Live Biotherapeutic Products, A Road Map for Safety Assessment.

H Jelena Cvejic ,Ingmar Claes,Nail Nasir,Christophe Chassard,Jos F M L Seegers,Bruno Pot,Garikai Midzi,Audrey Valo,Manfred Oberreither,Constance Bezulowsky,Benjamin Hadida,Marco Pane,Stéphanie Blanquet‐Diot ,Charlotta Movitz,Frédérique Vieville,Wynand Alkema,Alice Rouanet,Luca Mogna,Magali Cordaillat-Simmons,Charlotte Hemmingsen,Luc Sterkman,Audrey Bru,Cyrille Jeune,Sophie Mathys,Sidonie N Lavergne ,Sandrine P Claus,C Shortt ,Ashton Harper,Selin Bolca,Björn Lindman,Haymen Girgis

doi:10.3389/fmed.2020.00237

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 design non-clinical programmes and First in Human (FIH) early clinical trials appropriate to assess LBP safety.

Highlights

The development of molecular methods in recent decades has enabled the detection of non-cultivable microorganisms in different environments, including human and animal ecosystems, and has shifted the perception that most microorganisms are threatening, to a greater understanding of the importance of balanced microbial ecosystems in human and animal health
Drug-Drug Interactions The full understanding of the mode of action (MOA) of a living microorganism used as an Live Biotherapeutic Products (LBPs) is not a requirement for its registration as a medicinal product if quality, safety and efficacy have been demonstrated and documented through appropriate clinical trials
This should include proposals for the most suitable studies guaranteeing sufficient quality andclinical safety, and it should help developing protocols to demonstrate efficacy. These products represent a real challenge, because their MOA does not rely on their absorption in the systemic circulation nor on a simple direct liaison between a ligand and a receptor, but is rather related to an impact on the local ecosystem and the local host cells, involving various direct and indirect mechanisms

Summary

Introduction

The development of molecular methods in recent decades has enabled the detection of non-cultivable microorganisms in different environments, including human and animal ecosystems, and has shifted the perception that most microorganisms are threatening, to a greater understanding of the importance of balanced microbial ecosystems in human and animal health. Risk analysis for LBPs should consider any risk intrinsic to the strain(s), as well as any information originating from the literature or the sponsor’s data on the use of the strain(s) in different models or individuals (healthy humans or patients) and information on potential risks related to the particular characteristics of the intended population.

Results

Conclusion