Introduction

Asthma is one of the most prevalent chronic respiratory diseases, affecting more than 300 million people worldwide in 2019.1 An estimated 4–10% of people with asthma have severe asthma,2–4 which is defined as asthma that remains uncontrolled despite treatment with high-dose inhaled corticosteroids (ICS) plus a long-acting β2-agonist (LABA; with or without oral corticosteroids [OCS]) and treatment of contributory factors, or asthma that worsens when high-dose treatment is decreased.5,6 Patients with severe asthma experience frequent asthma exacerbations, leading to hospitalizations, emergency room (ER) visits, and decreased health-related quality of life.7–9 Consequently, despite the low overall prevalence of severe asthma, these patients account for a disproportionately large share of asthma-related healthcare resource utilization (HCRU) and costs, as well as substantial non-asthma-related HCRU and costs owing to steroid-related adverse events.7,8

Several classes of therapy may be given as adjuncts to ICS-LABA to improve disease control in patients with severe asthma, including biologics that target inflammatory molecules and pathways involved in asthma pathogenesis.5 The landscape of biologic therapy for asthma is rapidly evolving, with new therapies under evaluation and the long-term efficacy and safety of existing therapies becoming more established.10–12 To date, biologic therapies targeting immunoglobulin E (IgE; omalizumab), interleukin (IL)-5 (mepolizumab, reslizumab), IL-5 receptor (IL-5R; benralizumab), IL-4/13 signaling (dupilumab), and thymic stromal lymphopoietin (tezepelumab), have been shown to be beneficial for patients with severe asthma; these treatments approximately halve rates of exacerbations and hospitalizations while improving lung function, asthma control, and health-related quality of life in randomized controlled trial populations.13–16 The efficacy of these biologics is generally sustained during long-term use, and rates of adverse events, including those requiring therapy cessation, are low.11,12 Of the six US Food and Drug Administration-approved biologics for moderate or severe asthma, mepolizumab, reslizumab, benralizumab, and dupilumab have indications for patients with an eosinophilic/type 2 (T2) phenotype,17–20 omalizumab is indicated for patients with clinically relevant perennial allergen sensitization,21 and tezepelumab (the most recently approved, in 2021) has no asthma phenotype restriction.22

Patients’ access to biologic therapies in countries where they are licensed, at least through typical reimbursement processes, requires meeting prescription eligibility criteria (including phenotyping criteria) determined by national and regional regulatory bodies, and usually requires referral to a specialist. Access to biologics therefore varies between countries owing to differences in national healthcare systems regarding reimbursement policies and referral networks.23 For example, in 2021, one of the eligibility criteria for omalizumab in the United Kingdom (UK) was four or more exacerbations in the previous year, whereas in Estonia and the Netherlands, no exacerbations were required.23 Regarding referral systems, countries such as Switzerland, Sweden, and Germany have been found to have the lowest barriers to accessing specialists, whereas India had the highest barriers.24 Previous studies suggest that a significant proportion of patients with severe asthma who meet the eligibility criteria for biologic therapy are not prescribed these agents, although robust data on this topic are lacking.25–28 Furthermore, approximately 15–50% of patients with severe asthma, including those with nonallergic or non-eosinophilic phenotypes, are not eligible for any of the T2-targeted biologics (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab).25,29–31

Quantifying the current global clinical and economic burden of patients with severe asthma who lack access to T2-targeted biologic therapy and of patients who have access but do not receive therapy, as well as the remaining unmet need despite use of these biologics, is essential for understanding whether there is still a need for new treatments for patients with severe asthma. Although regional and national severe asthma registries collect valuable country-specific data pertaining to this,32–34 they typically contain relatively small numbers of patients. A larger data set that can be used to address this knowledge gap is the International Severe Asthma Registry (ISAR),35,36 a global registry that retrospectively and prospectively collects standardized, individual-level data from over 17,000 adult patients with severe asthma in 28 countries worldwide at the time of writing.37

The EVEREST study aimed to characterize the clinical burden and asthma-related HCRU of patients enrolled in ISAR between December 2017 and May 2022, evaluating patients by their access to biologic therapy in terms of receiving biologics or meeting national prescription eligibility criteria for these therapies.23 Patients with access to biologic therapy who received it and those who did not receive it were evaluated separately, as were patients with access to biologic therapy whose asthma remained suboptimally controlled despite receiving these therapies.

