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CSACI guidelines for the ethical, evidence-based and patient-oriented clinical practice of oral immunotherapy in IgE-mediated food allergy

Abstract

Background

Oral immunotherapy (OIT) is an emerging approach to the treatment of patients with IgE-mediated food allergy and is in the process of transitioning to clinical practice.

Objective

To develop patient-oriented clinical practice guidelines on oral immunotherapy based on evidence and ethical imperatives for the provision of safe and efficient food allergy management.

Materials and methods

Recommendations were developed using a reflective patient-centered multicriteria approach including 22 criteria organized in five dimensions (clinical, populational, economic, organizational and sociopolitical). Data was obtained from: (1) a review of scientific and ethic literature; (2) consultations of allergists, other healthcare professionals (pediatricians, family physicians, nurses, registered dieticians, psychologists, peer supporters), patients and caregivers; and patient associations through structured consultative panels, interviews and on-line questionnaire; and (3) organizational and economic data from the milieu of care. All data was synthesized by criteria in a multicriteria deliberative guide that served as a platform for structured discussion and development of recommendations for each dimension, based on evidence, ethical imperatives and other considerations.

Results

The deliberative grid included 162 articles from the literature and media reviews and data from consultations involving 85 individuals. Thirty-eight (38) recommendations were made for the practice of oral immunotherapy for the treatment of IgE mediated food allergy, based on evidence and a diversity of ethical imperatives. All recommendations were aimed at fostering a context conducive to achieving objectives identified by patients and caregivers with food allergy. Notably, specific recommendations were developed to promote a culture of shared responsibility between patients and healthcare system, equity in access, patient empowerment, shared decision making and personalization of OIT protocols to reflect patients’ needs. It also provides recommendations to optimize organization of care to generate capacity to meet demand according to patient choice, e.g. OIT or avoidance. These recommendations were made acknowledging the necessity of ensuring sustainability of the clinical offer in light of various economic considerations.

Conclusions

This innovative CPG methodology was guided by patients’ perspectives, clinical evidence as well as ethical and other rationales. This allowed for the creation of a broad set of recommendations that chart optimal clinical practice and define the conditions required to bring about changes to food allergy care that will be sustainable, equitable and conducive to the well-being of all patients in need.

Background

IgE-mediated food allergy is a condition that imposes food-related restrictions on patients and their caregivers in order to prevent allergic reactions. The burden of disease stems from both the actual and perceived risks of accidental ingestion, including the possibility of a life-threatening allergic reaction. This burden manifests itself in variable levels of anxiety and social limitations and significantly impacts quality of life. The current standard management for food allergy is complete avoidance of the offending allergen in the diet, combined with training on how to recognize and treat allergic reactions. And while avoidance is currently recognized as a safe approach, it has a limited ability to improve a patients’ perception of safety or sense of control over the condition and its associated limitations—this leads many to seek alternative management options [1,2,3,4,5,6].

Oral immunotherapy (OIT) consists of daily ingestion of the offending food allergen (food dosing), starting below a patient’s threshold dose (i.e. the minimum amount that would elicit a reaction), and increasing the dose over time with a goal of increasing clinical tolerance to that food. It had been proposed as a potential alternative to avoidance throughout the 20th and into the early 21st centuries [7], yet its development had been limited until recently. This is mainly due to the risk of allergic reactions associated with OIT, which is difficult to reconcile with current practice standards that focus on the avoidance of reactions at all cost and are arguably rooted in a culture of fear.

OIT can be viewed as a disruptive innovation as it challenges the current paradigm of care in food allergy and highlights its limitations in responding to patient needs. There is a need for patient-centered ethical clinical practice guidelines (CPGs) that include patients and caregivers as well as other stakeholders in the consultation and deliberation process, in order to develop best practice recommendations for providing OIT for food allergy. It is essential to understand patient and caregiver perspectives to ensure proper interpretation of published evidence and understand the ethical issues involved.

Previous CPGs on OIT [8,9,10] have used more traditional approaches, focusing mainly on quantitative clinical evidence. However, in order to ensure a clear vision of all that OIT entails and to benefit all patients with food allergy in need of care, CPGs must not only be based on experimental data (e.g., clinical trials) but also on observational, economic and sociopolitical data, as well as experiential narrative data from both patients and healthcare professionals. The optimal provision of OIT must also account for ethical and organizational data to promote the equitable, sustainable and responsible development of this treatment. In fact, evidence-based medicine has been defined as “the application of the best available research to clinical care, which requires the integration of evidence with clinical expertise and patient values [11].”

The development of these CPGs on OIT followed the Guidelines International Network 2015 recommendations including a policy for the management of conflicts of interests [12]. They were commissioned by the Canadian Society of Allergy and Clinical Immunology (CSACI), and was developed through a collaboration with the University Hospital Center Sainte-Justine and the methodological support of the Institut National d’Excellence en Santé et Services Sociaux (INESSS). CSACI acted as the sponsor and was responsible for creating a diversified Working Group. This working group and the executive team opted for a reflective multicriteria methodology, which has been used in the past to develop CPGs [13] using the EVIDEM (Evidence and Values Impact on Decision Making) ethical framework [14,15,16,17]. This approach encourages the collection of data from diverse sources, including both the scientific literature and consultations, thus offering a 360° view of the subject. This framework was also used to organize, analyze and ultimately integrate the data into a deliberation guide, providing an efficient and consistent approach throughout the project.

