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Microbiome Products

A microbiome describes the collection of microbial life (microbiota) that inhabits a specific environment and includes microorganisms as diverse as bacteria, yeasts, fungi, archaea and viruses such as phages. In humans, these organisms are resident primarily in the gastrointestinal tract but are also found on the skin, genitals and in the lungs. Although the extent of the relationship between the microbiome and human health is not fully known yet. The scientific community is gaining a better understanding of the role of these microorganisms in the development of pathologies such as obesity, gastrointestinal diseases (typically, Irritable Bowel Syndrome (IBS) or Crohn’s disease) depression and allergies. It is now possible to approach these and other challenges from a new angle. This includes the development of new foodstuffs to maintain beneficial flora, to restore a flora in dysbiosis as well as the development of new drugs that offer more targeted possibilities.

Microbiome products are typically designated as prebiotics, probiotics or postbiotics, or a combination thereof (Symbiotics).  However, these are not regulatory product categories. Applicable status may vary depending on the product intended purpose (e.g. target indication and population claims), composition, route of administration and mode of action. They can be either drug, Live Biotherapeutic Products LBPs, biological medicinal products, functional foods, food/dietary supplements, medical devices, transplants or tissues & cells.  Some are specific to microbiome products (e.g. Fecal Microbiota Transplant (FMT)) while others also apply to other types of health products.

Key challenges encompass:

  • Managing the presence of live microorganisms in production sites
  • Controlling the risk of transfer of antibiotic resistance between the live microorganism(s) given to the patient and its microflora
  • Ensuring and controlling the viability of a LBP to its site of action
  • Determining whether conventional nonclinical pharmacokinetics (e.g., ADME) and toxicological studies are applicable
  • Defining appropriate endpoints for evaluating the impact of a product on patients’ microbiome
  • Ensuring the use of appropriate biomarkers that will correlate to an acceptable clinical efficacy endpoint
  • Ensuring compliance with both pharmaceutical and GMO regulatory requirements
  • Navigating the moving and multiple potential applicable regulatory frameworks as no harmonized approach is in place

Main considerations to bear in mind if you are developing a microbiome-related product:

  • Microbiome products can fall under several regulatory statuses, in both the food and medicinal arenas
  • Their intended use, target population, presentation form, composition, mode of action and route of administration will be key in determining the corresponding statuses
  • Both drug and food pathways and associated regulatory statuses present specific benefits and constraints and will be directly related to the complexity, costs and timelines of development, and to the further marketing opportunities.

VCLS contributes to the development of products within a comprehensive range of regulatory statuses, including drugs,(biologics, ATMP), medical devices, FSMPs, Food supplements. We have a solid track of experience in various therapeutic fields including infectious diseases, inflammatory diseases, immunology (including allergies), metabolic disorders, oncology with common applications in the gastrointestinal tract, skin and gut-brain axis.

What VCLS can offer:

Early product positioning & strategical development planning

  • Identification of eligible regulatory paths, within the food and therapeutic arenas, as well as in the cosmetic field
  • Risk of re-qualification & identification of critical product features
  • Target Product Profile (TPP) definition
  • Assessment of optimal positioning based on subsequent development needs and risks

Regulatory activities implementation

  • Definition of an optimal regulatory roadmap for global market entry
  • Critical analysis of regulatory development plans
  • Eligibility assessment & application to accelerated development pathways and authorization programs
  • Support for request, preparation and participation at meetings with Competent Authorities at key steps of product development including Informational meetings, Scientific Advices, pre-IND meetings
  • Author, review and submission of authorization/notifications regulatory dossiers in key global markets

Learn more about our Regulatory Strategy & Submission service

CMC, Nonclinical and Clinical development support

  • Gap analysis of available CMC, nonclinical and clinical data in view of critical regulatory submissions
  • Strategy support for individualized nonclinical and clinical development programs including study protocol design

Learn more about our CMC, Nonclinical and Clinical service


What regulatory framework should be followed during the international development of a microbiome product?

The relevant regulatory framework should be defined on a case-by-case basis, taking into account in particular the region(s) of interest and the characteristics of the microbiome product. Regulations and therefore product positioning may vary from one region to another. Standards and/ or guidelines specific to the type of microbiome product of interest may be used, as well as non-product specific and transversal references.

For example, for Live Biotherapeutic Products (LBPs), both the US and the EU have set requirements specific to this type of product. Principles established in local and international guidelines for biological products can be followed, such as the ones from the EMA Guideline on quality documentation for biological investigational medicinal products in clinical trials and from the ICH Guidelines on quality of biotechnological products. Finally, transversal materials can also be (partially) applied, such as the FDA Guidance for Industry: INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, and Controls Information and the ICH General Principles for Planning and Design of Multi-Regional Clinical Trials.

To qualify as a MD in the EU, the product should not include viable microorganisms that achieve or support the intended purpose. These must also be considered in determining the risk class of the MD.

It should be demonstrated that the microorganisms incorporated in the MD have no potential for metabolism or multiplication.

Appropriate validation should be put in place to demonstrate the absence of viable microorganisms in the final product.

The selection and generation of a nonclinical study model for microbiome research remains a challenge, given the variability and complexity of the human microbiome. The main question is not “Are there any nonclinical models?” but more “What do we need to demonstrate using a nonclinical model?”. To date, many nonclinical models have been and are being developed such as the in vitro simulator of the human gut microbial ecosystem (SHIME), or germ-free or gnotobiotic (i.e., inoculated with a defined microbiota animal models). The panel of nonclinical models includes in silico, in vitro, ex vivo and in vivo models, which are selected on a case-by-case approach depending on the question to be addressed based in particular on the target clinical indication, the target population and the route of administration. Thus, there are a large number of models, that developers can choose and combine to demonstrate the safety and efficacy of their product.

As with any innovative therapy, it is crucial to demonstrate both safety and efficacy of a microbiome product before administration to humans. Microbiome products must therefore be tested in toxicology studies to obtain a safety profile. Given the variety of microbiome products, the toxicological evaluation program must be defined on a case-by-case basis and tailored to the intrinsic characteristics of the microbiome product. In the case of a live biotherapeutic product, the nonclinical studies must assess the potential effect(s) of the microorganisms themselves and of the molecules derived from them, on the recipient of the therapeutical product itself and on the host microbiota. Toxicology studies may include, but are not limited to, biodistribution, colonization, shedding, general toxicology, immunogenicity / immunotoxicity, genotoxicity and reprotoxicity assessments. Given the case-by-case approach, it is strongly recommended to initiate interactions with agencies early on to discuss the safety package to support clinical trials and future registration.

On top of clinical trials requirements, the regulatory framework for genetically modified organisms (GMO ) should be considered. Clinical development of GMO investigational medicinal products may be pursued under deliberate release or contained use conditions.  Authorities in charge of approval, process for application as well as required supportive documentation will depend on the selection of country(ies) in which the clinical investigation will be conducted.