Introduction

Chronic obstructive pulmonary disease (COPD), characterized by permanent airflow obstruction and respiratory symptoms, represents a widespread condition; recent estimates suggest that the global prevalence could be as high as 392 million people1,2 while many cases remain undiagnosed. A review of community-based studies concludes that between 50%-70% of COPD worldwide may be undiagnosed.3 In 2021, COPD caused 45.2 deaths per million population worldwide, making it the third leading cause of mortality (excluding COVID-19).4 COPD patients typically suffer from reduced quality of life and increased susceptibility to comorbidities, especially cardiovascular disease.5 The disease course for moderate-to-severe COPD is often marked by acute respiratory events (exacerbations) and hospitalizations.6

COPD, alongside other respiratory conditions, results in significant healthcare resource utilization (HCRU) and imposes a substantial burden on healthcare systems.7–10 In the European Union (EU), respiratory diseases account for about 6% of the yearly healthcare budget, with COPD responsible for 56% of these costs, approximately 38.6 billion euros.11 Exacerbations are frequently reported as the key driver of COPD’s economic burden,12 ranging from 45% to 70% of the total cost of managing the disease.13 Moderate-to-severe COPD patients experience increased likelihood and severity of exacerbations,14 contributing substantially to the disease burden and HCRU.15

COPD’s optimal management aims to reduce symptoms and improve quality of life while preventing exacerbations, disease progression and mortality. It requires a multifaceted approach, including pharmacological and non-pharmacological interventions tailored to patients’ needs16,17 and collaborative efforts between primary and secondary care providers. Pharmacological treatment choices are guided by the patient’s symptoms, exacerbation risk, existing comorbidities, treatment response, preference, and ability to use different drug delivery devices.18 Adherence to guideline-directed medical therapy ensures that treatment plans consider all these elements and lead to better outcomes for patients and healthcare systems.19

The Global Initiative for Obstructive Lung Disease (GOLD) strategy document recommends the combination of a long-acting muscarinic antagonist (LAMA), long-acting β2-agonist (LABA) and an inhaled corticosteroid (ICS), referred to as “triple therapy”, in moderate-to-severe COPD patients who are not adequately treated by dual therapy (LAMA/LABA). GOLD now also proposes first-line use of triple therapy in GOLD E patients (at risk of exacerbations) with > 300 blood eosinophils/µL.17 Triple therapy can be administered as Multiple Inhaler Triple Therapy (MITT) or Single Inhaler Triple Therapy (SITT). The approved European Medicine Agency (EMA) indication for SITT is for patients who are not adequately controlled by dual therapy.20–22

Large randomized controlled trials (RCTs) comparing SITT to dual therapy (LABA/LAMA or ICS/LABA) demonstrated lower exacerbation rates and potentially decreased mortality for patients receiving SITT.23,24 Reductions in COPD-related HCRU and costs have also been found,25–28 mainly linked to the enhanced convenience and improved adherence that SITT offers compared to MITT.29–33 Despite this evidence, access to SITT in primary care for moderate-to-severe COPD patients differs widely across Europe,34 influenced, among other factors, by payer-driven access criteria.35

These criteria are typically intended to ensure prescription appropriateness and control costs.35–37 On the other hand, they may affect the management of moderate-to-severe COPD patients in some primary care settings35 because they restrict the range of treatment options that primary care providers (PCPs) can prescribe. However, no studies have described or quantified this impact so far.

This expert panel aims to generate a shared understanding of the potential consequences of payer-driven access criteria for SITT in primary care in various EU healthcare systems and assess whether there is a need to revisit these criteria. Through a comprehensive review of the available evidence and expert opinion (the authors), this statement provides key arguments highlighting the importance of ensuring equitable access to SITT for moderate-to-severe COPD patients across primary and secondary care settings.

