drawn on data from a systematic review of the literature, more recent published studies and multistakeholder expert clinical opinion. This Guideline is aimed at healthcare professionals who are encouraged to take the recommendations into account in the context of delivering clinical care. This Guideline is not a substitute for professional clinical judgment, which professionals need to exercise in the context of delivering personalised healthcare. AbstractAllergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach.The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass 766 | ROBERTS, PFAAR ET AL. tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children. | ME TH ODOLOGYThis Guideline was produced using the Appraisal of Guidelines forResearch & Evaluation (AGREE II) approach, 17,18 a structured approach to guideline production (see Table S1). This is designed to ensure appropriate representation of the full range of stakeholders, a careful search for and critical appraisal of the relevant literature, a systematic approach to the formulation and presentation of recommendations and steps to ensure that the risk of bias is minimized at each step of the process. The process started on April 2015 beginning with detailed face-to-face discussions agreeing on the process and the key clinical areas to address, followed by face-to-face meetings, and regular web conferences in which professional and lay representatives participated. | Clarifying the scope and purpose of the guidelinesThe scope of this EAACI Guideline is multifaceted...

Background The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis. To inform the development of clinical recommendations, we undertook a systematic review to assess the effectiveness, cost‐effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis. Methods We searched nine international biomedical databases for published, in‐progress, and unpublished evidence. Studies were independently screened by two reviewers against predefined eligibility criteria and critically appraised using established instruments. Our primary outcomes of interest were symptom, medication, and combined symptom and medication scores. Secondary outcomes of interest included cost‐effectiveness and safety. Data were descriptively summarized and then quantitatively synthesized using random‐effects meta‐analyses. Results We identified 5960 studies of which 160 studies satisfied our eligibility criteria. There was a substantial body of evidence demonstrating significant reductions in standardized mean differences (SMD) of symptom (SMD −0.53, 95% CI −0.63, −0.42), medication (SMD −0.37, 95% CI −0.49, −0.26), and combined symptom and medication (SMD −0.49, 95% CI −0.69, −0.30) scores while on treatment that were robust to prespecified sensitivity analyses. There was in comparison a more modest body of evidence on effectiveness post‐discontinuation of AIT, suggesting a benefit in relation to symptom scores. Conclusions AIT is effective in improving symptom, medication, and combined symptom and medication scores in patients with allergic rhinoconjunctivitis while on treatment, and there is some evidence suggesting that these benefits are maintained in relation to symptom scores after discontinuation of therapy.

blind placebo controlled; EAACI, European Academy of Allergy and Clinical Immunology; FEF 25-75, forced expiratory flow at 25-75% of the pulmonary volume; FEV1, forced expiratory volume in 1 second; GINA, Global Initiative for Asthma; GRADE, The Grading of Recommendations Assessment, Development and Evaluation; HCP, healthcare professional; HDM, house dust mites; ICS, inhaled corticosteroids; MEF 25, maximal expiratory flow at 25% of forced vital capacity; MEF 50, maximal expiratory flow at 50% of forced vital capacity; MEF 75, maximal expiratory flow at 75% of forced vital capacity; PD20, provocative dose causing a 20% drop in FEV1; QoL, quality of life; RCTs, randomized control trials; ROB, risk of bias; SCIT, subcutaneous allergen immunotherapy; SLIT, sublingual allergen immunotherapy; SmPC, Summary of product characteristics; WAO, World Allergy Organization; WHO, World Health Organization.Agache and Lau are joint first co-authorship. External peer-reviewers: AbstractAllergen immunotherapy (AIT) has been in use for the treatment of allergic disease for more than 100 years. Asthma treatment relies mainly on corticosteroids and other controllers recommended to achieve and maintain asthma control, prevent exacerbations, and improve quality of life. AIT is underused in asthma, both in children and in adults. Notably, patients with allergic asthma not adequately controlled on pharmacotherapy (including biologics) represent an unmet health need. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline providing evidence-based recommendations for the use of house dust mites (HDM) AIT as add-on treatment for HDM-driven allergic asthma. This guideline was developed by a multi-disciplinary working group using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. HDM AIT was separately evaluated by route of administration and children and adults: subcutaneous (SCIT) and sublingual AIT (SLIT), drops, and tablets. Recommendations were formulated for each. The important prerequisites for successful treatment with HDM AIT are (a) selection of patients most likely to respond to AIT and (b) use of allergen extracts and desensitization protocols of proven efficacy. To date, only AITwith HDM SLIT-tablet has demonstrated a robust effect in adults for critical end points (exacerbations, asthma control, and safety). Thus, it is recommended as an add-on to regular asthma therapy for adults with controlled or partially controlled HDM-driven allergic asthma (conditional recommendation, moderate-quality evidence). HDM SCIT is recommended for adults and children, and SLIT drops are recommended for children with controlled HDM-driven allergic asthma as the add-on to regular asthma therapy to decrease symptoms and medication needs (conditional recommendation, low-quality evidence). K E Y W O R D Sallergen immunotherapy, allergy, asthma, asthma control, asthma exacerbations, GRADE, house dust mites, lung function

No abstract

Regulatory approaches for allergen immunotherapy (AIT) products and the availability of high-quality AIT products are inherently linked to each other. While allergen products are available in many countries across the globe, their regulation is very heterogeneous. First, we describe the regulatory systems applicable for AIT products in the European Union (EU) and in the United States (US). For Europe, a depiction of the different types of relevant procedures, as well as the committees involved, is provided and the fundamental role of national agencies of the EU member states in this complex and unique network is highlighted. Furthermore, the regulatory agencies from Australia, Canada, Japan, Russia, and Switzerland provided information on the system implemented in their countries for the regulation of allergen products.While AIT products are commonly classified as biological medicinal products, they are made available by varying types of procedures, most commonly either by obtaining a marketing authorization or by being distributed as named patient products. Exemptions from marketing authorizations in exceptional cases, as well as import of allergen products from other countries, are additional tools applied by countries to ensure availability of needed AIT products. Several challenges for AIT products are apparent from this analysis and will require further consideration. K E Y W O R D Sallergen immunotherapy, allergic diseases, allergy, regulation | INTRODUCTIONThe availability of medicinal products to provide a reliable diagnosis of clinical allergy and effective treatment(s) is of critical importance for patients with suspected or proven allergy. Products for allergen immunotherapy (AIT) have been approved by national competent authorities in different regions of the world. However, the regulatory landscape governing the approval of these products is enormously heterogeneous-both within the European Union (EU) and even more so when looking globally-thereby rendering it extremely complicated and challenging to develop a harmonized, international approach to regulating these products.Pharmaceutical companies are increasingly focused on global strategies to develop and market their products. It is therefore very important to understand the current regulatory situation for allergen products from an international perspective, as this will have a direct impact on the availability of these medicinal products to patients throughout the world. Certain regulatory patterns can be observed on a global scale. For example, whereas AIT was previously mainly used and placed on the market on the basis of expert opinions with limited regulatory oversight, the requirements for high-quality clinical data for granting market access have greatly increased during the last 20 years. In the EU, legislation applicable for new and existing products 1,2 has been in force since 1989 demanding that allergen products are registered as medicinal products with corresponding requirements for clinical data. The development of the guid...