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
Diseases “315 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