XVII. Legal Regulation

XVII. 1 Regulation: Why Good Intentions Are Not Enough – A Brief History

FMT's clinical evidence outpaced its legal framework; here we trace why oversight became essential and how its rules took shape across four eras.

Why good intentions are not enough

FMT is simultaneously one of the oldest and one of the newest medical interventions. The therapeutic use of human stool is described in 4th-century Chinese medical literature – Ge Hong documented the administration of a "yellow soup" prepared from the stool of healthy individuals to patients suffering from severe diarrhoea [727]. Modern FMT, however, is not this tradition: in European and North American clinical practice, it spread rapidly and widely from 2013, following the landmark randomised controlled trial published by Van Nood and colleagues [029].

The need for regulation arises precisely from this speed. Where the clinical evidence base for a procedure grows faster than the regulatory framework, a legal gap emerges [728] – and in that gap appear both enthusiastic but insufficiently prepared practitioners and commercial actors who disregard patient safety risks.

Anecdote

In 2019, two severely immunocompromised patients in the United States developed bacteraemia caused by ESBL-producing E. coli after FMT treatment; genomic sequencing linked both cases to the same stool donor, and one of the patients died of the infection. The donor had not been screened for this pathogen under the study protocol, because the guidelines at the time of preparation did not include that screening element. The incident immediately became the focus of FDA attention and accelerated the reconsideration of the entire FMT regulatory framework in the United States [476]. The tragedy was not the result of individual negligence – it was the consequence of a regulatory framework that could not keep pace with the spread of clinical application.

The evolution of regulation – four phases

The global history of FMT legal regulation can be divided into four distinct phases:

Unregulated experimental period (pre-2013): FMT was performed by individual clinicians, typically with institutional ethics committee approval, but without uniform national or international regulation. Donor selection and procedural standardisation varied enormously between institutions [728].
Attempted classification as a drug (2013–2020): The FDA classified FMT as an "investigational new drug" (IND) in 2013, subjecting it to drug law authorisation requirements. This decision would have immediately rendered most clinical application impossible – the FDA therefore soon provided partial enforcement discretion for rCDI, allowing FMT use in a form exempt from the IND requirement.
Emergence of differentiated regulation (2020–2023): Different regulatory models developed in different countries. The USA approved the first commercial FMT product on 30 November 2022 (Rebyota, RBX2660, rectally administered) [471] and the second on 26 April 2023 (Vowst, SER-109, oral capsule) [472], making part of FMT a genuine medicinal product. EU member states classify FMT variously as tissue/cell therapy, medicinal product, or special medicine, with differing consequences.
The SOHO regulation era (from 2024): The European Union's SOHO (Substances of Human Origin) regulation aims to create a unified framework for regulating substances of human origin – blood, tissues, cells, breast milk, and stool. This is the most important regulatory development for the future of FMT in the EU [729].

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Clinical Pearl FMT regulation is not merely a legal question – it directly determines whether a patient can access the procedure, under what quality guarantees, and at what cost. Both over-regulation and under-regulation are harmful: the former prevents access, the latter compromises patient safety.

References

[029] van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium. difficile. The New England Journal of Medicine. 2013. Link

The first randomised controlled trial comparing faecal microbiota transplantation with standard antibiotic therapy in recurrent *Clostridioides difficile* infection. Patients were assigned to three arms: donor faeces given through a duodenal tube after a short course of vancomycin, vancomycin alone, or vancomycin with bowel lavage. The trial was stopped early because the difference was so large: in the transplantation arm 81 percent of patients were cured after the first infusion and 94 percent including repeat infusions, against 31 and 23 percent in the two vancomycin arms. After treatment the diversity of the patients' faecal flora came to resemble that of the donors. This paper turned microbiota transplantation into an evidence-based treatment and is the starting point for the dosing regimen of the present protocol.

[471] . FDA Approves First Fecal Microbiota Product (Rebyota). . 2022. Link

FDA news release: on 30 November 2022 the U.S. FDA approved Rebyota (fecal microbiota, live-jslm; formerly RBX2660, Ferring/Rebiotix) — the first approved fecal microbiota product — for prevention of recurrent Clostridioides difficile infection (CDI) in adults (>=18 years) after completion of antibiotic treatment for recurrent CDI. It is administered rectally as a single dose.

[472] . FDA Approves First Orally Administered Fecal Microbiota Product (Vowst). . 2023. Link

FDA news release: in April 2023 the U.S. FDA approved Vowst (fecal microbiota spores, live-brpk; formerly SER-109, Seres Therapeutics) — the first orally administered fecal microbiota product — for prevention of recurrent CDI in adults after antibiotic treatment for recurrent CDI. Unlike rectally delivered Rebyota, Vowst is taken as oral capsules of purified bacterial spores.

[476] DeFilipp Z, Bloom PP, Torres Soto M et al. Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant. New England Journal of Medicine. 2019. Link

Case report of two patients in independent FMT clinical trials who developed ESBL-producing Escherichia coli bacteremia after the procedure; both cases were linked to the same stool donor by genomic sequencing, and one patient died. Highlights the risk of multidrug-resistant organism transmission via FMT and supports enhanced donor screening protocols. The report underpins regulatory updates requiring multidrug-resistant pathogen screening of all FMT donor material.

[727] Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize the 1,700-year-old fecal microbiota transplantation?. . 2012. Link

This widely cited article documents the historical roots of FMT: the earliest known description comes from the 4th-century Chinese physician Ge Hong, who in his handbook 'Zhou Hou Bei Ji Fang' recommended a faecal suspension ('yellow soup') for severe diarrhoea and food poisoning. The authors argue that this ~1,700-year-old procedure should be standardized in modern clinical practice. The source thus reliably supports the Ge Hong 'yellow soup' FMT-history claim.

[728] EMA/HMA. Faecal Microbiota Transplantation – EU-IN Horizon Scanning Report. EMA/204935/2022/Rev. 1 (updated May 2025). 2022. Link

The 2022 (updated May 2025) EMA/HMA 'Faecal Microbiota Transplantation – EU-IN Horizon Scanning Report' (EMA/204935/2022/Rev. 1) is the official European Medicines Agency horizon-scanning analysis of FMT regulation. It maps the heterogeneous EU regulatory landscape (tissue, drug, blood-component or hybrid frameworks across member states), reviews clinical evidence by indication (CDI, IBD, hepatic encephalopathy, decolonisation of MDROs), and identifies harmonisation priorities. The report informs the EU SoHO Regulation 2024/1938 negotiations and proposes a coordinated approach to donor screening, stool-bank licensing, traceability, pharmacovigilance and clinical-trial registries. It is a key policy reference for EU FMT governance.

[729] European Commission. Proposal for a Regulation on standards of quality and safety for substances of human origin intended for human application (SOHO Regulation). 2022. 2022. Link

The 2022 European Commission 'Proposal for a Regulation on standards of quality and safety for substances of human origin intended for human application (SOHO Regulation)' is the EU's draft replacement for the 2002/98/EC Blood and 2004/23/EC Tissues and Cells Directives. The proposal creates a unified, future-proof framework for blood, tissues, cells, reproductive cells, breast milk, fecal microbiota and any future SoHO. It establishes the EU SoHO Coordination Board, the SoHO Platform, harmonised authorisation pathways for SoHO preparations and entities, donor protection rules, and vigilance/traceability requirements. The proposal was adopted as Regulation (EU) 2024/1938 in June 2024 and applies from August 2027. It is the central EU regulatory instrument for FMT and stool banks.