Abstract
Background Biologics have proven efficacy for patients with severe asthma but there is lack of consensus on defining response. We systematically reviewed and appraised methodologically developed, defined, and evaluated definitions of non-response and response to biologics for severe asthma.
Methods We searched four bibliographic databases from inception to 15th March 2021 (PROSPERO: CRD42021211249). Two reviewers screened references, extracted data, assessed methodological quality of development, measurement properties of outcome measures and definitions of response based on COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN). Modified GRADE approach and narrative synthesis were undertaken.
Results Thirteen studies reported three composite outcome measures, three measures of asthma symptoms, one asthma control and one quality of life. Only four were developed with patient input; none were composite measures. Studies utilised 17 definitions of response: 10/17 (58.8%) were based on Minimal Clinically Important Difference (MCID) or Minimal Important Difference (MID) and 16/17 (94.1%) had high quality evidence. Results were limited by poor methodology for development process and incomplete reporting of psychometric properties. Most measures rated “very low” to “low” for quality of measurement properties and none met all quality standards.
Conclusion This is the first review to synthesize evidence about definitions of response to biologics for severe asthma. While high quality definitions are available, most are MCIDs or MIDs which may be insufficient to justify continuation of biologics in terms of cost-effectiveness. There remains an unmet need for universally accepted, patient-centred, composite definitions to aid clinical decision making and comparability of responses to biologics.
Footnotes
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Conflict of interests: Ekaterina Khaleva and Anna Rattu declare funding for the present manuscript from the 3TR European Union Innovative Medicines Initiative 2 paid to the university.
Conflict of interests: Chris Brightling declares grants from GSK, AZ, Novartis, Chiesi, BI, Genentech, Roche, Sanofi, Mologic, 4DPharma, consulting fees from GSK, AZ, Novartis, Chiesi, BI, Genentech, Roche, Sanofi, Mologic, 4DPharma, TEVA and support from the 3TR project.
Conflict of interests: Arnaud Bourdin reports being an investigator for clinical trials promoted by AZ, Chieisi, GSK, BI, Novartis, Regeneron, Sanofi; having received fees for lectures, attendance of meeting and consultancy from AZ, Chieisi, GSK, BI, Novartis, Regeneron, Sanofi; received research grant from AZ, and BI; participation on a Data Safety Monitoring Board or Advisory Board of AB science.
Conflict of interests: Apostolos Bossios has received lecture fees from GSK, AZ, Teva and Novartis; honoraria for Advisory Board Meetings from GSK, AZ, Teva, Novartis and Sanofi; and got support for attending meetings from AZ and Novartis, all outside the present work; reports being a member Member of the steering Committee of SHARP, Secretary of Assembly 5 (Airway diseases, asthma, COPD and chronic cough), European Respiratory Society and Vice-chair of Nordic Severe Asthma Network (NSAN).
Conflict of interests: Kian Fan Chung has received honoraria for participating in Advisory Board meetings of GSK, AZ, Roche, Novartis, Merck, and Shionogi regarding treatments for asthma, chronic obstructive pulmonary disease and chronic cough and has also been renumerated for speaking engagements for Novartis & AZ.
Conflict of interests: Rekha Chaudhuri has received lecture fees from GSK, AZ, Teva, Chiesi, Sanofi and Novartis; honoraria for Advisory Board Meetings from GSK, AZ, Teva, Chiesi, Novartis; sponsorship to attend international scientific meetings from Chiesi, Napp, Sanofi, Boehringer, GSK and AZ and a research grant to her Institute from AZ for a UK multi-centre study.
Conflict of interests: Courtney Coleman declares funding received to support this work by European Lung Foundation from European Commission's Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 831434 (3TR).
Conflict of interests: Ratko Djukanovic declares funding from ERS, TEVA, GSK, Novartis, Sanofi and Chiesi for the SHARP CRC; consulting fees for Synairgen; honorarium for a lecture from GSK; participation on a Data Safety Monitoring Board or Advisory Board for Kymab (Cambridge) and shares in Synairgen outside of the submitted work.
Conflict of interests: Sven-Erik Dahlen declares funding from 3TR IMI Grant; consulting fees from AZ, Cayman Co, GSK, Novartis, Regeneron, Sanofi and Teva; honoraria for lectures from AZ and Sanofi.
Conflict of interests: Andrew Exley declared being a Minority shareholder in GlaxoSmithKline PLC.
Conflict of interests: Louise Fleming declares participation in advisory boards and honoraria for lectures from Sanofi, Respiri UK, Astra Zeneca, Novartis and Teva outside of the scope of this publication. All payments were made to her institution.
Conflict of interests: Atul Gupta received speaker and advisory board fees from GSK, Novartis, Astra Zeneca. Boehringer Ingelheim. AG Institution received research grants from GSK, Novartis, Astra Zeneca Boehringer Ingelheim.
Conflict of interests: Eckard Hamelmann declares support from German Ministry of Education and Research (BMBF) and German Asthma Net (GAN) e.versus; funding for research in Severe asthma in children (CHAMP- 01GL1742D) and for Severe Asthma Register.
Conflict of interests: Gerard H Koppelman reports receiving research grants from Lung Foundation of the Netherlands, Ubbo Emmius Foundation, H2020 European Union, TEVA the Netherlands, GSK, Vertex, outside this work (Money to Institution); he reports memberships of advisory boards to GSK and PURE-IMS, outside this work (Money to institution).
Conflict of interests: Erik Melen has received consulting fees from AstraZeneca, Chiesi, Novartis and Sanofi outside the submitted work.
Conflict of interests: Vera Mahler has no conflict of interest but declares that the views expressed in this review are the personal views of the author and may not be understood or quoted as being made on behalf of or reflecting the position of the respective national competent authority, the European Medicines Agency, or one of its committees or working parties.
Conflict of interests: Florian Singer reports being an investigator for clinical trials promoted by Vertex and having received fees for lectures from Vertex and Novartis, outside the submitted work.
Conflict of interests: Celeste Porsbjerg declares grants, consulting fees and honoraria from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK (paid to institution and personal honoraria); participation in the Advisory Board for AZ, Novartis, TEVA, Sanofi and ALK, outside the submitted work.
Conflict of interests: Valeria Ramiconi reports grants paid to EFA from Pfizer, Novartis, Astra Zeneca, Sanofi, Chiesi Farmaceutici, Regeneron, DBV Technologies, MSD, GSK, Aimmune, LeoPharma, Abbvie, Boehringer Ingelheim, OM Pharma and Roche. Payment for expert testimony from Novartis Global Respiratory Patient Council 2021 and Novartis EPIS Steering Committee to EFA.
Conflict of interests: Graham Roberts discloses funding from EU IMI programme paid to his University from European Union to undertake this project; consulting fees from Astra Zeneca paid to his institution. Other co-authors have nothing to disclose.
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- Received August 30, 2022.
- Accepted December 6, 2022.
- Copyright ©The authors 2023
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