Materials and Methods Data Source

ISAR aggregates and standardizes data from existing and newly created severe asthma registries worldwide. Full details regarding asthma diagnostic criteria for ISAR, the definition of severe asthma used, and how data are extracted from registries in participating countries have been published previously.38 Data from 21 countries were included in this study (Argentina, Australia, Bulgaria, Canada, Colombia, Denmark, Greece, India, Italy, Japan, Korea, Kuwait, Mexico, Poland, Portugal, Saudi Arabia, Spain, Taiwan, United Arab Emirates, UK, and the United States [US]).

The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance Code of Conduct (registration number: EUPAS106967) and with all applicable local and international laws and regulations. Registration of the ISAR database with the European Union Electronic Register of Post-Authorization studies was also undertaken (ENCEPP/DSPP/23720). Ethical governance for ISAR was provided by the Anonymised Data Ethics Protocols and Transparency Committee (ADEPT) (approval reference number: ADEPT-1021).39 All data collection sites in ISAR have obtained regulatory agreement in compliance with specific data transfer laws, country-specific legislation, and relevant ethical boards and organizations. The study was approved by the ISAR International Steering Committee and was performed in accordance with the 1964 Declaration of Helsinki and its later amendments. All participating patients provided informed consent, and their data were anonymized.

Study Design

This was a historical cohort study of patients enrolled in ISAR, using prospective data collected between December 1, 2017, and May 11, 2022. The current analysis included patients who, at enrollment in ISAR, were aged 18 years or older and were receiving Global Initiative for Asthma (GINA; 2018 criteria)40 step 5 treatment or were receiving step 4 treatment but still had uncontrolled asthma (per GINA 201840 or the American Thoracic Society/European Respiratory Society guidelines).6 Patients who had received bronchial thermoplasty were excluded from the analysis.

The following five groups of patients were studied, with groups 3–5 being subgroups of group 1: 1) biologics accessible; 2) biologics inaccessible; 3) biologics accessible but not received; 4) biologics accessible and received (also referred to herein as biologic recipients); and 5) biologic recipients whose asthma remained suboptimally controlled (also a subgroup of group 4; see Figure 1 for group/subgroup stratification).

Figure 1 Patient groups evaluated during the baseline period and follow-up period (following biologic therapy).

Abbreviations: ATS, American Thoracic Society; BACS, Biologic Accessibility Score; ERS, European Respiratory Society; GINA, Global Initiative for Asthma; ISAR, International Severe Asthma Registry; LTOCS, long-term oral corticosteroid.

Notes: aThe overall cohort included patients aged 18 years or older receiving GINA (2018 criteria) step 5 treatment, or step 4 treatment but had uncontrolled asthma (ERS/ATS criteria).6 bThe biologics accessible group comprised patients who either had been prescribed a biologic during the study period (either omalizumab, mepolizumab, reslizumab, benralizumab, or dupilumab) or those who met the prescribing criteria from the BACS.23 cThe biologics accessible and received group comprised patients who received at least one dose of biologic therapy for asthma during the study period. dThe biologic recipients whose asthma remained suboptimally controlled group was defined as patients within the biologics accessible and received group who received at least three doses of a biologic and either had uncontrolled asthma defined by the GINA 2019 criteria41 following biologic initiation, had a severe exacerbation following biologic initiation, or received LTOCS. This group also included those who had switched or stopped their biologic treatment owing to a reported lack of clinical efficacy.

