In vivo biomarkers in AIT development programs: European implications
An increasing number of clinical trials in AIT have been published underlining both efficacy and safety of AIT as the only disease-modifying treatment option for patients with IgE-mediated respiratory allergic diseases.314 With country-specific exceptions, AIT products are regulated by Authorities such as the European Medicines Agency315 and others on the basis of methodological guidelines.
In its guideline “Clinical Development of Products for Specific Immunotherapy for The Treatment of Allergic Diseases315 the European regulatory authority, (European Medicine Agency (EMA)), has provided strict guidance for designing and performing clinical development programs in AIT.101,316 In Germany, these principles were followed in the “Therapy Allergen Ordinance (TAV)“ for future registration of allergens and allergen-mixtures (derived from grass pollen, early flowering trees pollen, house dust mites, and bee and wasp venom) based on the main prevalent respiratory allergies in Germany.317-319 First registrations have been granted fulfilling the TAV demands by the German Paul Ehrlich Institut (PEI).320 Besides, a sufficient body of evidence exists in the clinical documentation of both SLIT and SCIT AIT products.321-323
An important unmet need for further harmonization of methodological principles in AIT study design324 has been followed in a series of Task-force initiatives of the European Academy of Allergy and Clinical Immunology (EAACI)325 as overviewed in the 2019 report of our group.101 As such, position papers and guidelines on allergen-challenge procedures including clear standardization of procedures (SOPs) through the nasal326 or conjunctival327 route has been provided by the EAACI.
In addition, the combined symptom and medication score (CSMS) as defined by the EAACI as standard primary endpoint for future (pivotal) trials in AIT328 has been recently used recently in an increasing number of key trials in AIT.329-331However, further formal validation and amendments especially for the pediatric population are needed.320,332 As another example a further Task Force initiative aimed to provide clear clinically and aerobiologically justified definitions of pollen-counts for onset, peak and duration of pollen-seasons333 and those have been confirmed to be robust334 and clinically relevant as reflecting patients’ symptom load in different countries in Europe in recent reports.334,335Recently, the EAACI has published a Position Paper reporting the impact of the placebo effect in AIT from different methodological perspectives and outlining possible strategies to minimize this bias in clinical trials.336
Taken together, further emphasis should be put on international collaborations of clinical experts, methodologists and regulatory authorities to optimize methodological standards for AIT clinical development programs aimed to increase the level of evidence of AIT as the only disease-modifying therapy available.320,323,337