Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Mechanism of action-based approach for the evaluation of the paediatric strategy of CAR-T cell therapies and monoclonal antibodies authorised in the EU for the treatment of tumors of haematopoietic and lymphoid tissue ***

Dr. Olga Schneider (Abschlußjahr: 2023)

Summary
Language: English
Mechanism of Action (MoA) is a process impacting signalling pathways, which is triggered upon the interaction of medicinal products with a corresponding target. In line with upcoming changes of the Paediatric Legislation, the MoA of medicinal products would become highly relevant for future Paediatric Investigation Plans (PIPs). Applying the MoA to define the paediatric condition leverage additional options to address paediatric unmet medical needs.
The aim of this Master Thesis is to evaluate the paediatric strategy of medicinal products (CAR-T cell therapies; monoclonal antibodies) authorised in the EU for the treatment of tumours of hematopoietic and lymphoid tissue in adults using the MoA-based approach. For this purpose, a dataset composed of 24 medicinal products authorised within the timeframe 1998-2022 was generated. Very few of the medicinal products in the dataset were authorised for a paediatric indication: 12.5.% with already completed PIPs and 8.33% with still ongoing paediatric programs. Strikingly, 37.5% of these medicinal products did not undergo any paediatric development due to the full waiver.
Paediatric development of authorised medicinal products of the dataset was mostly driven by an adult indication. It was shown that 50% of medicinal products with a paediatric program represented the complete match and 37.5% the partial match of adult and paediatric indications according to the WHO categorisation. Those medicinal products with a complete and partial match between the paediatric and adult indication have shown significantly shorter durations of paediatric developments in comparison to medicinal products with no match.
Assignment of medicinal products to different groups of MoA was done according to the classification system by Mirones et al. At first the group A of MoA ("Amplification of immune response") and the group B of MoA ("Initiation of new immune response") were defined. Within these two main groups, three subgroups of MoA: "Adoptive T cell therapy", "Monoclonal antibodies (naked, conjugated and bispecific)" and "Immune checkpoint inhibitors" were introduced. Then, the criteria "Marketing Authorisation type (MA) granted", "Marketing Authorisation Application (MAA) evaluation process", "orphan status" and "paediatric development" of medicinal products assigned to groups/subgroups of MoA were compared.
It was shown that prolonged paediatric developments of the subgroup of MoA “Monoclonal antibodies (naked, conjugated, bispecific)” in comparison to the subgroup of MoA “Adoptive T cell therapy” could be related to age-staggered approaches of paediatric clinical trial starts due to granted deferrals. Initial findings obtained in this Master Thesis showing the difference in paediatric developments between subgroups of MoA could be regarded as a first step towards the understanding of the role of MoA in the definition of paediatric strategies. Further research would help us to expand our knowledge in this area and possibly to develop better strategies for paediatric developments based on the MoA in the future.
Pages: 62
Annexes: 10, Pages: 45