The biologics accessible group comprised patients who had been prescribed a biologic that was available during the study period (omalizumab, mepolizumab, reslizumab, benralizumab, or dupilumab; no patients receiving tezepelumab were included because of its recent approval) or who met the prescription criteria for those available biologics from the Biologic Accessibility Score (BACS) system developed by the ISAR group,23 at any time during the study period. Details of the BACS prescription criteria have been published previously.23 Briefly, the criteria are specific to each biologic and country, having been based on national regulatory/reimbursement authority criteria in June 2020. They are based on a list of 18 initial criteria: age, weight, asthma phenotype, blood eosinophil count, total serum IgE level, fractional exhaled nitric oxide (FeNO) level, allergic asthma diagnostic requirements (eg, skin prick test), background therapy, biologic history, treatment adherence, OCS use, exacerbation history, asthma control, lung function, symptoms, asthma diagnosis, care manager (eg, severe asthma specialist), and correct inhaler technique.

The biologics inaccessible group comprised patients in the overall cohort who did not meet the criteria for the biologics accessible group above at any time during the study period.

The biologics accessible but not received group comprised patients who met the biologics accessible group criteria above but were not prescribed a biologic therapy during the study period.

The biologics accessible and received group (ie, biologic recipients) comprised patients who met the biologics accessible group criteria and were prescribed an available biologic therapy during the study period.

The biologic recipients whose asthma remained suboptimally controlled group was defined as patients within the biologics accessible and received group who were prescribed at least three doses of a biologic and either had uncontrolled asthma (defined by the GINA 2019 asthma control classification41) following biologic initiation, had a severe exacerbation following biologic initiation, or received long-term OCS (LTOCS) treatment. Patients who had switched or stopped their biologic treatment owing to a reported lack of clinical efficacy were also included in this group.

A patient’s index date for the study was defined as the closest healthcare professional visit recorded in ISAR to when the patient first met the eligibility criteria for their group during the study period (Supplementary Table 1).

Study Measurements and Variables

Baseline patient demographics and asthma-related clinical characteristics were described for all groups. Patient demographic variables included age, sex, and body mass index. Asthma-related clinical characteristics included smoking status, smoking duration (pack-years), asthma duration, spirometry parameters, biomarker measurements (eg, FeNO level, blood eosinophil count, and serum total IgE level), and the presence of comorbidities.

To assess disease burden at baseline, asthma-related HCRU, asthma control, and medication use during the 12 months preceding the index date (baseline period) were described. Baseline disease burden was described for all groups except biologic recipients whose asthma remained suboptimally controlled, because this group was defined by their response to biologic therapy in the follow-up period. To assess disease burden following receipt of biologic therapy, asthma-related HCRU, asthma control, and medication use were described for the 12 months after the index date (follow-up period) for biologic recipients overall and for those whose asthma remained suboptimally controlled.

Asthma-related HCRU variables included the number of exacerbations, ER visits for asthma, invasive ventilations for severe asthma events, and hospital admissions for asthma. Asthma control was defined as uncontrolled, partly controlled, or well-controlled using the GINA 2019 Asthma Control Criteria/Asthma Control Questionnaire/Asthma Control Test criteria.41 Use of medications in addition to ICS-LABA, including LTOCS, theophylline, long-acting muscarinic antagonists, and leukotriene receptor antagonists, as well as use of biologics and macrolide antibiotics (including azithromycin), were also evaluated. The reasons for any lack of effectiveness of the biologic therapies received, or any changes in the biologics prescribed, were not assessed. Full details of the study variables are provided in Supplementary Tables 2 and 3.

Statistical Analyses

Descriptive statistics were generated for continuous variables (mean and standard deviation, or median and range) and categorical variables (proportion with 95% confidence intervals, as applicable); no statistical comparisons between groups were made. Missing data were quantified but excluded from the analyses.