Materials and methods

Multidisciplinary team

A multidisciplinary team comprised of experts from a diversity of fields was assembled, including allergists and other healthcare professionals, ethicists, and those with expertise in multicriteria deliberation methodology, literature review, consultations and sociology.

Multicriteria methodology

The aim of the methodological approach was to support reflection by all stakeholders during the development of fair and reasonable recommendations. To this end, a patient-centered and ethics-based multicriteria framework was used throughout the process. The framework was adapted from EVIDEM, included three additional patient focused criteria and organized 22 criteria into five dimensions defined to cover all relevant aspects of OIT. The framework also builds on the Accountability for reasonableness (A4R) conditions set forth by Daniels and Sabin [18] and the Triple Aim of healthcare systems set forth by Berwick and colleagues [19]. The five dimensions of the framework include:

  • How the use of OIT can contribute to a socio-politico-cultural context conducive to The Common Good (sociopolitical dimension),

  • How OIT contributes to a fair and equitable distribution of services (populational dimension),

  • How OIT responds to a need for health and well-being in an adequate way (clinical dimension),

  • How the use of OIT can contribute to improve the quality, organization and governance of healthcare services (organizational dimension), and

  • How OIT optimizes the use of resources and the associated costs to ensure sustainability of healthcare systems (economic dimension).

Each dimension contains criteria for operationalization, organized into a multicriteria grid. Data from the literature review and consultations were collected and organized per criterion to allow for a comprehensive assessment of OIT and provide a knowledge platform for the development of the CPG recommendations.

All documentation was compiled using a data management software program (CITAVI), which was adapted to organize data by criteria and provided an interactive interface for review by the working group.

Conflict of interest management and respect of persons

To avoid the impact of COI or conflicts of roles on the process, explicit guidelines regarding their declaration, evaluation and management were developed based on the GIN 2015 recommendations (see Additional file 1: Appendix 1) [12]. Each potential participant was required to complete a conflict of interest declaration, which was then analyzed by an ethicist. Participants who were deemed at risk of bias on a particular subject were excluded from the room during the deliberation meeting for the time during which the related recommendations were being discussed.

Every step was taken to ensure that best practices for respect of persons were carried out, with respectful atmosphere created by chairs for each group discussion and by interviewers for each individual interview; as well documentation was provided ahead of time to give each participant time to prepare. All patients completed an informed consent; they were informed that only their perspective on the topic was solicited, not personal clinical data, and that psychological support was available.

Literature review

Sources of data

An extensive literature review was performed. The primary sources of data were peer-reviewed full-text publications retrieved through searching multiple sources, including PubMed, MEDLINE (Ovid), Embase, EBM Reviews, CINAHL and Web of Science bibliographic databases. Searches for OIT clinical data were performed on April 17–18, 2019, and searches for epidemiological and burden of disease data were performed on May 30–31, 2019. Search terms are presented in Additional file 1: Appendix 2A. These searches aimed to collect data for all dimensions of the framework, including the sociopolitical, populational, clinical, organizational and economic dimensions. Bibliographical database searches were supplemented by individually searching the tables of contents of pertinent recent periodicals (up to September 2019), as well as bibliographies of key publications. Websites from government agencies, HTA bodies, professional associations and patient associations were also consulted. In order to capture the perception of OIT in the media, a review of the Canadian news media of the last 5 years was conducted via the FACTIVA Global News Monitoring & Search Engine using ‘oral immunotherapy’ and ‘immunothérapie orale’ (French) as search terms.

Data selection for each dimension

Retrieved records were screened based on title and abstract to select those for further assessment in full-text format. For the clinical dimension, patient focus groups or surveys providing insight on the importance of the therapy and its outcomes for patients, were considered for inclusion in addition to clinical studies (see details below), qualitative studies, and published CPGs. For the sociopolitical dimension, different types of publications on relevant topics such as the history of OIT and regulatory aspects were reviewed. Stakeholder’s positions were collected and informed by the media press review. For the populational dimension, records such as recent systematic reviews of epidemiological studies, original studies conducted in large, representative populations, preferably in the Canadian context, and recent reviews of qualitative research were considered for inclusion. For the organizational dimension, data concerning the healthcare system’s organization and requirements for the provision of OIT was sought. For the economic dimension, data collected included economic studies, such as cost of illness studies or economic analyses, and cost data (i.e., the costs of products and procedures for OIT). An analysis of associated ethical issues was included for each criterion throughout the framework, as applicable.