Materials and Methods

This study used three methods. First, a targeted literature review (TLR) was conducted to summarize the available evidence around SITT (clinical and economic impact compared to MITT and dual therapy) and how access to SITT in primary care varies across Europe. This was followed by in-depth semi-structured interviews to understand the views of various experts on how payer-driven access criteria that prevent PCPs from initiating SITT in eligible patients may affect clinical practice, patients and healthcare systems. Lastly, a consensus generation workshop was run to develop a series of position statements that deliver evidence- and expert-backed arguments about the impact of payer-driven access criteria in primary care to inform policy recommendations.

Targeted Literature Review (TLR)

Initial scoping searches were used to draft a series of hypotheses (potential arguments) and link them to relevant research questions for the TLR (see 1 Appendix). The research questions were then used to develop a PICO framework (see 2 Appendix) to guide pragmatic PubMed and Google Scholar searches. Manual searches of grey literature were conducted to identify information about payer-driven access criteria (eg, HTA and reimbursement policy documents, etc). Published articles and grey literature items were included based on their relevance to answering the research questions.

A refined structure of the hypotheses outlined in 3 Appendix was discussed with the experts; this was modified if there was insufficient evidence to back the arguments. Further amendments to the arguments were made based on the feedback provided by the experts (see section below on “Consensus generation activities”).

Predetermined data extraction frameworks were used to sort the TLR evidence, and narrative synthesis was used to analyze the findings.

In-Depth Semi-Structured Interviews

The semi-structured interviews were carried out by a team of two researchers (distinct from the expert panel) with a total of 14 experts: 11 clinicians involved in managing COPD (seven pulmonologists and four PCPs), one health economist, and two Patient Advocacy Group (PAG) representatives. The qualitative analysis followed the consolidated criteria for reporting qualitative research (CORE-Q) checklist.38 Anonymized interview data were analyzed using reflexive thematic analysis.

Participant Selection

A total of 15 potential participants (internationally recognized external experts whose clinical and research work includes COPD and inhaled therapy) were approached through an email invitation, and 14 agreed to participate in the study. The participants that were approached met one of the following criteria: 1) PCPs or respiratory specialists involved in the management of moderate-to-severe COPD patients working in any of the following countries at the time of the study: Austria, Belgium, England, France, Germany, Italy, Netherlands, Portugal or Spain; or 2) COPD PAG representatives with a global or European remit; or 3) health economist or policy expert with a deep understanding of payer rules for the pharmacological management of COPD in primary and secondary care.

Purposive sampling was used to identify experts from various European countries to provide a balanced comparison across healthcare systems that apply different rules to accessing SITT in primary and secondary care.

Data Collection

Interviews took place between December 2023 and January 2024 online via Microsoft Teams®. All participants were provided with documentation outlining the nature and purpose of the study and how the data would be used, stored, and shared (the use of recordings and any future uses of the data). Participants provided informed written consent to participate, including consent to quote their words to substantiate the findings. All communications with the experts who participated in the study were managed online, including initial contact, scheduling, and conducting the interviews via emails and virtual meetings.

An example of an interview discussion guide is provided in 4 Appendix. Two interviewers were present in each call: a lead and a notetaker. Transcripts were not returned to participants for correction, but a summary of key findings was shared with all participants, and they were requested to corroborate the interpretation of interview data. All participants consented to receive follow-up emails with clarifying questions regarding the interview content.

Data Analysis

A mix of deductive and inductive approaches was used. A predetermined coding framework derived from 1 Appendix guided the line-by-line coding in NVivo® to ensure that the interview data were organized in a similar structure as the TLR hypothesis. New codes were added to the framework wherever necessary (inductive component).

Consensus Generation Activities

Following the individual interview process, the experts were invited to participate in a consensus-generation workshop that shaped agreement on the consensus arguments.

The experts received a pre-read prior to the workshop, which included the results of the TLR, themes from in-depth interviews, and an initial draft of the consensus arguments for validation (3 Appendix). Given the different nature of challenges in each country, the experts ranked the arguments and statements based on their applicability and relevance to each expert’s country (5 Appendix).