Results Study Population

In total, 9587 patients were included in the study (Figure 1). Of these, 5073 (52.9%) had access to a T2-targeted biologic therapy and 3041 (31.7%) were classed as biologics inaccessible (insufficient data were available to determine biologic accessibility for 1473 patients [15.4%]). Among patients with access to biologics, 4651 (91.7%) received a biologic and 382 (7.5%) did not; 3346 biologic recipients (71.9%) had asthma that remained suboptimally controlled following biologic therapy. Among biologic recipients overall, 2751 (59.1%) received an anti–IL-5 therapy, 1834 (39.4%) received an anti-IgE therapy, 956 (20.6%) received an anti–IL-5R therapy, and 445 (9.6%) received an anti–IL-4/13 therapy (Supplementary Table 4). In total, 2666 biologic recipients overall were included in the follow-up analysis, including 1780 patients whose asthma remained suboptimally controlled following biologic therapy (Figure 1).

Patient Demographics and Clinical Characteristics

The baseline demographics and clinical characteristics of the patient groups are shown in Table 1 (split by biologic class for biologic recipients overall in Supplementary Table 4). Patients were predominantly female (ranging from 63.0% to 68.1% across groups), had a mean age of approximately 55 years, and had a mean asthma duration of approximately 20–25 years. Pre-bronchodilator forced expiratory volume in 1 second values were similar across groups (mean: 1.9 L) except for the biologics accessible but not received group (mean: 1.6 L). Approximately half of the patients in the biologics inaccessible and biologics accessible but not received groups, and approximately two-thirds of patients in the other groups, had FeNO levels of at least 25 ppb. Furthermore, approximately two-thirds of patients across groups had a blood eosinophil count of at least 300 cells/µL, except for the biologics inaccessible group (46.3%). Chronic rhinosinusitis was present in approximately 40% of patients across groups, but was more common in the biologics accessible but not received group (59.0%), while nasal polyps were present in approximately one-third of patients in the biologics accessible and biologic recipient groups.

Table 1 Baseline Demographics and Clinical Characteristics of Patient Groups

Asthma Burden at Baseline

In the biologics accessible group, 41.4% of patients experienced at least two exacerbations during the 12-month baseline period (Figure 2A), whereas 16.2% had at least one ER visit and 11.5% had at least one hospital admission (Table 2). The proportion of patients with uncontrolled asthma during this period was 47.9% (Figure 2B), and the proportion receiving LTOCS was 23.9% (Figure 2C). Use of non-biologic add-on controller medications is shown in Supplementary Table 5.

Figure 2 Proportions of patients with severe asthma who experienced at least two exacerbations (A), who had uncontrolled asthma (B), or who were receiving LTOCS (C) during the baseline period and follow-up period (following biologic therapy), by biologic accessibility and use.

Abbreviations: CI, confidence interval; GINA, Global Initiative for Asthma; ISAR, International Severe Asthma Registry; LTOCS, long-term oral corticosteroid.

Notes: Biologic accessibility/use was for therapies that were licensed during the study period (ie, omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab). The results reported here exclude missing data. The baseline period was the 12 months before the index date, defined as the first visit recorded in ISAR with measurements meeting the group eligibility criteria. The follow-up period was the 12 months after the index date. In panel B, asthma control as an outcome was assessed using GINA 2019 criteria.41 This differs from the group definition for biologic recipients whose asthma remained suboptimally controlled (see Figure 1).

Table 2 Asthma-Related Healthcare Resource Utilization During the Baseline Period and Follow-Up Period (Following Biologic Therapy)

In the biologics inaccessible group, 18.7% of patients experienced at least two exacerbations during the baseline period (Figure 2A), whereas 8.8% had at least one ER visit and 10.5% had at least one hospital admission (Table 2); 54.6% had uncontrolled asthma during this period (Figure 2B) and 8.6% were receiving LTOCS (Figure 2C).

