Microbiome-based Medicinal Products

The latest breakthrough discovery in human and veterinary health

The microbiome can be considered as the latest breakthrough discovery when it comes to health. It has forced us to move away from a host cell and host physiology-centered vision, towards the understanding that human and animal health is an ultimate result of a complex interaction between host (human or animal) and one’s microbiome, itself highly influenced by the host’s environment. Hence, medicine cannot only address the “host side” any longer but must integrate a full symbiosis and act at the level of the holobiont.

A new set of technologies, emerging from the last decade of developments in microbiome science, is intended to prevent or treat pathologies in human beings or animals. But what are these innovative technologies and what are the challenges developers can face during their efforts?


Acting on host physiology through ecosystemic effects

Even though technologies and products based on the recent progress in microbiome science are complex, they all have one thing in common: they act on the host (human and animal) homeostasis through ecological effects within the ecosystem where they reside or transit. The effects of microbiome-based medicinal products in this respect are not systemic, but “ecosystemic”. These ecosystemic effects are the ultimate result of all modifications which these products can induce within the microbiome, as well as further impacts that such microbiome modifications can have on the host itself. For this reason, attempts to create categories based on mode of actions, specific activities, or sites of action of these technologies/products, can be challenging and may not be entirely appropriate.

Another way to look at these numerous innovations, when it comes to pharmaceutical development, is to start with the risk analysis (as is done for all biological medicinal products). With respect to the variety of microbiome-based medicinal products, there are two key parameters when considering risk analysis:

  1. the origin of the active substance(s)
  2. the level of characterization of the product itself

One can easily understand that donor information is highly important when considering products which contain full ecosystems from human origin, whereas highly manipulated products for which the isolation of single strains took place decades ago, may not require such a complete documentation on the origin of the strain(s).

Microbiome-based medicinal products are a continuum of complex technologies

Microbiota transplantation

There is no consensus around the definition of microbiota transplantation at the EU level, nor a legal definition. Microbiota transplantation is a procedure, and could be defined as, “the transfer of biologic material containing a minimally-manipulated community of microorganisms from a human donor to a human recipient (including autologous use) with the intent of affecting the microbiota of the recipient“.

Within the European Union, various member states have varying positions with respect to the classification of fæcal material, some of them regulating it within the Tissues and Cells legislation, while others regulate it under the medicinal product framework. Ongoing revision of the Blood Tissues and Cells legislation as well as the General Pharma legislation could lead to clarification and harmonization in this area (find out more about this ongoing revision here).


Whole ecosystem-derived medicinal product

Medicinal products based on whole or highly complex ecosystems, for which the starting material is a human microbiome, are identified within the PRI as “whole ecosystem-derived medicinal products”. These products would differ from ‘Microbiota Transplantation’ in the sense that they are “industrially manufactured” and intended “to be placed on the EU market”.

Based on the regulatory interplay currently in place between the blood tissues and cells legislation and the Advanced Therapy Medicinal Products (ATMP) legislation, the classification (and therefore the regulatory status) of ATMP, for which Substances of Human Origin (SoHO) are the starting material, depends on the level of manipulation, on an industrial manufacturing process, as well as the placement on the market in more than one EU member state. Current revisions to the legislation via the revision of the BTC legislation (aiming at introducing human microbiomes and maternal milk as SoHO) and the revision of the EU general pharmaceutical legislation may very well affect the future classification for whole ecosystem-derived medicinal products. Thus, such updates will have to be monitored by all stakeholders involved in developing whole ecosystem-derived medicinal products.

The nature of large scale/industrial manufacturing processes, as well as the sheer number of patients these products could reach should any marketing authorizations be obtained, will necessitate safety assessment with public health in mind and will require robust post-market surveillance through phase IV studies and pharmacovigilance monitoring along the entire life of all such medicinal products.

When increasing the level of manipulation and moving towards the selection of specific strains and/or microbial functions, developers may move away from the whole ecosystem-derived approach towards another phase of the continuum referred to within the PRI as “rationally-designed ecosystem-based medicinal products”. However no clear limit exists between such “phases” and each product on the continuum should be assessed based on its specific characteristics.

Rationally designed ecosystem-based medicinal products

“Rationally-designed ecosystem-based medicinal products” are obtained through the manipulation of microbiome starting material or by co-culture of selected microbial strains. The objective is to shape a “controlled ecosystem” able to synthesize particular metabolites and/or to re-establish targeted microbial functions identified as desirable within the targeted indication and targeted population. These “rationally-designed ecosystem-based medicinal products” can contain dozens or even hundreds of different microbial strains.

With increased levels of manipulation of the starting material comes a better characterization of the products. Such manipulation may also help improve quality considerations such as batch-to-batch consistency. Nevertheless, batch-to-batch consistency will remain a challenge due to the variety of impacts which potential manipulation can have on different microbial components as well as the technical difficulties in co-fermenting multiple strains.