A consensus generation workshop was then launched as a videoconference, with a moderator (distinct from the expert panel members) leading all the sessions. The experts were organized into four panels based on the status of payer-driven access criteria in their countries: a) PCPs face restrictions to prescribe SITT, b) no restrictions, c) restrictions lifted recently and d) experience from PAGs. Each expert was actively involved by asking questions about the impact of the payer-access criteria, focusing on identifying the key components of the “call to action” and optimal solutions.

The consensus arguments and their corresponding rankings of relevance were shared and discussed in the workshop. Group agreement was reached on (1) streamlining the arguments by removing those that did not apply to all countries and (2) refining the language for the arguments.

Finally, a written document including unanimously endorsed position statements and a summary of the evidence from the TLR and qualitative research were shared offline with the experts for their final approval, alongside a live version to provide comments. Similar to the workshop, an independent moderator (not part of the expert panel) facilitated the resolution of contradicting views through mutual agreement between the experts to reach full alignment.

Ethics

No personal or patient-specific information was collected during the interviews and workshop discussions. Participants were asked questions regarding the healthcare services for COPD in their country. Therefore, the project was deemed a service evaluation, and no ethics approval or review was necessary. Any data collected before, during and after the interview was handled following the European Union’s General Data Protection Regulation (GDPR) legislation.

Results Targeted Literature Review

Only one published article described how access to triple therapy (focusing specifically on SITT) varies across Europe;34 most of the evidence on the status of payer-driven access rules for SITT was informed by grey literature. Table 1 describes some of the payer-driven access criteria that affect the pharmacological management of COPD in primary care. In most European countries, these restrictions are not in place or have been lifted recently (France and Spain). However, in several others (eg, Austria, Bulgaria, Czech Republic, Greece, Hungary, Italy, Lithuania, and Romania), PCPs cannot initiate SITT because its initial prescription is limited to a respiratory specialist (or in some cases to other specialists such as internists).

Table 1 Description of Some Payer-Driven Access Rules for Triple Therapy in Primary Care Across European Countries

No published evidence was identified to describe the impact of payer-driven access criteria for SITT in primary care. There was good availability of evidence on the impact of using triple therapy (both SITT and MITT) on patients and healthcare systems. Appendix 6 provides details from 46 articles that compared SITT with dual therapies, six articles that compared prompt initiation of triple therapy (both SITT and MITT) after a COPD exacerbation to delayed treatment initiation, and 23 articles comparing SITT to MITT.

Themes From Qualitative Analysis of Interview Data with the Experts

Following the in-depth interviews with 14 experts, we identified five themes: 1-Variations between countries; 2-Unintended consequences; 3-Specialist access; 4-Remaining challenges; and 5-Access inequalities for patients. The detailed themes and subthemes are presented in Table 2.

Table 2 Themes and Subthemes From Analyzing 14 Interview Transcript With Experts Across Nine Countries: Austria, Belgium, England, France, Germany, Italy, Netherlands, Portugal and Spain

The experts confirmed the TLR findings that while triple therapy is authorized in the EU as maintenance treatment for moderate-to-severe COPD patients who remain uncontrolled despite being on dual therapy, in some countries, it is subject to payer-driven access criteria that prevent its initiation in primary care. In these cases, either specialist initiation or approval of the therapeutic plan by a specialist is required. These restrictions may apply to MITT and SITT, but SITT seems disproportionally affected (in some countries, dual therapy initiation is also limited to specialist initiation only; see Table 1). The experts referred to cases where restrictions apply only to SITT while PCPs can initiate MITT (eg in Italy and Greece), posing logical inconsistencies and further complicating the treatment landscape.