In the biologics accessible but not received group, 49.6% of patients experienced at least two exacerbations (Figure 2A), 14.4% had at least one ER visit, and 6.2% had at least one hospital admission (Table 2); 71.2% had uncontrolled asthma (Figure 2B) and 11.0% were receiving LTOCS (Figure 2C).

In the biologics accessible and received group (ie, biologic recipients), 40.7% of patients experienced at least two exacerbations (Figure 2A), 16.4% had at least one ER visit, and 12.0% had at least one hospital admission (Table 2); 46.9% had uncontrolled asthma (Figure 2B) and 25.0% were receiving LTOCS (Figure 2C).

Asthma Burden Following Biologic Therapy

Among biologic recipients overall, 19.1% experienced at least two exacerbations during the 12 months following biologic treatment (Figure 2A), ranging from 17.3% for anti-IgE recipients to 22.3% for anti–IL-5R recipients (Supplementary Table 6). The proportion of biologic recipients overall who had at least one ER visit during this period was 5.9%, whereas 2.7% had at least one hospital admission. Approximately one-third of biologic recipients experienced uncontrolled asthma following biologic treatment (32.4% for biologic recipients overall; Figure 2B), ranging from 28.6% (for anti-IgE and anti–IL-4/13) to 35.7% (for anti-IL-5; Supplementary Table 6). The proportion of patients who received LTOCS during the follow-up period was 16.7% among biologic recipients overall (Table 2, Figure 2C), ranging from 11.5% for anti-IgE recipients to 20.3% for anti–IL-5 recipients (Supplementary Table 7).

Among biologic recipients whose asthma remained suboptimally controlled despite therapy, 23.0% of patients experienced at least two exacerbations during the follow-up period (Figure 2A), whereas 6.9% had at least one ER visit and 2.9% had at least one hospital admission (Table 2). The proportion of patients in this group who received LTOCS during the follow-up period was 22.0% (Figure 2C).

Discussion

A substantial disease burden was observed across the groups of patients with severe asthma studied here, including among patients who lacked access to T2-targeted biologics (omalizumab, mepolizumab, reslizumab, benralizumab, or dupilumab) and among those who had access but who did not receive these treatments during the study period. Among patients who did receive these biologics, a sizable proportion still experienced a considerable burden in terms of exacerbations, HCRU, asthma control, and LTOCS use.

Among the patients who lacked access to T2-targeted biologic therapy, approximately 40% experienced at least one exacerbation and over 50% had uncontrolled asthma during the 12-month baseline period. These findings suggest that many of these patients may require different therapy options. Prescription eligibility criteria and reimbursement availability for biologics vary substantially between countries,23 which may reflect a lack of consensus regarding which patients benefit most from which therapy. It was notable that approximately half of the patients who could not access T2 biologics had elevated FeNO levels (≥25 ppb) and/or elevated blood eosinophil counts (≥300 cells/µL), and approximately two-thirds had elevated serum total IgE levels (≥75 IU/mL) at baseline. These findings imply that many of the patients in this group did not have true T2-low phenotypes; rather, the fact that these patients did not qualify for access to T2 biologics according to the country-specific BACS criteria may indicate that the prescription eligibility criteria used in some countries are suboptimal. The dynamic nature of asthma phenotypes, including levels of inflammatory biomarkers, should also be considered;42 if applied too rigidly, phenotyping may not always help with appropriate biologic selection and may unnecessarily restrict patient eligibility.

In this study, 7.5% of patients who qualified for access to T2-targeted biologic therapy did not receive it. Various factors may have contributed to this, including limited availability of biologics and severe asthma services.23 Indeed, a large proportion of the global asthma population that may be eligible for biologics is not receiving them.43,44 In this study, patients who had access to T2-targeted biologic therapy but did not receive it had a very high burden of disease, with half experiencing at least two exacerbations and more than two-thirds having uncontrolled asthma during the baseline period. These findings highlight the impact of not prescribing biologic therapies to eligible patients.

