Table 1. Requirements, challenges, and consequences/risks of dose finding on the efficacy of preparations for allergen immunotherapy.

Requirements1 for dose finding studies	Challenges2 imposed by dose finding studies	Consequences/risks3 of dose finding studies
- Use of an in-vivo model and suitable endpoint (not only in-vitro and/or ex-vivo data) - Testing of an adequate dose range - Testing of ≥ 3 doses, e.g., below or above the marketed dose - Significant difference compared to placebo - Differences (clear trends) between the doses; but statistically significant differences not required	- Use of a suitable model, e.g.: titrated skin test (e.g., intradermal test with late-reading) • conjunctival or nasal provocation test • allergen challenge in exposure chamber field study (symptom and medication scores) - Selection and scaling of doses (doubling? triplication? semi-logarithmic?) - Minimization of placebo (intervention) effect - Sufficient number of cases (power calculation) - Study costs and efforts	- Too low doses (no relevant differences) - No real dose-response relationship, no plateau - Too small therapeutic window when pronounced placebo effect is present - When scattering is too big, possibly no clear difference (compared to placebo) - Lack of treatment effects in field studies due to lack of allergen exposure - Missing dose increase (when doses are too high) - Repeat dose finding if results are ambiguous or negative

¹Requirements are defined by the EMA guideline on the clinical development of AIT products [6], and compliance is monitored by the competent regulatory authorities (e.g., Paul-Ehrlich-Institute, Langen) based on the submitted study protocols. ²Challenges refer to study planning, design, and decisions before the study starts. ³Consequences/risks refer to possible impacts after conduct and evaluation of the phase II study.