The experts perceived several potential unintended consequences arising from payer-driven access criteria for SITT in primary care, including reduced PCP autonomy, perpetuation of lack of awareness about SITT, interruption of patient care journeys, and possibly suboptimal outcomes leading to higher long-term costs. The experts explained that the extent of these unintended consequences is influenced by the organization of the healthcare system, particularly regarding specialist access. They suggested that areas with limited specialist access may be disproportionately affected, whereas in healthcare systems where no referral to specialists is required (eg, Austria), some of the unintended consequences may be mitigated by direct access to specialists.

However, even in countries with no payer-driven access criteria for SITT, experts identified ongoing obstacles to optimal COPD management in primary care. These included their perceptions of insufficient PCP awareness about SITT, limited availability of quality spirometry, and the need for improved prescription appropriateness through education.

According to the PAG representatives, patients view payer-driven access criteria as drivers of inequality, especially when treatment initiation depends heavily on specialist access. They reported that patients prioritize timely access to effective treatment options at the first and most convenient point of contact with the healthcare system.

Finally, the experts highlighted the complex interplay between payer-driven access criteria for the pharmacological management of COPD, healthcare system organization, and the need for continuity of care for COPD patients. They suggested the need for potential policy initiatives to reduce avoidable barriers to guideline-directed medical therapy in primary care.

Results From Consensus Generation Activities

After considering the TLR evidence, qualitative evidence from the interviews, and the workshop discussions (see Appendix 4 for the experts’ ranking of the initial hypothesis), seven position statements were endorsed by all the 14 experts in the panel (Figure 1).

Figure 1 Final position statements (seven) emerging from the expert consensus panel on the need to revisit payer-drive access rules that prevent primary care physicians from prescribing single-inhaler triple therapy to moderate-to-severe COPD patients that meet clinical criteria according to the guidelines.

Discussion

The findings from the in-depth interviews and the consensus generation activities showed that the views of the experts in this panel were aligned; payer-driven access criteria can have unintended consequences on the clinical practice when managing COPD patients in primary care. The lack of peer-reviewed publications that quantify this impact can be a barrier to providing payers with sufficient evidence for revisiting the criteria. However, the position statements provided by the expert panel could serve as a valid indication that the payer-driven access criteria in primary care represent an avoidable barrier to the continuum of care for COPD patients in countries where they are applicable.

This discussion further elaborates on each statement to showcase the rationale behind each statement and provide further interpretation in light of available evidence on SITT.

The position statements are shaped by the experts’ views and their interpretation of the available evidence. The expert’s previous experience with inhaled therapy for COPD and, more specifically, with SITT may introduce an unavoidable selection bias that must be considered when interpreting each statement.

Position Statement 1

There is an unmet need for appropriate pharmacological management among COPD patients who remain inadequately treated by dual therapy or MITT in primary care, adding to COPD’s clinical and economic burden.

A significant proportion of moderate-to-severe COPD patients in primary care who are eligible for SITT remain inadequately controlled with dual therapy or MITT.35,46–55 The persistence of symptoms and exacerbations despite being on treatment highlights potential issues with current COPD management strategies in primary care.46 Among other reasons (eg, issues related to medication adherence and the severity of individual cases), inappropriate therapy selection53,55,56 and a lack of treatment adjustments57 based on patient-specific disease progression are important contributors.

It is worth emphasizing that the nature of the unmet need in primary care may be different for patients on LAMA/LABA dual therapy from those treated with MITT, given that patients on MITT already have an ICS in their regimen and the poor symptom control may be attributable to issues with persistence and adherence58 (further explored in Position Statement 2).

Patients who do not respond to dual therapy often experience a lower quality of life, marked by increased dyspnoea, fatigue, and limited physical activity.26,28,46 Frequent exacerbations, which are common in this population, lead to a further decline in lung function, increased hospital admissions, increased cardiopulmonary risk, and a greater risk of mortality.59–62 The physical and psychological distress associated with uncontrolled symptoms significantly impacts patients’ overall well-being and ability to perform daily activities.46,59

From an economic perspective, inadequately managed COPD places a burden on healthcare systems; frequent exacerbations, hospitalizations, and cardiovascular events associated with poorly controlled COPD result in high direct medical costs.61–64

Policymakers, payers, and healthcare providers must understand this unmet need and revisit any policies or access rules that further complicate the care pathway to optimized treatment for COPD patients who remain uncontrolled on dual therapy or MITT in primary care.