Approximately half of the overall patient cohort in this study were prescribed a biologic therapy, a higher proportion than observed in a similar ISAR cohort using data from 2014–2017 (approximately one-quarter),38 indicative of the growing use of biologics worldwide. However, a sizable disease burden was observed here among biologic recipients overall despite use of these treatments, with one-fifth experiencing at least two exacerbations and one-third having uncontrolled asthma during the 12-month follow-up period. Furthermore, over two-thirds of biologic recipients had asthma that remained suboptimally controlled despite treatment with a biologic. A direct comparison of patients’ disease burden pre- and post-treatment was not performed, so these results should not be interpreted as an analysis of the effectiveness of the biologic therapies received. The impact of T2-targeted biologic therapy in real-world severe asthma cohorts has been assessed previously, finding that these therapies generally improve the outcomes assessed, such as exacerbation rates, asthma control, lung function, OCS exposure, and HCRU.12,45–47

A contributing factor to the considerable remaining disease burden among biologic recipients may have been the presence of symptoms resulting from comorbidities such as chronic rhinosinusitis and nasal polyps. However, it was largely expected that the disease burden would remain high among patients who received biologic treatment with omalizumab, mepolizumab, reslizumab, benralizumab, or dupilumab, because these therapies have been shown to produce only an approximate 50% reduction in exacerbation rates in clinical trial populations,13–15 while approximately 30–50% of patients in real-world studies achieve remission when treated with these biologics (although definitions of remission vary).48–50 The mechanisms of the biologics studied here (anti-IgE, anti–IL-5/IL-5R, and anti–IL-4/13) are most effective in patients with high baseline levels of T2 inflammatory biomarkers, such as blood eosinophil counts (≥260–300 cells/µL) and FeNO levels (≥25 ppb), while demonstrating reduced or negligible efficacy in patients with low T2 biomarker levels.51–55 Biologics with broader actions on asthma disease mechanisms, particularly those whose mechanisms reach beyond T2 inflammation, may be licensed for the treatment of severe asthma without biomarker or phenotypic restrictions, widening eligibility compared with the T2-targeted biologics. These include the recently introduced tezepelumab,22 a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an upstream mediator of inflammation in asthma that also has T2-independent effects.56 However, owing to its recent approval, insufficient data were available for tezepelumab to be included in the present study. Further targets under investigation for biologic therapy in severe asthma include the IL-33/ST2 pathway, IL-6, OX40 ligand, and TNF-like ligand 1A.57–62 Future real-world studies to assess clinical characteristics and HCRU among patients who receive newly approved biologics such as tezepelumab are needed to better understand the remaining unmet medical need in patients with severe asthma.

The variation in biologic accessibility criteria between the participating countries in this study meant that biologic recipients accessed these therapies at different stages of disease severity. Furthermore, health system complexities and potential delays in referral to specialists in some countries24,63,64 may have caused patients to experience delays in receiving appropriate care, including biologic therapies. Because longer asthma duration may be associated with a weaker response to biologics,65 the benefits of early biologic initiation in reducing the observed disease burden in patients with severe asthma should be investigated in future studies.

A strength of the present study is the use of ISAR, which provides a large global data set of the characteristics of patients with severe asthma and their treatment. The database consists of high-quality, patient-level, real-world, standardized data collected from multiple countries. However, the differences between countries’ healthcare systems (including biologic accessibility criteria) described above, as well as the differences in patient characteristics between the registries included in ISAR and in the amount of missing data in each registry, influenced assignment of patients to the different groups used here and constrain the generalizability of this study’s findings. The considerable variation in the observed disease burden of patients with severe asthma from different registries is clear in a recent systematic review.66 Missing data are an inherent challenge in real-world research: 15% of patients in the overall ISAR cohort here had insufficient data to determine biologic accessibility, and over 40% of biologic recipients could not be included in the follow-up period analysis. Furthermore, despite best efforts at standardization, there was inevitable variability in data recording quality and practices across the many countries and sites involved in this study. For instance, although most countries recorded exacerbations directly, in the US, exacerbations were captured by proxy via OCS use. The use of prescriptions as a proxy for receiving biologic therapy was another limitation, because in some countries patients may be prescribed biologics but not actually receive them if not covered by health insurance. A further limitation is that the study was not designed to perform statistical comparisons between groups – future studies that are designed to compare disease burden between relevant subgroups should be considered. Finally, the study did not evaluate changes in medication use, such as switching biologics, or the reasons for any lack of effectiveness of the biologic therapies received – this has been assessed previously in a similar ISAR cohort.67

