Mapping the European landscape and specificity of ATMPs guidance.

A good amount of guidance has been issued by various national and international organizations in addition to the global regulation of Advanced Therapy Medicinal Products (ATMPs) at the European Union (EU) level. These include regulatory, technical, and scientific documents (mainly, but not only, guidelines), which aim to support the operability of the European pharmaceutical legislative framework. Guidance documents are highly necessary, especially in a rapidly evolving field such as ATMPs in which scientific achievements may translate quickly into therapeutic innovations. They provide the needed flexibility and adaptation that the legislative level could never afford to the same extent when considering the usual delays for revision, adoption, and application of binding legislative acts such as the ATMPs Regulation or the European Directives on medicinal products. This has led to the early adoption of guidance documents in the field of gene and cell therapy, the first of which appeared in the 1990s. However, with this early adoption comes complexity and difficult readability due to the accumulation of new soft law rules in the wake of new scientific findings and hard law regulations. Our study provides the first comprehensive analysis of guidance produced and currently applicable in the field of ATMPs and its relationship with categorization of biological medicinal products. We base our analysis on the collection of available guidance documents from the websites of the most active institutions in the production of guidance on ATMPs applicable within the European Union. We also obtained relevant material via the search engines of those websites by using a list of keywords corresponding to ATMPs or their subcategories. Our search resulted in a collection of 126 guidance documents applicable to ATMPs from July 1990 to September 8, 2023. We found that the distribution of current ATMP guidance mainly comes from the European Medicines Agency (EMA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use regarding their sources, and are mainly guidelines regarding their types. This demonstrates that for the majority of currently applicable ATMP guidance documents, there is no overlap with other categories of biologicals, indicating that they are strictly specific to ATMPs. Our data indicate that the overlap between ATMPs and other biologicals essentially deals with the active substance and finished products among transversal categories and with biotechnologicals among various types of biological medicinal products. We discuss these results in light of their usefulness in regard to medical and socioeconomic actors of biotherapies. Finally, we conclude that the singularity of ATMPs is quite well reflected through their guidance landscape with a high number and diversity of documents. Although the overlap of guidance applicable to biologicals is important and could be anticipated based on the common biological origin as well as common technological approaches and associated risks, there is a drive from regulators, especially the EMA, to ensure that all documents applicable to ATMPs are accessible in one place, on the EMA website. However, with this large quantity and high diversity of guidance may come complexity and confusion: almost no difference is made between cell therapy and tissue engineering medicinal products in guidance documents. The near absence of a link between ATMPs and biosimilars suggests that the latter were not thought of as ATMPs given their recent development and low number in comparison with biotechnologicals; thus, the current navigability of ATMP guidance could be improved.