Probiotics have been defined as “Live microorganisms that when administered in adequate amounts confer a health benefit on the host”. This definition covers a wide range of applications, target populations and (combinations of) microorganisms. Improved knowledge on the importance of the microbiota in terms of health and disease has further diversified the potential scope of a probiotic intervention, whether intended to reach the market as a food, a food supplement or a drug, depending on the intended use. However, the increased interest in the clinical application of probiotics may require specific attention given their administration in a diseased population. In addition to safety, the impact of the type of product, in terms of quality, production method and, e.g., the acceptance of side effects, is now part of the current regulatory constraints for developers. In the European Union, foods are regulated by the European Food Safety Authority and drugs by the European Medicines Agency; in the United States, the Food and Drug Administration (FDA) deals with both categories. More recently, the FDA has defined a new “live biotherapeutic products” (LBP) category, clarifying pharmaceutical expectations. Since 2019, the quality requirements for this category of drug products have also been clarified by the European Pharmacopoeia (Ph. Eur.). Similar to all products intended to prevent or treat diseases, LBPs will have to be registered as medicinal products to reach the market in the US and in Europe. In this area, regulatory authorities and the pharmaceutical industry will routinely use guidelines of the “International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use” (ICH). Although ICH guidelines are not legally binding, they provide very important recommendations, recognized by almost all drug authorities in the world. In this review, we discuss some aspects of this regulatory framework, especially focusing on products with an intended use in a diseased or vulnerable target population.

Recent developments in the understanding of the relationship between the microbiota and its host have provided evidence regarding the therapeutic potential of selected microorganisms to prevent or treat disease. According to Directive 2001/83/EC, in the European Union (EU), any product intended to prevent or treat disease is defined as a medicinal product and requires a marketing authorization by competent authorities prior to commercialization. Even if the pharmaceutical regulatory framework is harmonized at the EU level, obtaining marketing authorisations for medicinal products remains very challenging for Live Biotherapeutic Products (LBPs). Compared to other medicinal products currently on the market, safety assessment of LBPs represents a real challenge because of their specific characteristics and mode of action. Indeed, LBPs are not intended to reach the systemic circulation targeting distant organs, tissues, or receptors, but rather exert their effect through direct interactions with the complex native microbiota and/or the modulation of complex host-microbiota relation, indirectly leading to distant biological effects within the host. Hence, developers must rely on a thorough risk analysis, and pharmaceutical guidelines for other biological products should be taken into account in order to design relevant non-clinical and clinical development programmes. Here we aim at providing a roadmap for a risk analysis that takes into account the specificities of LBPs. We describe the different risks associated with these products and their interactions with the patient. Then, from that risk assessment, we propose solutions to Rouanet et al. LBPs Safety Assessment design non-clinical programmes and First in Human (FIH) early clinical trials appropriate to assess LBP safety.

During the last decade, a plethora of novel therapies containing live microorganisms as active substance(s) has emerged with the aim to treat, prevent, or cure diseases in human beings. Both the Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines and Health Care (EDQM) codified these biotherapies as Live Biotherapeutic Products (LBPs). While these innovative products offer healthcare opportunities, they also represent a challenge for developers who need to set the most suitable designs for non-clinical and clinical studies in order to demonstrate a positive benefit/risk ratio through relevant quality, safety, and efficacy data that are expected by the drug competent authorities. This article describes how YSOPIA Bioscience, supported by the Pharmabiotic Research Institute (PRI), addressed the regulatory challenges during the early development phase of their single-strain LBP, Xla1, in order to obtain the necessary authorizations to bring this drug to the clinical stage.

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