A regulator's view on AIT clinical trials in the United States and Europe: Why successful studies fail to support licensure

Clinical studies demonstrate that efficacy and safety in allergen immunotherapy (AIT) are linked to a multiplicity of factors decisively influencing success or failure. In recent years, numerous trials were performed with correspondent study results published. Yet, the number of AIT products successfully obtaining licensure in the analogous time frame is comparably limited. Essential for licensure is that the AIT product investigated remains comparable in its qualitative and quantitative composition throughout the clinical development. Verification of efficacy is not solely demonstrated by a statistically significant difference between the test and control populations; it must also be shown to be clinically relevant. Choice of meaningful inclusion and end-point criteria is critical. Post hoc or subgroup analysis can be supportive but needs verification as predefined criteria in additional studies. Data analysis may be presented on varying analysis populations, while it should be based on the intention-to-treat population for regulatory review to allow objective assessment of the treatment effect on the overall study population. Apparently conflicting interpretations of clinical data between publications and regulatory review are frequently based on their inherently different objectives, with regulatory review taking into considerations the full data sets of all relevant clinical studies for the concerned AIT product to allow an informed decision on licensure.

Automated summary

Clinical studies on allergen immunotherapy (AIT) show that its efficacy and safety depend on various factors. Obtaining licensure for AIT products requires consistent qualitative and quantitative composition throughout clinical development. Validating efficacy involves statistically significant differences and clinical relevance. Selection of meaningful inclusion and endpoint criteria is crucial. Data analysis should be based on the intention-to-treat population for objective assessment. Interpretations of clinical data in publications and regulatory reviews may differ due to their different objectives. Regulatory reviews consider the full data sets of all relevant clinical studies for informed decision-making on licensure.