Conclusions

Descriptive disease burden data provide important information to healthcare researchers and policymakers; these data may prompt strategies to improve healthcare delivery and treatment, and help in planning future need, setting resource priority, and informing future research. Data regarding the disease burden experienced by various subgroups of patients with severe asthma – for example, those with and without access to biologic therapy – are limited in the literature. However, this evidence is critical for understanding these patients’ unmet need and for informing development strategies of new treatments. The global real-world data reported here suggest a persistently high disease burden among patients with severe asthma who lack access to T2-targeted biologics and among those who have access but do not receive them. The results also highlight the remaining disease burden among patients currently receiving therapy with these biologics. Overall, the substantial unmet medical need in this population indicates the need for regulators to increase and standardize access to biologics and for researchers to develop more effective therapy options to improve the management of patients with severe asthma.

Data Sharing Statement

The dataset supporting the conclusions of this article was derived from the International Severe Asthma Registry (ISAR). This study was approved by the Anonymised Data Ethics Protocols and Transparency (ADEPT) committee – the independent scientific advisory committee for ISAR. The authors do not have permission to give public access to the study dataset; researchers may request access to ISAR data for their own purposes. ISAR research requests and proposals can be made via the ISAR website (https://isaregistries.org/research-proposal-requests/) or via the enquiries Email to [email protected]. In line with ISAR governance restrictions, sharing individual deidentified participant data is subject to the consent of the ISAR steering committee in accordance with patient consent, patient confidentiality and ethical considerations. The study documents (protocol, statistical analysis plan, clinical study report) will be made available in accordance with the criteria of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS38128). Proposals should be directed to [email protected]; to gain access, if approved by the regulatory boards, data requestors will need to sign a data access agreement.

Ethical Approval and Informed Consent

The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance Code of Conduct (registration number: EUPAS106967) and with all applicable local and international laws and regulations. Registration of the ISAR database with the European Union Electronic Register of Post-Authorization studies was also undertaken (ENCEPP/DSPP/23720). Ethical governance for ISAR was provided by ADEPT (approval reference number: ADEPT-1021). All data collection sites in ISAR have obtained regulatory agreement in compliance with specific data transfer laws, country-specific legislation, and relevant ethical boards and organizations. The study was approved by the ISAR International Steering Committee and was performed in accordance with the 1964 Declaration of Helsinki and its later amendments. All participating patients provided informed consent, and their data were anonymized.

Acknowledgments

The authors thank all the ISAR collaborators (Appendix 1) and study participants, and Ekaterina Maslova of AstraZeneca for her contributions to the study design. Medical writing support was provided by Priyanka Narang, PhD, and Richard Claes, PhD, of PharmaGenesis London, London, UK, with funding from AstraZeneca.

Collaborators: EVEREST Study Working Group

Mona Al-Ahmad, Riyad Al-Lehebi, Peter Barker, Leif Bjermer, John Busby, Giorgio Walter Canonica, Borja G Cosio, Richard Costello, João A Fonseca, Peter G Gibson, Liam G Heaney, Enrico Heffler, Mark Hew, Takashi Iwanaga, David J Jackson, Piotr Kuna, Désirée Larenas Linnemann, Sverre Lehmann, Jorge Maspero, Andrew Menzies-Gow, Andriana I Papaioannou, Diahn-Warng Perng, Matthew Peters, Todor A Popov, Celeste Porsbjerg, Mohsen Sadatsafavi, Sundeep Salvi, Camille Taillé, Carlos A Torres-Duque, Eileen Wang and Michael E Wechsler.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was funded by AstraZeneca. ISAR is jointly funded by Optimum Patient Care Global and AstraZeneca.

