Placebo effects in allergen immunotherapy—An EAACI Task Force Position Paper

Oliver Pfaar*, Ioana Agache, Karl Christian Bergmann, Carsten Bindslev-Jensen, Jean Bousquet, Peter S. Creticos, Philippe Devillier, Stephen R. Durham, Peter Hellings, Susanne Kaul, Jörg Kleine-Tebbe, Ludger Klimek, Lars Jacobsen, Marek Jutel, Antonella Muraro, Nikolaos G. Papadopoulos, Winfried Rief, Glenis K. Scadding, Manfred Schedlowski, Mohamed H. ShamjiGunter Sturm, Ronald van Ree, Carmen Vidal, Stefan Vieths, Bettina Wedi, Roy Gerth van Wijk, Anthony J. Frew

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The placebo (Latin “I will please”) effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients’ expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials.

Original languageEnglish
Pages (from-to)629-647
Number of pages19
JournalAllergy: European Journal of Allergy and Clinical Immunology
Volume76
Issue number3
Early online date23 Apr 2020
DOIs
Publication statusPublished - Mar 2021

Bibliographical note

Funding Information:
Dr Pfaar reports grants and personal fees from ALK‐Abelló, Allergopharma, Stallergenes Greer, HAL Allergy Holding BV/HAL Allergie GmbH, Bencard Allergie GmbH/Allergy Therapeutics, Lofarma, ASIT Biotech Tools SA, Laboratorios LETI/LETI Pharma and Anergis SA; grants from Biomay, Circassia and GlaxoSmithKline; and personal fees from Meda Pharma/Mylan, Mobile Chamber Experts (a GA2LEN Partner), Indoor Biotechnologies, Astellas Pharma Global, EUFOREA, ROXALL, Novartis and Sanofi‐Aventis, outside the submitted work. Dr Bergmann reports personal fees from Bencard Allergy, outside the submitted work. Dr Bousquet reports personal fees from Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan, Novartis, Sanofi‐Aventis, Takeda, Teva, Uriach and Purina, and other from KYomed INNOV, outside the submitted work. Dr Creticos reports grants from ALK; grants and personal fees from Greer Laboratories and Stallergenes Greer; and personal fees from Allergy Therapeutics, ASIT, Biomay, Cliantha‐Inflamax and UpToDate, outside the submitted work. Dr Devillier reports personal fees from Stallergenes Greer and ALK‐Abello, outside the submitted work. Dr Jutel reports personal fees from ALK‐Abello, Allergopharma, Stallergenes, Anergis, Allergy Therapeutics, Circassia, LETI, Biomay and HAL, during the conduct of the study; and personal fees from AstraZeneca, GSK, Novartis, Teva, Vectura, UCB, Takeda, Roche, Janssen, MedImmune and Chiesi, outside the submitted work. Dr Kaul has nothing to disclose. She indicates that the views expressed in this paper are the personal views of the author as an expert in the field of allergology and may not be understood or quoted as being made on behalf of or reflecting the position of the respective national competent authorities, the European Medicines Agency or one of its committees or working parties. Dr Kleine‐Tebbe reports personal fees from Allergen Online (Nebraska, USA), Allergy Therapeutics, Allergopharma, ALK‐Abelló, AstraZeneca, Bencard, Dr Pfleger, HAL Allergy, InfectoPharm, LETI, Merck US, Sanofi Genentech, Springer International Publishers, Thermo Fisher Scientific and Thieme Publishers, Germany; grants and personal fees from GSK, Lofarma, Novartis and Stallergenes Greer; nonfinancial support from American Academy of Allergy, Asthma and Immunology, European Academy of Allergy and Clinical Immunology and WHO/IUIS Allergen Nomenclature Subcommittee; and personal fees and nonfinancial support from German Society for Allergy and Clinical Immunology, outside the submitted work. Dr Klimek reports grants and personal fees from Allergopharma, Meda/Mylan, LETI Pharma and Sanofi; personal fees from HAL Allergie and Allergy Therapeut.; grants from ALK‐Abelló, Stallergenes, Quintiles, ASIT Biotech, Lofarma, AstraZeneca, GSK and Inmunotek, outside the submitted work; and membership in AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunologie, HNO‐BV, GPA and EAACI. Dr Papadopoulos reports personal fees from Novartis, Nutricia, HAL, Menarini/Faes Farma, Sanofi, Meda, AstraZeneca, GSK, MSD, ASIT Biotech, Boehringer Ingelheim and Medscape; and grants from Gerolymatos International SA, Capricare and VIAN, outside the submitted work. Dr Scadding reports personal fees from ALK‐Abello, GSK, Mylan and Bayer, outside the submitted work; and Chair in EAACI Ethics Committee. Dr Shamji reports grants and personal fees from ASIT Biotech SA; grants from ALK, Regeneron, Merck, Immune Tolerance Network and ASIT Biotech SA; and personal fees from ALK and Allergopharma, outside the submitted work. Dr Sturm reports grants from ALK‐Abello; and personal fees from Novartis, Bencard, Stallergenes, HAL, Allergopharma and Mylan, outside the submitted work. Dr van Ree reports personal fees from HAL Allergy BV, Citeq BV, Angany Inc and Thermo Fisher Scientific; and grants from European Commission and Dutch Science Foundation, outside the submitted work. Dr Vieths reports personal fees from Ärzteverband Deutscher Allergologen, Swiss Society of Allergy and Immunology, Schattauer Allergologie Handbuch, Elsevier Nahrungsmittelallergien und Intoleranzen, Pharmacon and Karger Food Allergy: Molecular Basis and Clinical Practice; nonfinancial support from German Research Foundation, European Directorate for the Quality of Medicines and Health Care, European Academy of Allergy and Clinical Immunology, German Chemical Society (GDCh), AKM Allergiekongress, International Union of Immunological Societies and Spanish Society for Allergy and Clinical Immunology (SEAIC), outside the submitted work. He indicates that the views expressed in this paper are the personal views of the author as an expert in the field of allergology and may not be understood or quoted as being made on behalf of or reflecting the position of the respective national competent authorities, the European Medicines Agency or one of its committees or working parties. Dr Wedi reports grants, personal fees, nonfinancial support and other from Novartis; grants, personal fees and nonfinancial support from Shire; and personal fees from ALK‐Abéllo, HAL Allergy, Sobi, Bencard, CSL Behring and Leo Pharma, outside the submitted work. Dr Gerth van Wijk reports personal fees from ALK‐Abello outside the submitted work. Dr Agache, Dr Bindslev‐Jensen, Dr Durham, Dr Hellings, Dr Jacobsen, Dr Muraro, Dr Rief, Dr Schedlowski and Dr Vidal have nothing to disclose.

Funding Information:
This Position Paper is written in memory to Professor Anthony Frew, a wonderful friend and brilliant scientist, who unexpectedly passed away on November 28, 2018. He will be dearly missed. The TF was financed by the EAACI. The authors would like to thank the EAACI for their financial support in the development of this TF report, and David Fraser D.Phil. (Biotech Communication SARL, France) for editorial assistance (financed by a grant from the EAACI).

Publisher Copyright:
© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

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