Position Statement 2

Being able to step up or switch eligible COPD patients to SITT in primary care reduces the need for PCPs to rely on potentially less effective treatment options such as MITT; benefits include improved treatment adherence, patient outcomes, costs and health system resilience.

In the management of COPD, the availability of SITT can influence the choice of treatment strategies for healthcare providers; when PCPs lack access to initiate SITT, it impacts their prescribing patterns and attitudes towards managing moderate-to-severe COPD patients.35,36,65 This limitation often forces PCPs to rely on MITT (in countries where they can initiate it), which involves the use of multiple inhalers.35 This can lead to increased complexity in managing medication regimens for patients and decreased treatment adherence.30 Prescribing MITT instead of SITT can adversely affect patient-reported outcomes; compared to MITT, SITT is preferred by patients and associated with higher quality of life.29,66 The impact of prescribing MITT instead of SITT also extends to clinical outcomes. Studies have demonstrated that SITT can lead to better symptom control, reduce the rate of exacerbations, and potentially lower mortality compared to MITT.31,32,67,68

The effectiveness of COPD treatment regimens relies significantly on patient adherence and proper inhaler technique. Current evidence suggests that treatment adherence rates are notably higher with SITT compared to MITT,30,32,69,70 supporting a stronger case for the preferential use of SITT in clinical practice for patients who are eligible for triple therapy. This is primarily due to SITT’s simplified regimen, which involves only one inhaler instead of the multiple devices required in MITT. This is easier for patients to manage and reduces the likelihood of missing doses, a common issue involving multiple inhalers.71 Moreover, the potential for inhaler usage errors is markedly reduced with SITT.66 The complexity of handling multiple inhalers may lead to incorrect use,30,72 which can significantly undermine the effectiveness of the therapy.

Lastly, the economic implications of prescribing SITT versus MITT are significant. SITT is cost-saving compared to MITT due to higher adherence rates, decreased exacerbations, and hospital visits.32,33 This reduces direct healthcare costs associated with treating exacerbations and decreases the overall healthcare resource utilization.32,73 Patients also benefit from switching to SITT as this reduces out-of-pocket payments due to prescription charges (patients that are prescribed MITT pay more than one prescription charge); in the UK, the prescription charge is £9.99 per medicine74).

Enabling step-up or switching to SITT for COPD patients who remain poorly controlled despite receiving dual therapy or MITT can improve prescribing patterns for PCPs, enhance patient-reported and clinical outcomes, and lead to cost savings when managing COPD. Healthcare policies must align to support the use of the most effective and efficient therapies in primary care.

Position Statement 3

Having the option to initiate SITT in eligible patients may empower PCPs, leading to improved confidence and clinical autonomy; this contributes to improved uptake of guideline-directed medical therapy for COPD in primary care.

Primary care settings play a pivotal role in managing COPD,75 including regularly reviewing patient conditions, modifying treatment plans, and making necessary specialist referrals.76 PCPs’ active engagement in these areas is crucial for timely adjustments to treatment as the disease progresses. When PCPs are restricted from initiating treatment options like SITT, their ability to provide optimal care is limited. This impacts PCPs’ clinical autonomy, diminishing their ability to make independent, informed decisions regarding the pharmacological management of moderate-to-severe COPD patients. Such constraints can also affect the interest and engagement in managing these patients altogether, leading to therapeutic inertia marked by clinical and economic consequences.46,77 Moreover, the restrictions can lead to frustration and dissatisfaction among PCPs, further complicating the management landscape of COPD.

