In a review paper, The Pharmabiotic Research Institute (PRI) calls for action to address a lack of standard clinical trial formats, as products, target populations and application modes are likely to differ on a case-by-case basis.
The Institute adds that development of LBPs should comply with the ‘spirit of the authorities’ expectations’ laid out in guidelines developed for these products.
“In a field where, regulatory confusion often exists we perceive a strong need for clarification of the general concepts and specific constraints associated with 'probiotic strains' intended for prevention or treatment of a human disease,” says Dr Magali Cordaillat-Simmons, executive director of the PRI.”i.e. in the context of their registration as biological drug products."
Europe's authority for the development of microbiome-based drug products outlines the current situation in which LBPs have no “separate status”.
As a result, LBPs comply with the biological medicinal product legislative and regulatory framework.
The PRI recommends that in the absence of this regulation, developers should rely on applicable and relevant regulatory concepts available for the subcategories of biological medicinal products.
This course of action is advised even if their LBPs are not within the scope of specific legislations/guidelines (e.g., advanced-therapy medicinal products, cell-based therapies, etc.), as the Institute highlights the spirit of these guidelines is often applicable and helpful for LBPs.
Three key pillars
The review goes on to outline three key pillars that are required in order to demonstrate a favourable benefit–risk balance.
These are parameters that establish the quality of LBPs as key elements in drug assessments and should also be thoroughly addressed according to existing guidelines, such as the Ph. Eur. Monograph on LBPs.
Efforts also need to be made on how can the safety of LBPs can be demonstrated with the review, prioritising this parameter in the early stages and always in relation to the target population and their clinical characteristics, as results might impact the early selection of the strain(s).
The research team also identify and recommend how can the efficacy of LBPs can be effectively demonstrated with diet a key consideration as an environmental influence on LBP performance.
On the use of biomarkers to assess efficacy, the team stresses the importance of discriminating between general disease-related biomarkers and biomarkers for the microbiota and the level of validation used.
“Many disease-related markers have been validated in the past,” the team writes. “Their use in microbiota-related interventions is perfectly defendable, and their outcomes will be considered valid if obtained by standard clinical research practices.
“Microbiota-related biomarkers are often not validated. Although their use may be more restricted in terms of regulatory acceptance, there are a number of documents that can help to set up proper validation studies.”
Regulatory challenge
One of the review’s authors, Professor Bruno Pot, Science Director for Yakult Europe and PRI President concludes, "New medicinal products directed to the gut microbiota pose big scientific challenges, because of the complexity and variability of the microbiota.
“The regulatory challenge, however, is also real, maybe because of the complexity and variation of the possible paths to success!
“Time and money can be gained in making decisions as early as possible on the regulatory path to follow: it will help to decide on the study planning and result in the preparation of a valid and credible dossier for the evaluation by competent authorities.
“Our hope is that this paper could assist you somehow in this complex process."
Source: Experimental & Molecular Medicine
Published online: doi.org/10.1038/s12276-020-0437-6
“Live biotherapeutic products: the importance of a defined regulatory framework.”
Authors: Magali Cordaillat-Simmons et al