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Wise et al.

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ACC studies have contributed to our understanding of the pathophysiology of allergic diseases. For example, it has been demonstrated that controlled allergen exposure exacerbates atopic dermatitis. 1026 Also, the impact of exposure with pollen allergen fragments on AR symptoms has been shown. 1027 Furthermore, the importance of the integrity of the epithelial barrier for induction of local and systemic inflammatory responses has been investigated in patients with allergic rhinoconjunctivitis using the ACC setting. 1028 The use of ACCs in clinical trials for efficacy testing of investigational new drugs, and their acceptance by regulatory authorities is peremptorily dependent on the technical and clinical validation of ACCs. Many ACCs have been intensively validated regarding specificity and dose-dependency of symptom induction as well as technical aspects such as temporal stability and spatial homogeneity of the allergen exposure. 1029-1037 Also, repeatability of outcome measures in the ACC has been systematically investigated and found to have excellent repeatability as measured by TNSS. 1038 With the given level of technical and clinical validation, ACCs have been intensively used in clinical drug development to study pharmacological properties of new drugs during phase II trials, such as dose-finding, 1039-1041 onset of action, 1042-1046 and duration of action. 1047-1049 In this respect, numerous randomized, placebo-controlled clinical trials have been conducted using parallel-group or crossover designs in order to test the efficacy of drugs with immediate therapeutic activity, such as antihistamines, 1050-1053 or with prophylactic therapeutic potential, such as topical steroids, 1054-1056 novel anti-inflammatory compounds, 1057-1060 or probiotics. 1061 Major advantages in the ACC setting compared to field studies are better signal-to-noise ratios, a safeguarded minimum level of symptomatology in the ACC, and repeatability of symptoms allowing intraindividual comparisons. With availability of a variety of validated allergen atmospheres in challenge chambers, 1029,1030,1034,1035 efficacy testing for dose-finding of AIT has also been performed in RCTs. 1062-1066 While regulatory authorities accept the use of ACC in phase II of drug development, 1067,1068 they have been reluctant to approve them in pivotal phase III studies because the clinical validation is still imperfect. Differences between natural exposure in field studies and ACC studies exist, for example with regard to exposure time (continuous vs intermittent), exposure atmosphere complexity (natural mix vs artificial purity), or selection of study population (all-comers vs allergen-challenge responders). Therefore, evaluation of efficacy during natural exposure in phase III field studies is still mandatory. However, recent joint activities of the EAACI with experts from academia, chamber owners, and regulators have defined the most relevant unmet needs and prerequisites for clinical validation to further develop the use and regulatory acceptance of ACC in pivotal phase III studies. In summary, numerous well-designed RCTs using technically validated ACCs for efficacy testing of investigational new drugs with detailed analysis of dose-response, onset of action, and duration of action provide evidence for the use of ACCs in phase II of clinical drug development. VIII.H.2. Local allergen challenge tests— Challenging the target organs of respiratory allergy (ie, nose, bronchi, eye) with a suspected allergen is aimed at demonstrating the actual clinical reactivity when the results of the initial allergy tests (skin

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Int Forum Allergy Rhinol . Author manuscript; available in PMC 2020 June 10.