Selection of clinical studies and assessment of their methodological quality

Clinical studies were selected using eligibility (inclusion/exclusion) criteria listed in Additional file 1: Appendix 2B. Study designs included experimental, comparative studies, randomized [RCTs], non-randomized controlled clinical trials [CCTs], and observational studies reporting outcomes from clinical practice. RCTs are best suited to answer the questions whether an intervention is efficacious and safe, compared to another intervention or management option. These, however, can be limited in their ability to answer certain specific questions that arise in clinical practice, including how patient characteristics may impact outcomes or how to adapt to what happens over the course of treatment [20]. These limits stem from highly selective patient eligibility criteria, rigid study protocols, non-patient-centered end-points, short follow-up durations or small population sizes. A blinded study design, in particular, is not best suited to study personalized care, nor to investigate the impact of a treatment on patient-reported quality of life outcomes—examples include topics such as food-allergy related anxiety and the burden of allergen avoidance, both of which require awareness of the treatment received and the results achieved (e.g., level of desensitization). Observational studies can complement experimental comparative studies, especially when they involve larger less strictly selected patient populations that are closely followed over a long-term horizon in a real world practice setting.

The methodological quality of RCTs was assessed according to the Cochrane risk of bias approach [21], using published risk of bias assessments from systematic reviews, whenever available [22,23,24]. For case series, the Institute of Health Economics Quality Appraisal of Case Series Studies Checklist was applied [25]. Among its 20 items, 10 core items on study conduct and reporting were selected to operationalize quality assessment. A case series was deemed of high methodological quality (low risk of bias) if all 10 were positive, moderate if 8 to 9 were positive, and low (high risk of bias) if less than 8 were positive. The methodological quality of meta-analyses was determined by checking whether all eligible studies had been included, and by repeating key analyses based on the data reported in the original publications.

Extraction, analysis and synthesis

Clinical study data was extracted and synthesised in evidence tables in a per-criterion report format. The extraction tool was validated by a clinical expert. The report was validated by two assessors and then reviewed and revised by the Working Group. Clinical data was further synthesized and integrated into the multicriteria grid for the deliberation. Data pertaining to the other dimensions were directly synthesized in the multicriteria grid.

Consultations

Objective

The objective of the consultation process was to capture relevant experiential and contextual data from diverse perspectives to develop a comprehensive understanding of the topic. Data for each dimension of the multicriteria grid was collected through discussions with allergists, patients and other healthcare professionals. Healthcare professionals were able to provide insight into two main aspects: first, to validate and enrich the data collected through the literature review, and second, enhance the data with relevant clinical practice experience that might not have been elucidated from published studies. Patients with food allergy contributed their unique perspective of the condition and its impact, as well as their view and experience of food allergy therapy, including its benefits and its constraints.

General approach

In order to ensure diversity of participants, an open call for applications was posted on the website of applicable patient associations and the CSACI, and targeted calls were made by sending e-mail invitations to relevant professional societies and all CSACI members. The calls provided a short text explaining the objectives of the project, as well as the goals and format of the consultation, followed by a link to a small questionnaire covering the necessary information to enable selecting a diversity of participants to be consulted. The recruitment process was completed by applying a chain-referral sampling strategy. For each potential consultant, the geographical location, gender, general opinion of OIT and, when relevant, the type of practice (e.g. academic vs community, pediatric vs adult) were considered for participant diversification.

Selected participants were contacted and, upon confirmation of participation, asked to complete COI and consent forms. Subsequent steps differed depending on the format of the consultation for each specific group. Possible steps were discussion panels, individual interviews and an online questionnaire. Discussion panels served to create a debate around the various aspects of OIT from different contexts and viewpoints. Individual interviews allowed for the collection of in-depth data from a specific context and its implications. The online questionnaire allowed for the collection of a broad range of experience from a greater number of experts than would have been possible through discussion panels and interviews alone. For every consultation, participants received a consultation guide with questions adapted to their contexts and expertise, which was based on the multicriteria grid and grouped by criteria, in order to facilitate data collection and analysis. All participants were provided with the consultation document a week prior to the consultation in order to give time to familiarize themselves with it. During the discussion panels, the Chatham House Rule [26] was applied, which guarantees anonymity of all information provided by participants. These panels were led by co-chairs experienced in data appropriation while fostering an environment of respect, attentiveness and constructive exchanges.

Allergists

Consultations with allergists were twofold, with two different groups. A panel discussion was first conducted with the 15 Working Group members to identify key points on which to focus the CPGs. The group was well diversified in terms of experience with OIT: some participants had never offered it, some had offered it only in research settings, and those offering it in clinical practice reported using different methods and protocols. The discussion followed the multicriteria questionnaire, discussing every issue per criteria. Data was collected through recording and notetaking. Secondly, 42 CSACI members completed an online questionnaire, following the same structure. The data obtained from both the panel discussion and the questionnaire were compiled per criteria. Key themes within each criterion were identified through thematic analysis.

Patients and caregivers

Consultations with patients also occurred in two formats to fit two purposes. A panel discussion was held with 8 participants, diversified according to their individual context pertaining to OIT, which included whether or not they had direct experience with it, what their vision of the therapy was and the type and impact of their food allergy condition. Discussions were guided by the multicriteria grid. Patient perspective narrative data was collected for each of the criteria through recording and notetaking. The second consultation format consisted of individual interviews with 6 participants, following the same diversification criteria and using the same questionnaire as the panel discussion. The data from both sources was then compiled in the same way as the allergist consultations and analyzed thematically to identify key points raised by the patients.