However, all clinicians should recognize the negative consequences of inappropriate prescribing of ICS78 and ensure the step-up to SITT is done in line with clinical guidelines and treatment indications. Education of PCPs and improved awareness of guidelines will have an impact on prescribing.

Enabling PCPs to initiate the full range of the necessary treatment options in primary care, alongside improved training and education around SITT, could mitigate some of the therapeutic inertia and the associated burden; a balanced view of benefits and risks is essential to ensure the step-up to SITT leads to improved outcomes.

Position Statement 4

Recent evidence shows that patient profiles in which SITT is prescribed are generally consistent between primary and secondary care; this addresses concerns about its overuse or misuse in primary care.

One of the reasons why payers sometimes impose access rules on SITT is concerns about prescription appropriateness, particularly in primary care settings compared to secondary care.34 These concerns stem from assumptions that PCPs might not have the same specialized expertise as their secondary care counterparts, potentially leading to inappropriate prescribing. However, although relatively limited, the available evidence indicates that the characteristics of the patients for whom SITT is prescribed are the same, irrespective of whether PCPs or specialists in secondary care initiate the treatment.70,79–81 This evidence supports the argument for equitable access to SITT across different care settings, ensuring that all patients who meet the clinical criteria can benefit from this treatment option at the earliest point of interacting with the healthcare system without unnecessary restrictions.

However, even when there are no restrictions in place, there is insufficient awareness among PCPs about the availability of more convenient and effective treatment options such as SITT compared to MITT.82 Moreover, the diagnosis and assessment of COPD severity are often hindered by the availability and quality of spirometry,36,65,83,84 which can lead to delays in diagnosis or misclassification of disease severity,85 affecting the initiation of any COPD treatment, including SITT. Programmes to improve access to and use of spirometry are needed to overcome this challenge. They should be linked to targeted education and training in primary care settings to improve the appropriateness of treatment prescriptions for COPD.86

Position Statement 5

Some referrals to specialists for SITT initiation may be unnecessary, introducing further delays in accessing guideline-directed medical therapy due to typically long waiting times to access specialist care.

PCPs are central in COPD management,75 including making decisions about when to escalate treatment and refer to a specialist. When PCPs have access to all available treatment options, they are more likely to assume greater responsibilities in managing COPD patients in primary care.35,87,88 If they cannot provide the necessary treatment option, they might default to referring patients to specialists. Some of these referrals could be unnecessary or contribute to increased waiting times before COPD care is provided,65 leading to inefficiencies in patient pathways.89

This is particularly relevant in countries where a PCP referral is requested to see a specialist. The waiting time to see a specialist for COPD varies widely,90 and it is determined by various factors, but the experts in this panel reported that it ranges from a few weeks to up to 12 months. The clinical outcomes of delayed access to SITT are significant; prolonged periods without optimal treatment can lead to increased rates of exacerbations,91–93 and poor symptom control.94 As a correlate, delays in receiving the most effective treatment can lead to increased HCRU, including more frequent hospital admissions, emergency visits, and a general escalation in healthcare costs associated with managing acute exacerbations and complications of inadequately treated moderate-to-severe COPD.58,93,95–97

Streamlining the patient pathway to SITT by removing unnecessary barriers where possible could result in more efficient use of healthcare resources.

Position Statement 6

Integrating clinical management between primary and secondary care and strengthening the role of primary care in this process would improve continuity of care for moderate-to-severe COPD patients.

