Santiago Quirce; Dr Lorena Soto Retes; Dr Andrea Trisan.

539

UK: Dr John Busby; Dr David Jackson; Dr Paul Pffefer.

540

USA: Ms. Jennifer Brandorff; Ms. Margo Brown; Ms. Jessica Cummings; Ms. Christena

541

Kolakowski; Mr. Seth Skelton; Dr. Michael Wechsler; Ms. Joy Zimmer.

542

25 | P a g e

543

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Table 1

638

International Severe Asthma Registry (ISAR) Global Core projects and prioritized research DESCRIPTION GLOBAL CORE PROJECTS Demographic and clinical baseline characteristics of severe asthma patients worldwide The characterization and comparison of eosinophilic and non-eosinophilic phenotypes Comparative effectiveness across severe asthma biologic classes (Anti-IL-5 vs. Anti-IgE) in patients eligible for both modalities PRIORITIZED RESEARCH Hidden severe asthma patients in primary care versus ISAR on the impact of exacerbation burden on lung function trajectory in a broad asthma population and severe asthma population Biologics in severe asthma: Utilization patterns, causes for discontinuation and switching, and adverse outcomes Biomarker Relatability in the International Severe Asthma Registry (BRISAR) Identification of predictors (i.e. biomarkers) of response to biologics Hidden chronic asthma within the COPD/ACO population Age at onset of asthma in severe asthma patients Relationship between socio-economic status & asthma outcomes Describe the OCS landscape: Annual consumption, prevalence, outcomes, and side-effects of long-term OCS users Characterization of health disparities (burden of illness or mortality) across countries Characterization of health disparities (burden of illness or mortality) across countries Criteria for choosing and switching between similar biological treatment options in patients with atopic and non-atopic severe eosinophilic asthma Describe the characteristics of severe asthma patients with inflammatory phenotypes and FEV1 <40% ACOS: Asthma COPD Overlap Syndrome; COPD: Chronic Obstructive Pulmonary Disease; FEV1: forced expiratory volume in one second; IgE: Immunoglobulin E; IL: interleukin; ISAR: International Severe Asthma Registry; OCS: oral corticosteroid

639

31 | P a g e

640

Figure Legends

641

Figure 1: What does the International Severe Asthma Registry (ISAR) brings to our

642

understanding of severe asthma

643

Figure 2: Global coverage of the International Severe Asthma Registry (ISAR). Green: current

644

contributors to ISAR; Blue: Future contributors to ISAR; Orange: Engaged with ISAR.

645

32 | P a g e