Other healthcare professionals and lay representatives

These consultations served the purpose of obtaining the viewpoints of stakeholders involved in the care of food allergy patients other than allergists, namely family physicians, pediatricians, nurses, registered dieticians, psychologists and caregivers engaged in peer support activities. They were consulted via a discussion panel involving 10 participants diversified by their professions and the differences in their experience with OIT, which followed the same format as the patient panel. Another two healthcare professionals completed an online questionnaire. Representatives from patient associations were also interviewed, via phone, using the same questionnaire as the panel, to provide patient-centered contextual knowledge on OIT. This data was collected through notes and recording, per criteria, compiled in the same way as for the other consulted groups, and thematically analyzed, bringing forward essential notions associated with OIT provision to include in the CPGs.

Data from milieu of care

Data from Canadian clinical practices (milieu of care) was collected in the form of economic data provided by the working group members from their clinical practice offer of OIT, which was extracted and compiled into criteria of the economic dimension.

Deliberation

Data integration

Compiled data from the literature review, consultations and milieu of care were integrated into the deliberation guide in a highly synthesized format in order to facilitate comprehension of the data by all participants during the deliberation. Prior to this integration, the data from the literature review was revised and enriched by the Working Group. Data for each criterion was separated into three sections: literature review data, consultation data and ethical aspects. The deliberation guide consisted of the synthesized data integrated into a multicriteria grid, with an additional column in which participants were invited to add their interpretation of the data provided in order to facilitate discussion. Empty recommendation boxes at the end of each dimension were also included to allow discussion and the formation of informed recommendations for one subject at a time.

Deliberation process

The participants in the deliberation included the allergists of the Working Group along with selected participants from the consultations, in order to provide relevant data from a global patient perspective. These included two patients with different and longstanding experiences, two family physicians, a pediatrician, a nurse, a registered dietician, a pharmacist and a peer supporter. Each participant received a copy of the deliberation guide 1 week prior to the meeting. The deliberation meeting was chaired by three methodologists who were experts in multicriteria deliberation, multicriteria literature review and synthesis and multicriteria consultations, for a total of 22 participants. The deliberation was divided into four sessions according to the dimensions of the multicriteria grid, during which the literature review and consultation data were presented by the co-chairs. Corresponding recommendations were discussed and determined at the end of each session. All recommendations were based on a group consensus—recommendations for which a COI was identified were based on a consensus of the group excluding those with a COI.

Rationales for recommendations

Recommendations were based on a variety of rationales that included evidence from consultations and scientific studies, ethical imperatives, such as promotion of equity or patient autonomy, and other considerations, such as general standards of clinical care, clinical reasoning, and biological plausibility.

For recommendations that included evidence from clinical studies, the strength of the evidence supporting the recommendation was determined using a method that builds on the approach of the Oxford Centre for Evidence-Based Medicine [8, 27]. The risk of bias was assessed using the Cochrane approach [21] and the Institute for Health Economics (IHE) method for case series [25]. These methods, developed for quantitative data, were adapted to include qualitative data from consultations such that the strength of the evidence supporting the recommendation takes into account:

  • risk of bias (study design, including the methodology chose for data collection and analysis can affect the risk of misleading results);

  • type of study (meta-analyses, RCTs, non-randomized controlled trials (CCTs), case series); studies could be carried out in usual clinical practice or in a research context;

  • consistency of evidence across studies; and

  • the level of coherence between evidence from studies and data obtained from the consultation process.

The amount, quality and consistency of the evidence supporting the recommendation is defined at three levels:

  • High Large amount of consistent evidence from RCTs (or meta-analyses) and large studies in clinical practice, ideally at a low risk of bias; AND coherence with data from consultations and/or qualitative studies.

  • Moderate Moderate amount of consistent evidence from RCTs (or meta-analyses) and/or studies in clinical practice, ideally at a moderate or low risk of bias; AND coherence with data from consultations and/or qualitative studies.

  • Low Small amount of evidence OR evidence with some incoherence in data from RCTs (or meta-analyses) and/or studies in clinical practice OR data at moderate to high risk of bias; AND coherence with data from consultations and/or qualitative studies.

Strength of recommendations The strength of recommendations in CPGs is often graded based on the quality of clinical evidence regarding the efficacy and safety of an intervention. However, this approach does not apply to recommendations that do not rest on clinical trial outcomes, but for which the body of evidence from clinical research and practice shows a clear clinical benefit because conducting such trials would neither be reasonable nor ethical [28]. Moreover, grading in such a way does not take into account factors other than clinical outcomes, such as ethical imperatives, social context or economic considerations, which can be key elements of the rationale underlying a recommendation. Therefore, to ensure that all types of recommendations in these CPGs will be regarded on an equal footing, the strength of recommendations was not given a rating. Rather, in the spirit of accountability for reasonableness (A4R) [18], the rationale for each recommendation, the level of supporting evidence, where appropriate, and the necessary contextualization and nuances were all clearly stated.

