Abstract
Phase II studies on allergen immunotherapy (AIT) should define the dose with the best balance between efficacy and safety (“optimal dose”). Their key role is based on dose selection for subsequent pivotal studies (phase III, field studies). Since products for AIT differ in composition and unit definitions, phase II trials are mandatory for new products and preparations being developed according to the German Therapy Allergen Ordinance (“Therapie-Allergeneverordnung”, TAV) due to current EMA guidelines since 2009. The latter permit various in-vivo models and endpoints for phase II studies, e.g., AIT-induced changes in skin test, nasal, conjunctival or bronchial provocation, or in exposure chamber or field trials. Selection and graduation of the doses, minimization of placebo effects, and sufficient numbers of patients are a challenge. Effort, required time, and costs are important variables for the initiators of phase II trials. Risks are characterized by e.g., a) too small doses without relevant differences compared to placebo, b) missing true dose-response relationships, c) strong placebo effect and consequently small “therapeutic window”, d) large heterogeneity and missing distinct differences (compared to placebo), e) too small effects in field studies due to low allergen exposure, f) missing dose-related increase (in case of too high doses). In the view of the Paul-Ehrlich-Institute, the unambiguous phase II trials with TAV products performed until today were not able to confirm the marketed doses for AIT. Regardless of the utilized model, more raw and single data should illustrate the individual outcome of AIT during phase II trials, facilitating an improved and more intuitive interpretation of the data (placebo effects? scattering?). In the medium term, evidence regarding AIT efficacy will considerably increase due to phase II trials as a prerequisite for subsequent phase III field studies. This affects all manufacturers offering AIT products in Germany and Europe.
Highlights
Introduction and definitionsClinical studies using allergen preparations have some special features that distinguish them from phase I and phase II studies with conventional drugs: A
Phase I studies with various application forms of preparations for allergen immunotherapy (AIT) [1] are already carried out in allergic subjects
This does not apply to AIT products, as safety testing in allergic patients with regard to the maximum acceptable dose already was carried out in the previous phase I studies
Summary
Clinical studies using allergen preparations have some special features that distinguish them from phase I and phase II studies with conventional drugs (e.g., small molecules): A. Future publications should contain more individual data from both placebotreated and actively treated subjects This would lead to a higher transparency of DFS results, i.e., the (inevitable) placebo effects, the absolute and relative differences between dosages, and the individual response of subjects would become clearer. Since current regulations force all manufacturers that develop products for the European market to test the most important allergen sources in a stepwise approach, valuable data, e.g., on dose finding, are generated that are relating to safety and, and to efficacy. This closes an important gap that often remained in the past in the recommended dosage of AIT products. Since pivotal trials involving symptom and drug use assessment entail effort, costs, and risks for the manufacturers, the preceding DFS plays an important role, as the most successful and later-on possibly approved dose, which is to be tested in at least one field study, will be selected here
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