Abstract
Potency assays associated with the efficacy of investigational pharmaceutical products are one of the critical quality attributes that need to be carefully monitored during advanced therapy medicinal product (ATMP) development projects. Ensuring integrity of relevant potency assays for stem cell-based ATMPs is of paramount importance for safety and efficacy of clinical interventions. Yet, due to the complex and heterogeneous nature of stem cell-based ATMPs, creation of an appropriate set of potency assays is associated with a number of specific challenges ranging from intrinsic and operational to legal and regulatory ones. This chapter provides an overview of the EU regulatory landscape for advanced therapies, highlighting important aspects that need to be taken into consideration when preparing a strategic plan to meet the EU regulatory requirements.
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Notes
- 1.
As the pharmaceutical industry operates also on a global level, insight can be gained from observing foreign practices. For further reading, see: Takashima et al. [24]; Ghinea et al. [11]; for a US-EU overview of policies see: Iglesias-Lopez et al. [15]; however, this review intends to give a short introduction into the EU regulatory scheme, and is thus limited in scope.
- 2.
These molecular markers could include diagnosis of transcriptional, epigenetic, and metabolic states of stem cells.
- 3.
A simple indicator could be, for instance, a specific cell surface marker.
- 4.
Further analysis of these intrinsic challenges is left outside the scope of this chapter. Still, it can be briefly mentioned that it is very difficult to characterize the complete mode of action of a stem cell-based ATMP. The mode of action can also be associated with a number of different factors that are not clearly indicated. Some of these factors may also take place in different stages of the in vivo response to the therapy. It can be an impossible task to develop an assay that reflects complete mode of action each and every element of a complex stem cell-based ATMP to qualify all steps of the organism’s response to the therapy. Furthermore, stem cell-based ATMPs often comprise of may active cell types involving potential biological activity. There may also be different kind of synergies and interferences that depend on the composition of the product.
- 5.
Despite operational challenges are left outside the scope of this chapter, it can be mentioned that such challenges include, for instance, short shell lives of the products requiring potency assays that can be read fast, limited amount of starting materials resulting in small batch-sizes, and also any sample taken for purposes of quality assurance reduces the quantity of product available to the patient.
- 6.
- 7.
Interestingly, some individual action plans have been made within the EU to facilitate the introduction of new developments, see: Cuende et al. [3].
- 8.
Such as cell surface markers, activation markers, or expression pattern of specific genes.
- 9.
It is stated that: “The selection of the dose should be based on the findings obtained in the quality and the non-clinical development of the product and it should be linked with the potency of product.”
- 10.
In practice, this necessitates characterization of the cells’ phenotypic and functional properties, which will help to tailor the assays.
- 11.
These could for instance include the number of genetically modified cells, the gene copy number, the expression level of the transgene, and the product activity level, as shown to be efficacious in clinical studies.
- 12.
See for instance Mansnérus [17].
- 13.
Interestingly, it is noted by Pimpaneau et al. that some products have been granted approvals when utilizing the surrogate endpoints as a measure of potency. This shows how adaptive regulatory pathways are now emerging in Europe and can be justified by means of a robust scientific rationale and data. It is further noted that development of a potency assay strategy is a long-term-process, that depends on a number of factors ranging from the aetiology and the knowledge of the disease, availability of relevant scientific publications, the desired composition of the final product to result of characterizations as well as available modes of action studies. Altogether these elements have impact on the chosen regulatory strategy for development of potency assays for stem cell-based ATMPs. This process could start with (1) selection of a first potency test followed by (2) continued investigation of modes of action and product characterization; resulting in (3) proposal of orthogonal methods as knowledge is gained; thereafter (4) building correlations between tests and select the most relevant ones in order to refine the selection of the most relevant potency assays and specifications; and thereafter (5) building correlation with biological activity and clinical outcome in order to verify whether the potency assay can be used to analyze meaningful clinical differences between batches allowing identification of a linkage to the dose; and finally (6) create the final strategy using surrogates, taking into consideration complementarity to comprehensively cover and correlate well with the modes of action.
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Roslin, W., Mansnérus, J. (2023). From the Integrity of Potency Assays to Safe Clinical Intervention: Legal Perspectives. In: Burns, J.S. (eds) Potency Assays for Advanced Stem Cell Therapy Medicinal Products. Advances in Experimental Medicine and Biology, vol 1420. Springer, Cham. https://doi.org/10.1007/978-3-031-30040-0_10
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