Results

Multicriteria grid

The multicriteria grid used for this project included five dimensions divided into 22 criteria and is shown in Fig. 1.

Fig. 1
figure1

Multicriteria grid: dimensions and criteria

Data used as basis for recommendations

The literature review yielded a total of 8157 records; 468 of them were assessed for eligibility in full-text records and 145 were included in the multicriteria grid (Fig. 2). An additional 17 articles were included from the media press review.

Fig. 2
figure2

PRISMA diagram

A total of 14 patients or caregivers, 13 allergists and 16 other healthcare professionals or patient association representatives were consulted through panel discussions or individual interviews. In addition, 42 CSACI allergists responded to the online consultation survey.

Data on the economic aspects of OIT was available from three Canadian practices, and data on quality of life impact of OIT was collected from one practice.

The synthesis of the data collected through the literature review, consultations and from the milieu of care is presented by criteria along with complete references in the deliberation guide (Table 1). Detailed clinical evidence tables with results of quality assessments are available in Additional file 1: Appendix 3.

Table 1 Multicriteria grid with data from literature review, consultations and milieu of care synthesized by criteria and used for the deliberation

Deliberation guide

The deliberation guide includes the synthesized data for each criterion along with a section prompting participants to interpret and discuss the data. Boxes for the development of recommendations were added at the end of each dimension.

Recommendations

Recommendations are presented in the following format:

  1. 1.

    A lay summary of the data synthesis that led to the recommendation(s) written in a format that is accessible to a non-physician audience (for the clinical dimension, detailed narrative summaries of the data are available in Additional file 1: Appendix 4).

  2. 2.

    Additional key points discussed during deliberation that led to the recommendation(s)’ development.

  3. 3.

    Recommendations and rationales.

To facilitate the understanding of the presented data, key concepts and definitions pertaining to OIT are illustrated in Fig. 3.

Fig. 3
figure3

Key concepts and definitions pertaining to OIT

Sociopolitical dimension: promotion of the common good

Populational dimension: promotion of equity

Clinical dimension: promotion of health and well-being

Organizational dimension: promotion optimized organization of care

Economic dimension: promotion of sustainability

Discussion

This development process of these CPGs consisted of a comprehensive approach to both the data collection and the collection of perspectives from all stakeholders. This allowed for the collaborative development of 38 recommendations guided by the five principles of the common good, equity, health and wellbeing, optimized organization of care and sustainability of healthcare systems, allowing a 360° view of OIT.

This comprehensive approach included the full extent of a traditional review of the available clinical data. The large number of both RCTs and diverse observational studies provided a rich body of complementary evidence. In addition, the inclusion of patients in both the consultation and the deliberation phases provided key experiential knowledge and contributed to the interpretation of data and the development of recommendations. Similar involvement of first line and allied healthcare professionals ensured a multidisciplinary perspective for optimal organization and provision of care as well as efficient use of healthcare resources. Throughout the aforementioned steps, the multicriteria methodology drove the systematic collection of scientific and experiential knowledge for all dimensions, the sociopolitical, populational, clinical, organizational and economic. This was instrumental in developing balanced recommendations allowing us to address issues beyond what is usually covered by traditional CPGs.

This was critical in the specific context of OIT, which poses challenges beyond its clinical aspects. Offering OIT requires adapting the organization of care in a setting of highly limited resources. It marks a rupture with a culture focusing on avoiding reactions at all cost, which creates confusion and tensions. Competing developments as a drug-based versus a food-based therapy also create a number of ethical issues. The methodology provides an ethics-based framework to identify and address these issues in the elaboration of recommendations.

The 360° approach necessitates a team with diverse expertise in various methodological domains and fields of knowledge to collect and integrate the body of knowledge in the multicriteria grid. Expertise in communicating in lay language and chairing a discussion on all these aspects is essential to ensure an understanding by all. The inclusion of participants with diverging perspectives is important to stimulate individual and group reflection during discussions. A tailored multidisciplinary team and a method that allows for efficient organization of data per criteria are essential to the process and key to promote understanding of numerous complex concepts and fulfill the A4R conditions.

Accountability for Reasonableness (A4R) defines four main conditions that can enhance legitimacy and help stakeholders develop a mutual basis for decision making: publicity of rationales for choices; relevance of criteria agreed to by a broad range of stakeholders; revisability of the decision in light of new evidence or arguments; and enforcement that means the other conditions are met [14]. The multicriteria approach facilitates meting these four conditions. The use and publication of the multicriteria grid completed with the data, from which detailed and lay rationales were developed, addresses the publicity and the relevance conditions. The multicriteria grid also offers a pragmatic tool to update the CPGs as significant advancements in knowledge emerges, which contributes to revisability. The implication of a large number of stakeholders, of methodologists and ethicists, the participation of external observers at the deliberation, as well as oversight by the CSACI board contributed to the enforcement of these three conditions.