COPD is a highly prevalent disease,98 and integrated clinical management between primary and secondary care is crucial for maintaining continuity of care throughout the healthcare system, particularly for patients with moderate-to-severe COPD.99 Strengthening the role of primary care in this integrated model is expected to enhance the patient experience by ensuring that the care journey is responsive to the patient’s needs at various stages of their treatment.100–102 Collaboration and integration between primary care and specialists are crucial for limiting therapeutic inertia in COPD, especially in patients with inadequate pharmacological treatment regimens.103 Furthermore, such models contribute to better overall health outcomes and have been shown to be cost-effective.104–107

PCPs are well-positioned to manage patients with comorbidities, as they can integrate and coordinate information from different specialities.88 This is particularly beneficial in COPD management, where comorbid conditions such as cardiovascular disease, diabetes, and anxiety frequently coexist and can complicate treatment protocols.88,108 Primary care physicians’ holistic view of their patients’ health allows for more comprehensive management for moderate-to-severe COPD patients.109

Enhancing the role and autonomy of primary care and improving collaboration, communication and integration with secondary care is essential for ensuring continuity of care for moderate-to-severe COPD patients.35,110,111

Position Statement 7

Limiting SITT initiation only to secondary care or specialized centres may worsen existing inequalities in accessing optimal care and undermine efforts to provide universal health coverage.

Access to specialist care for COPD varies between and within countries,112,113 often reflecting broader healthcare resource distribution and infrastructure differences.36 In some areas, access to specialists may be limited and requires travel time, which places a burden on patients who need regular and specialized COPD management.36,114

Geographic and socioeconomic factors significantly influence the unequal access to quality care for COPD patients.113,115 Those living in remote or economically disadvantaged areas are less likely to have timely access to specialist care, including access to treatment such as SITT.36 This uneven access landscape can lead to disparities in health outcomes.116,117

The timing and appropriateness of pharmacological interventions play a critical role in managing moderate-to-severe COPD,91,92 often outweighing the importance of who initiates the treatment (PCP or specialist).38,46 For example, treatment optimization at the first point of call following an exacerbation is vital for COPD patients. When access to specialists is limited, PCPs become crucial in ensuring the continuity of care. They carry out critical tasks such as adjusting and optimizing treatment plans based on the current clinical status and recent exacerbations.76

Considering all the above, payer-driven access criteria may inadvertently affect the equity and continuity of care for moderate-to-severe COPD patients; health policies must promote equitable access to COPD treatments across all levels of care, ensuring that all patients, regardless of their geographical location or economic status, can receive the best possible care for their condition.

Conclusion

Payers need to consider reassessing the criteria that limit PCPs’ ability to initiate SITT in countries where they are still applicable to mitigate the unintended consequences that may affect patient outcomes, healthcare system efficiency, costs and equitable access to care. This reassessment should be done in line with considerations about the unique features of each country’s healthcare system and the available evidence that demonstrates the impact.

Acknowledgment

Yuchen Hsu and Emma Crawford supported the main authors with the narrative synthesis of the targeted literature review.

Author Contributions

All authors made a significant contribution to the work reported. All coauthors drafted, revised or critically reviewed the article; agreed on the journal to which the article will be submitted; gave final approval of the version to be published; and agreed to take responsibility and be accountable for the article’s contents.

Funding

Aquarius Population Health was funded by AstraZeneca to carry out this research. The study design, data collection, data analysis and interpretation of results were carried out independently by the authors. AstraZeneca reviewed the manuscript for medical and scientific accuracy. The authors confirm they had full access to all the data in this study and take complete responsibility for the integrity and accuracy of the analysis.

