COFAITH and COMFA: A Collective Roadmap for Past and Future Food Allergy Clinical Trials and Observational Research on Interventions

Abstract

Traditionally, immunoglobulin E (IgE)–mediated food allergy (FA) management required (near) total avoidance of the known allergen(s) and, for those with a history of, or who are at risk of anaphylaxis, the constant possession of an adrenaline autoinjector [1]. Unsurprisingly, FA-associated behaviours contribute to substantial psychosocial [2, 3] and financial [4] burdens. Recent emerging therapies have contributed to a paradigm shift in FA management, which warrant clinical consideration informed by patient preferences [5]. Such shared decision-making is vital to detecting the most critical outcomes that are meaningful and respectful of individual cultural influences on food consumption. On the contrary, a core outcome set (COS) is defined as ‘an agreed standardised set of outcomes that should be measured and reported, as a minimum, in all clinical trials in specific areas of health or health care’ [6]. Recently, two initiatives aiming at outcome harmonisation published important papers on FA outcomes. The first considered clinical outcomes of efficacy in food allergen immunotherapy trials (COFAITH) [7], whereas the second involved a two-stage e-Delphi to identify core outcomes for FA (COMFA) [8] that ought to be included in FA clinical trials henceforth. Importantly, these initiatives also provide considerable opportunity for discussion on how these core outcomes can, and should be implemented in forthcoming studies.

COFAITH, a task force of the European Academy of Allergy and Clinical Immunology produced a systematic review, covering FA immunotherapy randomised controlled trials and large case series published until 30 March 2022. This review included a total of 45 papers [7]. COFAITH authors noted that primary outcomes should be clinically relevant, unambiguous and meaningful to patients, and aligned with best practice for the reporting of clinical trials (Table 1). They also considered outcomes in the context of the type of food allergen and found out that peanut allergy immunotherapy trials have a different approach to these definitions compared with milk and egg trials, that normally share similar endpoints. The most frequently reported outcome identified in COFAITH was desensitisation, which was further stratified as at or below the maintenance dose or an increase in threshold or success at end-of-trial oral food challenge. One secondary outcome was sustained unresponsiveness, which is not yet likely widely uptaken, and thus may be less frequently considered an outcome, given that long-term sustained unresponsiveness results are poorer than those seen in the short-term. Similarly, thresholds were inconsistently reported across studies, reflecting variation in food types. For example, thresholds for milk and egg were consistent with amounts in regular servings, whereas thresholds for peanuts were based on 1–2 peanut kernels, which is far below regular peanut consumption. Additionally, the authors identified quality of life as a secondary outcome, albeit in a small number of studies. The authors highlighted the increasing need to recognise patient-reported outcome measures, but acknowledge that there has been minimal consideration to quality of life in allergy immunotherapy trials to date.

COMFA, an international initiative seeking consensus regarding COMFA research, included demographically diverse representation from allergy-specialist clinicians and researchers (including basic, clinical and population health researchers), and patient organisations from 52 countries across six continents [8]. This study was the first attempt to agree on a COS for FA trials and observational research on interventions, including the need for international patient representation. After systematic literature search, a list of FA outcomes was developed, and during a two-round e-Delphi process and a hybrid consensus meeting, two core outcomes, namely ‘allergic symptoms’ and ‘quality of life’, were agreed on to be critically important to participants and thus should be measured in all trials and observational studies on interventions. The additional outcomes of desensitisation and remission/sustained unresponsiveness were identified as being critically important by most groups (Table 1).

COFAITH identified desensitisation as the most commonly reported outcome [8] which was critically important for some of the above-listed groups in COMFA, but was insufficiently relevant in its current definition to reach consensus [9]. Another clinical outcome namely sustained unresponsiveness (which COMFA authors also classified as remission) [8, 9] captures the hope that emerging therapies may provide meaningful persistent relief of the physical, psychosocial [2, 3] and financial [4] burdens of FA. Remarkably, a mismatch exists between what has been considered primary outcomes in clinical trials, and what has been agreed by a wider representation of interested groups to be the COS in FA trials. A potential contributing factor to this disparity might be the higher proportion of researchers in the process of trial design compared with other interested groups such as clinicians or patient representatives, who had a larger collective voice in COMFA. Another explanation is that COFAITH systematically reviewed the specific intervention of food immunotherapy, whereas COMFA was focused on any FA interventions. Please also see https://osf.io/fth56/ for additional details.

Core outcomes are important when setting primary outcomes for clinical trials. Nonetheless, it behoves the scientific community to remember that they must also be meaningful to patients. Consideration of COS must also exist within the healthcare system, dietary habits and social norms of the given country/region where the trial is taking place. Similarly, dissemination of the findings must provide detailed descriptions of the participant demographics, and regional diet and social systems that influence patients' FA experiences.

Refinement of existing instruments, and where necessary, the development of new instruments to measure these core outcomes, represents the next unique opportunity for continued partnership between clinicians, researchers, industry and patient representatives, who share a collective goal of measurably improving the lives of those managing FA during an era of emerging therapies.

The authors takes full responsibility for this article.

Jennifer L. P. Protudjer is Section Head, Allied Health; and Co-Lead, Research Pillar for the Canadian Society of Allergy and Clinical Immunology, and is on the steering committee for Canada's National Food Allergy Action Plan. She reports consulting for Ajonomoto Cambrooke, Novartis, Nutricia and ALK Abelló.

Daniel Munblit, India Capper and Pasquale Comberiati declared no relevant conflict of interests to report.

Christian Apfelbacher has received institutional funding from the Dr Wolff Group and Bionorica SE, and consultancy fees from tDr Wolff Group, Bionorica SE, Sanofi, Incyte Biosciences, RHEACELL and LEO Pharma for outcomes research outside food allergy.

Mary Jane Marchisotto is Advisor to the patient organisation IFPIES, which deals with non IGE Mediated Food Allergy. She is also a patient representative on Novartis' Global Food Allergy Patient Council and on National Peanut Board Patient Advisory Group.

Emma E. Cook is on the board of the patient organisation NPO アトピッ子地球の子ネットワーク (ATOPICCO Network for Children of the Earth), which deals with allergic disease in Japan. She is also a patient representative on Novartis' Global Food Allergy Patient Council (2023–2024).

Pablo Rodríguez Del Río reports grants from the Spanish Society of Allergy and Clinical Immunology (SEAIC) and lecturing fees from Aimmune Therapeutics. FAES, GSK, Novartis, ALK, Sanofi, Stallergenes and Miravo.