Clinical recommendations developed here are generally concordant with those from the European Academy of Allergy and Clinical Immunology (EAACI) [8]. That said, in addition to the recommendations made outside the clinical dimension, there are some noteworthy differences between the CPGs, which likely stem from the difference in methodology. The authors of the EAACI guidelines explicitly stated in their discussion that “there is no evidence that the efficacy and safety are affected by the type and nature of the food allergen used in allergen immunotherapy”. However, their methodology resulted in limiting the indication for OIT to milk, egg and peanut only. The current guidelines diverge from those from EEACI in a few other recommendations, namely regarding the indication for OIT in children less than 4 years of age or in adults and the recognition that OIT can promote sustained unresponsiveness in some patients, over the long term.

There was also a difference in the overall vision surrounding the development of OIT. In the EAACI guidelines, the need for standardized protocols and products was identified as a high priority, while these CPGs emphasize that there is a need for more personalization. Standardization is often seen as a desirable objective in modern medicine because it allows generating quantitative data that can be used as the basis for more recommendations using a traditional CPG methodology. However, the ability to adapt protocols to patients’ needs is essential in OIT. Standardized products and protocols have not been shown to provide clinical benefits over their adaptable alternatives and can actually increase barriers and costs, thus threatening sustainability and access.

Personalized approaches, however, represent a challenge for the transfer of expertise. The development of training initiatives, clinical tools, and organizational models adapted to the delivery of personalized care should therefore be made a priority. Shared decision-making tools should include clear information on food allergy management, consent forms, home dosing instructions, and a reaction management plan. Specific training tools directed toward allergists, primary care physicians and allied healthcare professionals should focus on the biological, psychological and social aspects of the therapy and be included in training curricula and continuing professional development (CPD).

Clinical tools will be developed collaboratively as a second step of these CPGs and made available online at http://www.csaci.ca/OIT-guidelines.

These CPGs also identified a number of data gaps that require further research, including:

  • long-term patient-centered outcomes

  • underrepresented groups, e.g. adults

  • optimal use of biomarkers to guide therapy

  • optimal use of medication to support treatment

  • determinants of reactivity, e.g. cofactors, individual differences in absorption and distribution of allergens

  • benefits and optimal use of nutritional, psychological, and peer support

  • economic and organizational aspects of the treatment.

Conclusion

These guidelines bring to the forefront the critical importance and value of placing patients at the center of the development of clinical practice guidelines. Here, this approach was instrumental to developing recommendations for the responsible implementation of OIT in clinical practice, adapted to individual patient needs. The multicriteria approach offers an alternative to technocentric approaches in CPG development by balancing human, ethical and technical considerations in decision making (Fig. 4).

Fig. 4
figure4

Considerations for balanced decision-making in medicine

Technocentric approaches tend to create a pressure to standardize patient care in order to generate quantitative data, which may not always be in patients’ best interest. Rather than adapting patient care to meet methodological needs for quantitative data, the methodology should be adapted to patients’ needs for best care. As the saying goes, ‘Not everything that counts can be counted, and not everything that can be counted counts [75].’

Availability of data and materials

Additional data is included in the supplemental repository. Clinical tools for implementation in practice will be made available at http://www.csaci.ca/OIT.

Abbreviations

A4R:

Accountability for reasonableness

CCT:

Controlled clinical trial

CPG:

Clinical practice guidelines

CSACI:

Canadian Society of Allergy and Clinical Immunology

EAACI:

European Academy of Allergy and Clinical Immunology

EoE:

Eosinophilic esophagitis

EPIT:

Epicutaneous Immunotherapy

IHE:

Institute for Health Economics

OIT:

Oral immunotherapy

RCT:

Randomized controlled clinical trial

SLIT:

Sub-lingual Immunotherapy

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Acknowledgements

We would like to acknowledge the other members of the deliberative committee. The deliberative committee was composed of members of the working group as well as A Boisvert, Peer supporter, Montréal, QC; MJ Cadieux, BPharm, Pharmacist and Peer supporter, University of Montreal, QC; B Francoeur, MD Family physician, Trois-Rivières, QC; J Garnavos; L Lavallée, RN, Allergy nurse, CHU Ste-Justine, Montréal, QC; G Parizeault MD, Pediatrician, Chicoutimi, QC; S Pernice, MSc, Nutritionist, CHU Ste-Justine, Montréal, QC; M Stasiuk; C Vaillancourt, MD, Family physician, St-John, NB.

Regarding methodological contributions, we are indebted to the ethics support of I Ganache, PhD, ethicist, Unit Methods, ethics and participation, INESSS, National Institute for excellence in health and social services, Montreal, QC, as well as to the contribution of S Nairn, PhD Department of Sociology, McGill University, Montreal QC, to patient consultation and literature review. We also would like to acknowledge V Berretta, PhD, Pavia University, Italy for setting up the multicriteria software interface (CITAVI), P Bush, PhD, INESSS, for clinical data extraction, P Dodin, librarian, Information Unit services, CHU Sainte-Justine, Montreal, QC, for the search strategy, A Maurice, Research center of the university hospital center Sainte-Justine, Montréal QC for IT support and L Tremblay, CSACI Executive Director, Canadian Society of Allergy and Clinical Immunology, Ottawa, ON, for administrative support.

