Abstract
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.
Highlights
Over the last few decades, biomedical science has evolved from a state where all microorganisms are considered health threats towards a better understanding of the importance of microorganisms in supporting and maintaining important physiological functions of the host
We saw the emergence of dietary supplements and foods with live microorganisms that were generally called “probiotics”, as well as registered medicines for which the active substance comprised living microbial strains and that were granted national marketing authorization in a number of European countries
There exists no standard clinical trial format, as products, target populations and application modes are likely to differ on a case-bycase basis
Summary
“probiotic” concept, much later officially defined by WHO/FAO in 20014. Avoiding confusion between the product type and its regulatory status Historically, two kinds of products, able to maintain or “rebalance” the microbiome, were developed. Clinical efficacy can theoretically only be considered proven if (i) confirmed by independent trials of acceptable quality (sufficiently powered, randomized and blinded, placebo-controlled trials), (ii) performed with a specified product including one or several active substance(s), reproducibly produced under GMP conditions, and (iii) applied to a well-defined patient population, using (iv) well-defined treatment conditions and dosage and (v) with preliminary defined, validated endpoint(s) This turns out to be quite difficult for LBPs. The viability of microorganisms, even when produced under GMP conditions, can be affected by environmental factors (e.g., transport and storage conditions) as well as by host-related factors (e.g., health status, stomach pH, interference with diet, the composition of the recipient microbiota, ethnicity, etc.). The intake of an LBP intended to influence the host’s immune system may have a secondary impact via cross feeding or through
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