Disclosure

Tham T. Le, Clement Erhard, Bill Cook, Anna Quinton, Neil Martin, and Trung N. Tran are employees of AstraZeneca and may own stock or stock options in AstraZeneca. David B Price has participated in advisory boards with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermo Fisher, and Viatris; has consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GSK, Medscape, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance, and Viatris; has received grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, the UK National Health Service, and Viatris; has received payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GSK, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, and Viatris; has received payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Circassia, Mundipharma, Novartis, Teva Pharmaceuticals, and Thermo Fisher; has received funding for patient enrollment or completion of research from Novartis; has stock or stock options with AKL Research and Development Ltd; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); owns 5% shareholding in Timestamp; is a peer reviewer for Health Technology Assessment and the grant committees of the UK Efficacy and Mechanism Evaluation Programme; and was an expert witness for GSK. Rohit Katial is a former employee of AstraZeneca and has been an advisory board participant and speaker for GSK and Sanofi/Regeneron. Luis Perez-de-Llano has received grants from AstraZeneca, Chiesi, and Teva Pharmaceuticals; personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, FAES, GEBRO, GSK, Mundipharma, Novartis, Sanofi, and Teva Pharmaceuticals; and nonfinancial support from Boehringer Ingelheim, Esteve, GSK, Menarini, Mundipharma, Novartis, and Teva Pharmaceuticals. Alan Altraja has received lecture fees from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, CSL Behring, GSK, MSD, Norameda, Novartis, Orion, Sanofi Regeneron, and Zentiva; sponsorships from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, CSL Behring, GSK, MSD, Norameda, Novartis, and Sanofi Regeneron; and has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, CSL Behring, GSK, Novartis, Sanofi Regeneron, and Teva Pharmaceuticals. Celine Bergeron has participated in advisory boards for GSK, Sanofi-Regeneron, AstraZeneca, Amgen, Takeda, and Valeo Pharma; has received honoraria for presentations for AstraZeneca, Amgen, Grifols, GSK, Sanofi-Regeneron, and Valeo Pharma; and her institution has received grants from AstraZeneca, Biohaven, GSK, OPRI/ISAR, Novartis, Sanofi-Regeneron and Teva. Arnaud Bourdin has received industry-sponsored grants from AstraZeneca, Boehringer Ingelheim, Cephalon/Teva, GSK, Novartis, and Sanofi-Regeneron; and been a consultant for Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, MedinCell, Merck, Novartis, Regeneron-Sanofi, and Roche. Mariko Siyue Koh has received grants from AstraZeneca; and honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from GSK, AstraZeneca, Boehringer Ingelheim, Novartis, Roche, and Sanofi. Lauri Lehtimäki has received personal fees from ALK, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis, Orion Pharma, and Sanofi. Nikolaos G Papadopoulos has been a speaker and/or advisory board member for Abbott, AbbVie, ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GSK, HAL, Faes Farma, Medscape, Menarini, MSD, Mylan, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, and Viatris. Paul Pfeffer has attended advisory boards for AstraZeneca, GSK, and Sanofi; has given lectures at meetings supported by AstraZeneca and GSK; has taken part in clinical trials sponsored by AstraZeneca, GSK, Novartis, and Sanofi, for which his institution received remuneration; has received speaker fee from Chiesi for an educational webinar and has a current research grant funded by GSK. Chin Kook Rhee received consulting/lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, GSK, MSD, Mundipharma, Novartis, Sanofi, Takeda, and Teva. Victoria Carter is an employee of Optimum Patient Care, a co-funder of ISAR. The authors report no other conflicts of interest in this work.

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