Finally, we wish to acknowledge all the other participants to the consultations including C Avril; MJ Bettez, Peer supporter at Déjouez les allergies, Quebec, QC; G Briand; S Beugnot, PhD Psychologist, Montreal, QC; A Boisvert, Peer supporter, Montréal, QC; V Brousseau; P Chainé; L Couture; N Ford; J Gerdts, Food Allergy Canada; J Gomis, RN, Nurse, CHU Sherbrooke, QC; J Huang, Food Allergy Canada; L Lavallée, RN, Nurse, CHU Ste Justine, Montréal, QC; C Marcoux; H Matharu, MD, Family Physician, Toronto, ON; O Nazarko; S Pietrzykowski; S Sissons; MA Therrien; J Trudel MD, Pediatrician, Shawiningan, QC; W Toma, MD, Pediatrician Vancouver, BC; G Van Herck, Social worker & psychotherapist, Montreal, QC; G Zheng.

Funding

CSACI.

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P. Bégin, E. S. Chan, H. Kim, E. M. Abrams, M. Ben-Shoshan, S. B. Cameron, S. Carr, D. Fischer, A. Haynes, S. Kapur, M. N. Primeau, J. Upton, T. K. Vander Leek are members of the OIT CPG working group, in alphabetical order except for the executive team. MSC adapted the EVIDEM framework to transform it into a patient-centered ethical framework. MMG reorganized the criteria of the EVIDEM framework into five dimensions and adapted the framework to a qualitative MCDA approach (no weighting and no scoring) to deepen the reflective aspects of the framework. HK, ESC, PB, MW, MMG were responsible for executive decisions throughout the development of the clinical practice guidelines. MW performed the review of the literature to which all authors contributed, except for the ethical aspects, which was performed by CFG. MSC, MW, MMG and PB performed consultations and chaired consultations panels. MSC organized and analyzed the consultations. MMG performed the data integration. All authors had full access to all of the data collected through the literature review and consultations. MSC, MW, MMG and PB take responsibility for the accuracy of the data synthesis. All authors contributed to the analysis and interpretation of data. MSC, MW, MMG and PB drafted the deliberation guide. MSC, MW and MMG chaired the deliberation committee. All authors drafted the recommendations during the deliberation. MSC, MMG, MW, and PB drafted the manuscript. All authors read and approved the final manuscript.

Correspondence to P. Bégin.

Ethics declarations

Ethics approval and consent to participate

The study was performed according to the current practices at INESSS for clinical practice guidelines; patients consulted on their perspectives of the different dimensions of OIT completed an informed consent.

Consent for publication

Not applicable.

Competing interests

Direct competing interests related to the topic of the guidelines P. Bégin and J. Upton are non-remunerated investigators on an investigator-instigated trial sponsored by the Canadian Institutes of Health on the use of omalizumab in oral immunotherapy (in-kind contribution of investigative drug product by Novartis worth > $100,000 CAD). They were excluded from the room for the discussion and deliberations on recommendations related to the use of omalizumab in oral immunotherapy. M. Ben-Shoshan was a principal investigator on a trial on the use of pharmaceutical peanut flour preparations in OIT sponsored by Aimmune Therapeutics (> $100,000 CAD in grant support). J. Upton was a non-remunerated sub-investigator on clinical trial sponsored by Aimmune Therapeutics on the use of pharmaceutical peanut flour preparations in OIT. They were excluded from the room for the discussion and deliberations on recommendations related to the use of pharmaceutical food products in OIT.

Direct competing interests unrelated to the topic of the guidelines P. Begin reports speaker and/or advisor fees from Food Allergy Canada, Novartis, Pfizer, Sanofi, ALK and Aralez Pharmaceuticals, as well as research grant support from Canadian Institutes for Health Research, Fonds de Recherche en Santé du Québec, Canadian Allergy, Asthma and Immunology Foundation, DBV technologies, CHU Ste-Justine Foundation, Regeneron and Sanofi outside the submitted work. M. Ben-Shoshan reports advisor fees from Food Allergy Canada, as well as research grant support from Canadian Institutes for Health Research, Fonds de recherché en Santé du Québec and Canadian Foundation of Allergy and Clinical Immunology outside the submitted work. S. B. Cameron reports an unrestricted educational grant from Pfizer outside the submitted work. S. Carr reports speaker and/or advisor fees from Aralez, Pfizer, Nutricia, Meda (Mylan), Sanofi, GSK, ALK, and Pediapharm. E. S. Chan reports speaker and/or advisor fees from Pfizer, Kaleo, Food Allergy Canada, Pediapharm, Leo and DBV technologies as well as research grant support from DBV Technologies outside the submitted work. D. Fischer reports speaker and/or advisor fees from ALK, AstraZeneca, Aralez, Bausch Health, Merck, Mylan, Pfizer, Novartis, Pediapharm, Sanofi and Teva outside the submitted work. A. Haynes reports advisor fees from Sanofi outside the submitted work. S. Kapur reports speaker and/or advisor fees from Pediapharm and has been a member of advisory boards for, Bausch, Kaleo, Mylan, Novartis, Pediapharm, Pfizer, and Sanofi outside the submitted work. He also holds shares in ABK Biomedical, who are not involved in the field of allergy. H. Kim reports speaker and/or advisor fees for ALK-Abelló, Aralez, Astra Zeneca, CSL Behring, Shire, Novartis, Pediapharm, Stallergenes, Kaleo, Sanofi, Pfizer, and Mylan outside the submitted work. M. N. Primeau reports speaker and/or advisor fees from ALK, Allergie Québec, Aralez, Bausch Health, Food Allergy Canada, Mead Johnson, Mylan, Novartis, Nutricia, Pediapharm and Pfizer outside the submitted work. J. Upton reports advisor fees from Food Allergy Canada, ALK-Abelló, Kaleo, as well as research grant support from Toronto SickKids Foundation, DBV technologies and Regeneron outside the submitted work. T. K. Vander Leek reports speaker and/or advisor fees from Pediapharm, Pfizer and Aralez outside the submitted work. Other authors and members of the deliberative committee declared no financial conflicts of interest.

