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Page 12 of 20 Manrique et al. Microbiome Res Rep 2024;3:23 https://dx.doi.org/10.20517/mrr.2023.80

composition between samples. Furthermore, because the microbiota is not an active human cell or a tissue,
[152]
they were not considered within the scope of EU directive 2004/23 . In June 2022, the EU published a
Faecal Microbiota Transplantation report, labeled EMA/204935/2022, with an updated regulatory
framework in Europe, which should be used as a roadmap for the development of these products. Even
though microbiota-based therapies are still not within a legislative framework at the EU level, the European
Commission has published a report referring to them as biological medicinal products or biological drugs.
Every Member State has decided to include these products in an appropriate regulatory framework at the
national level, including quality and safety requirements. Most EU countries, such as Spain, France, or
Germany, currently regulate MBPs as biological medicinal products, as suggested by the European
Commission. Others, such as Belgium or Italy, presently regulate them within their national Tissues and
[153]
Cells legislation . Outside of the European Union, there is also a lack of harmonization at the regulatory
level. The United Kingdom, Canada, Australia, and the United States are regulating MBPs as biological
[154]
drugs with some exceptions .

As biological drugs for human use, MBPs are subject to stringent regulations [Figure 2]. Mandatory
regulations include the European Guideline on the requirements for quality documentation concerning
biological investigational medicinal products on clinical trials, the ICH Harmonized Guideline for Good
Clinical Practice and Regulation (EU) No 536/2014 of the European Parliament and of the Council on
clinical trials on medicinal products for human use . According to these regulations, the manufacturing
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process, control, and release of these products must be carried out under GMP standards and the clinical
trials that guarantee the safety and functionality of the product under development must be
performed [154-156] . Based on this, the first requirement for manufacturing is to have a facility certified as GMP
by the corresponding regulatory agency and to have a license as a pharmaceutical manufacturing laboratory.
It is also essential to register the dossier of the drug for approval at the regulatory agency, which
exhaustively details all the drug information, including the name and general properties, traceability
information, and safety tests of the raw materials used. Final approval of the product has not been granted
until the first phases of clinical trials have been completed to corroborate its safety (Phase 1 toxicity trials)
and efficacy for a given therapeutic indication (Phases 2 and 3).

Thanks to the efforts to harmonize the regulatory framework for MBPs, together with increasing
investments and satisfactory results in clinical trials, there are currently three products with regulatory
approval. These products are derived from healthy donors and focused on the treatment of Clostridioides
infection and have been approved by the FDA or the Australian drug agency [157-159] . In spite of these efforts,
the regulation of non-standardized therapies remains extremely complex across different countries, making
the development of standardized and equally efficacious products essential as we move forward.

3RD GENERATION PRODUCTS TO MODULATE THE MICROBIOTA - PERSONALIZED
MICROBIOME-BASED THERAPIES
Traditional medicine is largely based on statistical averages on responses to treatment - the treatment that
works for most people is applied to everyone - generating mixed results. This approach does not consider
that the unique human and microbial genetic profile of each patient impacts disease profile and response to
treatment, and all should be considered when choosing therapeutic options. This is the basis for precision
medicine - using an individual’s unique genetic signature together with microbiome profile, tumor genetics
(in case of cancer treatment), and other patient variables - to empower health professionals to determine the
best course of action for each individual .
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