Disclosure

FDM has received honoraria for lectures at national and international meetings, served as a consultant, and received financial support for research funds and fees from AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Chiesi Farmaceutici, Guidotti/Malesci, GLAXOSMITHKLINE., and fees (advisory boards, consultation, education, presentations) from Austral, Biosency, MSD., AstraZeneca, Chiesi, Menarini, Nuvaira, Neopharmed Gentili, Novartis, Sanofi, and Zambon. OS declare no conflicting interests in relation to this work. AV has received honoraria for lectures at national and international meetings and served as a consultant for Astra Zeneca, Boehringer Ingelheim, Chiesi, GLAXOSMITHKLINE, Menarini, Sanofi, and Zentiva. CJ reports serving as an advisory board member and a paid speaker for Amgen, AstraZeneca, BMS, CSL, Behring, Gilead, Incyte, MSD, Roche, Sanofi, and Takeda. Outside the submitted work CJ has carried out research projects in the last 3 years funded by AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Biogen, B.M.S., Boehringer Ingelheim, Daiichi Sankyo, Egualia, Gilead, Incyte, Janssen Cilag, Lundbeck, MSD, Novartis, Roche, Pfizer, Sandoz, Sanofi, Takeda, and Teva. BL reports personal fees from ASTRA ZENECA, GSK, and CHIESI. CM received fees as a speaker from AstraZeneca, GLAXOSMITHKLINE, Sanofi, Chiesi, Menarini, Guidotti, Novartis, Zambon, and Boehringer. GP has received lecture and consultancy fees from Alfasigma, AstraZeneca, Chiesi, GlaxoSmithKline, Guidotti-Malesci, Menarini, Mundipharma, Novartis, Sanofi, and Zambon. CFV has given presentations at symposia and/or served on scientific advisory boards sponsored by Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL, Behring, Grifols, GLAXOSMITHKLINE, Insmed, MedUpdate, Menarini, Novartis, Nuvaira, Roche, and Sanofi. DF has received honoraria for lectures from AstraZeneca, GLAXOSMITHKLINE, and Chiesi, provided funded consultant support to AstraZeneca and received support for local healthcare projects from AstraZeneca. JWHK reports grants, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, grants and personal fees from Chiesi, grants, personal fees and non-financial support from GLAXOSMITHKLINE, non-financial support from Mundi Pharma, grants and personal fees from Teva, personal fees from MSD, personal fees from COVIS Pharma, personal fees from ALK-Abello, grants from Valneva outside the submitted work; and JWHK holds <5% shares of Lothar Medtec GmbH and 72.5% of shares in the General Practitioners Research Institute. LA has served as an advisor or consultant for AstraZeneca, GlaxoSmithKline, and Merck Sharp & Dohme; served as a speaker or a member of a speakers bureau for AstraZeneca, GlaxoSmithKline, BIAL, Viatris, and Novartis Pharmaceuticals Corporation. He is also a member of the Education Subcommittee of the International Primary Care Respiratory Group and a member of the GRESP, the Portuguese Primary Care Study Group for Respiratory Diseases. MCR has received speaker fees from AstraZeneca, Boehringer Ingelheim, Bial, Chiesi, CSL, Behring, GlaxoSmithKline, Menarini, Novartis, Pulmox, Zambón and Grifols, and consulting fees from GlaxoSmithKline and Bial. RP has received consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, MSD and Sanofi and has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, Chiesi and GlaxoSmithKline. SP reports grants from AbbVie, AstraZeneca, Aimmune, Boehringer Ingelheim, Chiesi, DBV Technologies, OM Pharma, GlaxoSmithKline, Novartis, Pfizer, Regeneron, Roche, and Sanofi. SP reports employment at the European Federation of Allergy and Airways Diseases Patients Associations (EFA). EFA receives unrestricted grants from corporate entities, as mentioned above. SP serves as EFA representative in the following advisory groups of these entities: AstraZeneca (COPD Advisory Committee, Global Respiratory Taskforce), GlaxoSmithKline (Health Advisory Board), Novartis (European Patient Advisory Group and Steering Committee of European Patient Innovation Summit), and Sanofi (Severe Asthma Working Group). TW received paid speaker and advisor fees for AstraZeneca, GSK, Merck/MSD, Novartis, and Sanofi Regeneron outside the submitted work. NR reported receiving grant funding from Boehringer Ingelheim, Novartis AG, Pfizer Inc, and GlaxoSmithKline and personal fees from Boehringer Ingelheim, Novartis AG, Pfizer Inc, GlaxoSmithKline, Austral Pharma, Biosency, MSD, AstraZeneca, Chiesi Farmaceutici SpA, Menarini Group, Nuvaira, Sanofi SA, and Zambon outside the submitted work. The authors report no other conflicts of interest in this work.

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