Indirect competing interests related to the topic of the guidelines E. M. Abrams is a pediatric allergist currently offering OIT in clinic. She has contributed to a national cohort study published on the topic. She is on the national advisory board of Food Allergy Canada. P. Begin is an adult-trained allergist currently offering OIT in the academic setting. He pursues clinical research projects on OIT. He is the director of a pilot public OIT program funded through philanthropy and government support. He collaborates with a parent committee doing fundraising for a public-funded OIT program in the province of Quebec. He is a clinician-scientist with a research program including clinical trials, epidemiologic and health technology assessment studies on food allergy and OIT. He has published original research as well as editorials and review articles on the topic of OIT. He is a member of the advisory board for Food Allergy Canada. He has given public and scientific lectures on the topic of OIT. M. Ben-Shoshan is a pediatric allergist currently not offering OIT outside research. He is a clinician-scientist with a research program including clinical trials OIT. He has previously published on the topic of OIT. He is on the national advisory board of Food Allergy Canada. A. Boisvert is a peer-supporter at byebyeallergies.ca and Food Allergy Canada. M. J. Cadieux, is a peer-supporter at Déjouer-les-allergies. S. B. Cameron is a pediatric allergist currently offering OIT in clinic. He has contributed to a national cohort study and a review published and has given scientific lectures on the topic. S. Carr is a pediatric allergist currently offering OIT in clinic. He has contributed to a national cohort study and a review published and has given scientific lectures on the topic. E. S. Chan is a pediatric allergist currently offering OIT in the academic setting. He collaborates with a parent committee doing fundraising for a public-funded OIT program in Vancouver. He as contributed to a national cohort study published on the topic. He is a member of the advisory board for Food Allergy Canada, is an eosinophilic esophagitis guideline member for the Joint Task Force/American Gastroenterological Association, and was an expert panel and coordinating committee member of the National Institute of Allergy and Infectious Diseases–sponsored Guidelines for Peanut Allergy Prevention. D. Fischer is an adult-trained allergist currently not offering OIT in clinic. He has given scientific lectures on the topic. B. Francoeur is a family physician from a region without allergist with a practice focus on allergy. He currently follows patients on OIT but does not initiate treatment himself. H. Kim is an adult-trained allergist currently offering OIT in clinic. He has published an editorial on the topic of OIT. He is the president of Canadian Society of Allergy and Clinical Immunology. A. Haynes is a pediatric allergist currently not offering OIT in clinic. S. Kapur is a pediatric allergist currently offering OIT in clinic. He has previously contributed to a national cohort study published on the topic. G. Parizeault is a pediatrician with a practice focus on allergy in a region without allergist. He is currently offering OIT in clinic. S. Pernice, is a registered dietician practicing in an academic allergy clinic offering OIT. M.N. Primeau is a pediatric allergist currently not offering OIT in clinic. J. Upton is an adult-trained allergists currently not offering OIT outside research. She is a clinician with a research program including clinical trials OIT. She is on the national advisory board of Food Allergy Canada. She has given public and scientific lectures on the topic of OIT. C. Vaillancourt is a family physician with a practice focus on allergy in a region without allergist. He is currently offering OIT in clinic. T. K. Vander Leek is a pediatric allergists currently offering OIT in clinic. He has previously contributed to a national cohort study published on the topic. Other authors and members of the deliberative committee declared no indirect conflicts of interest.

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Bégin, P., Chan, E.S., Kim, H. et al. CSACI guidelines for the ethical, evidence-based and patient-oriented clinical practice of oral immunotherapy in IgE-mediated food allergy. Allergy Asthma Clin Immunol 16, 20 (2020). https://doi.org/10.1186/s13223-020-0413-7

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Keywords

  • Food allergy
  • Oral immunotherapy
  • Clinical practice guidelines
  • Avoidance
  • Patient-centered
  • Evidence
  • Ethics
  • Quality of life
  • Indication
  • Contraindication
  • Multi-criteria decision analysis