As such, rationally designed ecosystems-based medicinal products may allow for better identification and characterization of the risks and lead to better risk mitigation strategies, thereby decreasing the impact of the donor/origin of the starting material in the risk analysis. Nonetheless, the impact of the process applied must be considered as well, and due to the complexity of these products, risks may arise from lack of control of the early manipulations or co-fermentation steps as well as stabilization procedures.


Highly characterized and controlled microbiome-based medicinal products

When specific microorganisms are isolated from microbiome starting material (from human or other origin) and thoroughly characterized, the impact of the donor or origin of the strain in terms of risk analysis becomes less significant in most cases (however the strain’s origin must always be documented). Examples of this type of highly characterized products can be found below.

Live Biotherapeutic Products (LBP)

(single strain or a mixture of several strains)

LBP are the only microbiome-based medicinal products with an official definition both in Europe and the USA.

In Europe, LBP are defined by the European Pharmacopoeia general monograph 3053 as “ medicinal products containing live microorganisms (bacterial or yeasts) for human use”.

In the USA, LBP are defined by the guidance for industry “Early clinical trials with live biotherapeutic products: chemistry, manufacturing and control information” as “a biological product that: 1) contains live organisms, such as bacteria; 2) is applicable to the prevention, treatment, or cure of a disease or condition of human beings; and 3) is not a vaccine”.

As for all the microbiome-based medicinal products, safety and efficacy of LBP have to be demonstrated before obtaining a marketing authorization. The fact that the LBP is based on commensal, QPS or GRAS microorganisms is not sufficient to support the safety of the medicinal product in the targeted indication and targeted population.

Non-Living Biotherapeutic Products

Non-living biotherapeutic products (as we describe them within the PRI) are medicinal products containing microorganisms intentionally rendered ‘non-living’. This means that an inactivation step(s) is part of the production process, and thus key parameters and controls will have to be defined. Furthermore, a confirmation of the “non-living” state of the cells is needed following any inactivation step(s).

As for all microbiome-based medicinal products, ‘non-living biotherapeutic products’ have to be demonstrated as safe in the targeted indication and for their intended use. The “non-living” state of these microorganisms does not qualify the safety of these products. In addition, QPS or GRAS status of the progenitor microorganisms (microorganism before the “inactivation” step) is not sufficient to demonstrate the safety of a non-living biotherapeutic product.

As the safety and quality standards of this kind of product has yet to be defined, the PRI is coordinating a Task Group working towards a consensus regarding regulatory and technical considerations for these products.

Phage Therapy Medicinal Products

Phage therapy-based medicinal products represent a rather particular type of medicinal product in the sense that they are based on viruses (bacteriophages) highly specific to their target bacterial organism. Such high specificity can be obtained through appropriate phage selection from environmental or human starting material. For these products as well, due to the heavy manipulation applied to the starting material, the donor/origin of this starting material is less significant with respect to risk analysis. Approaches applied to ATMP are often very relevant to phage therapy development (as explained here).

In addition, thanks to the fine-tuning of their targets and activities, phage therapy medicinal products can be associated with a high level of safety as long as the ecological role of their bacterial target is well-documented. For this reason, phage therapy medicinal products are currently being developed for their highly specific antimicrobial activity. Recent research on the impact of phages in microbiome shaping could lead to new product development, which will however require in-depth risk analysis and safety assessment of the long-term implications of microbiome modulation.

Challenges in developing phage therapy medicinal products may reside in production as they enter in a more “personalized” approach to medicines and may need adaptation on a case-by-case basis, which is a challenge under today’s pharmaceutical regulatory framework (see here).

A science-driven approach

The key to developing and assessing microbiome-based medicinal products

Overall, microbiome-based medicinal product developers should not fear the absence of a dedicated regulatory framework and guidelines for these products, as it would likely slow down innovation due to the complexity of products which can be envisaged in the future. Rather than applying a check-list approach, developers and assessors should make the extra effort to consider any applicable guidelines for their spirit, for the important concepts the guidelines convey, and have a more proactive approach through involvement in regulatory science activities, risk analysis-based and science-driven developments and assessments.

All stakeholders should also consider involvement in pre-competitive projects aiming at the emergence of new and more appropriate tools, methods, assays, models, and standards allowing for robust documentation of the benefit/risk balance of the full spectrum that microbiome-based medicinal products can represent. And more largely, expertise in microbiome science and microbial ecology should be encouraged among all stakeholders involved in pharmaceutical development, not only to be able to better evaluate these innovative products, but for the general evaluation of all medicinal products which may impact or be impacted by the microbiome, such as the PK/PD or toxicity of new chemical entities.