Allergen immunotherapy – many studies, few approvals – how come?
Many clinical trials on allergen immunotherapy (hyposensitisation) have been conducted in Europe and in the US in recent decades, but only a small number of products have been approved. A team from the Paul-Ehrlich-Institut and the US regulatory authority FDA, led by Dr Andreas Bonertz from the Test and Therapy Allergens Section at the Paul-Ehrlich-Institut, looked into this discrepancy. They summarise their findings and the requirements for the successful preclinical and clinical development of allergen immunotherapy products in their review paper (Journal of Allergy and Clinical Immunology, 3 March 2022).
Allergies are a common condition. While there are many authorised treatments for allergy symptoms, only allergen immunotherapy (AIT) offers the possibility of a curative treatment for allergies. AIT “trains” the immune system so that adverse allergic reactions no longer occur. Treatment usually takes place over several years. Regulatory authorities in both the United States and the European Union (EU), and thus also in Germany, require that AIT products are demonstrated to be safe, effective and of adequate quality during the approval process.
Evidence for the safety and efficacy of a product is usually demonstrated in randomised double-blind placebo-controlled trials. Phase 2 trials are used to determine a safe and effective dose, and large phase 3 trials are used to demonstrate efficacy and safety of the therapy. In recent decades, an unprecedented number of such controlled clinical trials have been conducted for many AIT products. Many of these studies occurred as a result of the Therapy Allergens Ordinance (Therapieallergen-Verordnung, TAV), which came into force in Germany in 2008. This ordinance obliges manufacturers of AIT products to apply for marketing authorisation for the treatment of allergies that affect a large number of patients in Germany and for which the implementation of a clinical development programme is considered feasible and reasonable. For these marketing authorisation applications, manufacturers must conduct state-of-the-art clinical development programmes to demonstrate the safety and efficacy of their products. This also applies if the product had already been marketed without authorisation before the currently valid requirements for proof of safety and efficacy existed.
Although publicly available clinical trial registries show that numerous AIT clinical trials have been completed, the exact results of many trials remain unpublished and comparatively few AIT products were subsequently approved in Europe or the United States. For example, of the 123 AIT products initiated in Germany in response to the TAV authorisation process, only two have received authorisation so far, while 50 products are still awaiting authorisation and 73 products may no longer be used (either due to rejection by the competent authority or withdrawal by the applicant).
Experts from the Paul-Ehrlich-Institut, which is responsible for the authorisation of AIT in Germany, led by Prof Stefan Vieths, worked with associates from the US Food and Drug Administration (FDA), which is responsible for AIT in the USA, led by Dr Jay Slater. In their review paper, the team provided an overview of the most important regulatory aspects of clinical trials on AIT in the EU and the US, followed by an overview of problems and critical aspects identified in regulatory assessments of data from clinical trials.
One of the points that the regulators make clear in their paper is that the AIT product under evaluation must remain comparable in its qualitative and quantitative composition throughout the entire clinical development process – a significant challenge in the development of such medicinal products. Moreover, proof of efficacy cannot only be shown by a statistically significant difference between the test and control populations, but must also be demonstrated to be clinically relevant. An important and crucial point for successful clinical development is also the selection of meaningful inclusion and endpoint criteria. Post-hoc or subgroup analyses can be supportive, but they must be verified as predefined criteria in additional studies and cannot be used spontaneously after completion of a study as decisive evidence of efficacy. Different patient groups (analysis populations) from the clinical trials can be considered in the data analysis, but data analysis for the regulatory review should be based on the intention-to-treat (ITT) population to allow for an objective assessment of the treatment effect on the entire study population. The intention-to-treat principle means that all participants in a study group are included in the final evaluation of the study (as was the intention), even if they drop out or change therapies during the course of the study. The ITT principle strengthens the reliability of study results.
The seemingly conflicting interpretations of clinical data between publications and regulatory review are often due to the variations in their objectives. Regulatory review takes the full data sets of all relevant clinical trials for the AIT product in question into account to enable an informed decision on approval.
"Allergen immunotherapies train the immune system to stop overreacting to harmless allergens. This can help many people who suffer from allergies. Our review paper shows which requirements must be met in the preclinical and clinical development of allergen immunotherapy products in order to get more of these products approved," explains Prof Stefan Vieths, Vice President of the Paul-Ehrlich-Institut and study lead.
Bonertz A, Tripathi A, Zimmer J, Reeb C, Kaul S, Bridgewater J, Rabin RL, Sl JE, Vieths S (2022): A regulator's view on AIT clinical trials in the United States and Europe: Why successful studies fail to support licensure. J Allergy Clin Immuno Volume 149, Issue 3, March 2022, Pages 812-818
https://www.sciencedirect.com/science/article/abs/pii/S0091674922000719?via%3Dihub - Abstract
https://www.pei.de/EN/newsroom/press-releases/year/2022/05-allergen-immunotherapy-many-studies-few-approvals-how-come.html - This press release on the Website of the Paul-Ehrlich-Institut