Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Legal Status of Donor-Lymphocyte Infusions manufactured by transiently activated Memory T cells in the context of the European Regulatory Framework

Dr. Werner Schmidt (Abschlußjahr: 2009)

Language: English

Beside B-lymphocyte derived antibodies T lymphocytes play a major role in the adoptive immune response against many infectious diseases. In addition they are believed to be important effector cells against malignant diseases. Therefore much effort has been spent to develop strategies for adoptive T cell therapy of infections and tumors beside vaccination.
In principle one can distinguish two alternative strategies for the generation of antigen-specific memory/effector T cells:

  • a. Generation/selection of T cells with natural (inherent) specificity for the desired antigen,
  • b. Generation of antigen-specific T cells engineered by genetic modification, i.e. transduction/transfection of T cell receptor (TCR) or Immunoglobulin-like Receptors for the desired antigen.


The grade of manipulation (please refer to Regulation (EC) 1394/2007, Art. 2 (1) c and Annex I to get an overview on minimal manipulated cells) in conjunction with the status of manufacturing of memory/effector T cells guide their regulatory status in the European Community legislation. In summary there are two different scenarios thinkable:

  • a. The common centralized marketing authorization procedure based on quality, safety and efficacy data,
  • b. The newly established national accreditation procedure based on quality, safety and functionality.


During the years the european regulatory framework dealing with cells and tissues as medicinal products has been transferred to german law. The german "Gewebegesetz" has been adapted according to the legal input of Directive 2004/23/EC. In the following the "Gewebegesetz" will cause an amendment to the german Drug Act ("Arzneimittelgesetz; AMG") as follows:

  • a. The new accreditation system for tissue establishments of Directive 2004/23/EC, Art. 5 to 11 will be implemented in §20b AMG which will further on serve as legal basis for the procurement authorisation for cells, e.g. memory/effector T cells for adoptive immune response which are non-industrially manufactured. During accreditation the local authority (e.g. "Regierungspräsidium") will take the regulatory leadership whereas the PEI will only participate on request.
  • b. Subsequently §20c AMG dealing with the so-called tissue/cell processing authorisation will lead to the implementation of non-full GMP (the so-called GFP or Good Practice) for tissue establishments dealing with non-industrial cell processing. Again the local authority (e.g. "Regierungspräsidium") will take care for inspection. The PEI is involved due to administrative assistance.
  • c. At the end §21a AMG is laying down the new tissue/cellular preparation approval for tissue establishments which is based on the assessment of quality, safety and functionality aspects of the manufacturing process as well as of the cells (e.g. memory/effector T cells) in question.The PEI will serve as competent authority guiding this regulatory process.


Further on the CTD content for memory/effector T cells as Advanced Therapy Medicinal Products (ATMPs) is discussed with respect to quality, safety and efficacy/funtionality. These issues are discussed regarding a post-authorisation pharmacovigilance system as part of the Risk Management Plan which is mandatory for ATMPs with only poorly understood safety and efficacy/functionality. Reimbursement strategies in Germany as example are shortly introduced for ATMPs like memory/effector T cells.

Pages: 26

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