What we learned from TAO – 10 years of German therapy allergen ordinance
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The Therapy Allergen Ordinance (TAO) came into force in Germany in 2008 in order to ensure proven and tested quality, efficacy and safety of therapy allergens for the treatment of allergies to frequent allergen sources (birch, alder, hazel, sweet grasses (without maize), bee-, yellow jacket-venom). It excludes exemptions from marketing authorizations (MA) for AIT-products containing these allergens. Due to the particular nature of the therapeutic allergens, rather long transitional periods are legally defined to resolve deficient clinical data. The aim was to analyze the status quo of AIT products developed according to TAO.
Quality data and clinical trials of AIT products subjected to TAO (obtained until 2019) were analyzed and findings were clustered.
The first two AIT products (for tree-pollen allergy) received a national MA in 2018. Of the 123 initial MA applications submitted, 65 are still active (26 for grass-, 17 for tree-, 5 for grass-/tree-pollen-mix and 17 for house dust mite allergy). Quality issues frequently identified were: Lack of comparability of the drug due to extensive changes in the manufacturing process, insufficient/missing stability data or process validation, insufficiently validated analytical methods, unsuitable in-house reference preparations, inadequate specifications and/or in-process controls. Dose-finding and phase III studies are required for MA. Doses of best benefit/risk balance were recommended for phase III studies. PEI takes measures to ensure that products of presumptive lacking efficacy based on study results do not gain access to the market.
In Germany, TAO ensures that all previously untested named patient products for the treatment of frequent allergies are subjected to an assessment of their risk/benefit ratio according to the current state of science.
KeywordsAllergen immunotherapy Quality Safety Efficacy Marketing authorization Named patient product
Arzneimittelgesetz, German Medicinal Products Act
Bundesgesetzblatt, Federal Law Gazette
Decentralized procedure (glossary: The procedure for authorizing medicines in more than one European Union Member State in parallel.)
European Economic Community
European Medicines Agency
Good Clinical Practice (glossary: GCP is an international ethical and scientific quality standard for the performance of a clinical trial on medicinal products involving humans.)
Good Manufacturing Practice (glossary: GMP is a system for ensuring that products are consistently produced and controlled according to quality standards. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product.)
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (glossary: Initiative that brings together regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of pharmaceutical product development and registration. The mission of the ICH is to promote public health by achieving greater harmonization through the development of technical Guidelines and requirements for pharmaceutical product registration.)
Marketing authorization (glossary: The approval to market a medicine is based on a Process of reviewing and assessing the dossier to support a medicinal product in view of its suitability for being marketed based on quality, efficacy and safety.)
Marketing authorization application
Mutual recognition procedure (glossary: A procedure through which an authorization of a medicine in one European Union Member State is recognized by another Member State.)
Named patient product (glossary: individually prepared specific allergen product on the market without the requirement of a marketing authorization.)
Pediatric Committee (glossary: European Medicines Agency’s scientific committee responsible for activities on medicines for children and to support the development of such medicines in the European Union by providing scientific expertise and defining pediatric needs.)
Paul-Ehrlich-Institut (glossary: German Federal Institute for Vaccines and Biomedicines.)
Pediatric investigation plan (glossary: A PIP is a development plan aimed at ensuring that the necessary data are obtained through studies in children, to support the authorization of a medicine for children. All applications for marketing authorization for new medicines have to include the results of studies as described in an agreed PIP, unless the medicine is exempt because of a deferral or waiver.)
Therapy Allergen Ordinance (glossary: With the therapy allergens ordinance which has been in effect in Germany since 14 November 2008, the exemption from marketing authorization was restricted to therapy allergens indicated for the treatment of rare allergies.)
Therapieallergene-Verordnung, Therapy Allergen Ordinance
The authors thank Ms. Anja Hampe for support in data management and preparation of Table 1.
Conflict of interest
V. Mahler, A. Bonertz, C. Ruoff, D. Hartenstein, D. Mentzer, S. Kaul and S. Vieths declare that they have no competing interests.
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