Live Biotherapeutic Products, A Road Map for Safety Assessment

Abstract

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.

Lactic acid bacteria as probiotics for the nose?

“…Overall, for next-generation probiotics, such as the more recently suggested D. pigrum, the safety profile is less well-known and animal studies are thus of more interest to evaluate the safety before clinical studies are performed (Cordaillat-Simmons et al, 2020;Rouanet et al, 2020). The more traditional strains, especially strains that belong to the Lactobacillaceae, are already used on a large scale and have an established safety profile, hence animal studies might not be essential before proceeding to clinical trials in humans.…”

Whole-genome analysis of probiotic product isolates reveals the presence of genes related to antimicrobial resistance, virulence factors, and toxic metabolites, posing potential health risks

“…The widely accepted definition of probiotics is “live microorganisms which when administered in adequate amounts confer a health benefit on the host” [ 1 ]. Strains of Lactobacillus , Bifidobacterium and Streptococcus are commonly used as probiotics in foods or feed additives, and strains of Enterococcus in “Live biotherapeutic products (LBP)” or “Microecologics for therapeutic use” [ 2 ]. According to the “Guidelines for the Evaluation of Probiotics in Food” [ 1 ], multiple assessments are essential to demonstrate the safety and health benefits of probiotic strains, which include the assessment of antibiotic resistance, toxin production, hemolytic activity, metabolic activity, and adverse effects.…”

Topical Microbial Therapeutics against Respiratory Viral Infections

“…While prophylactic intranasal application of beneficial bacteria or their lysates appears promising, their efficacy is yet to be further explored in more robust clinical trials specifically against respiratory viral diseases. Regarding safety, appropriate guidelines covering the risks related to isolation and selection of the strains, their intrinsic characteristics, production process and the administration of such therapeutics in vivo are in development to assist their rational design and clinical implementation in different human body sites [96].…”