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 [7]. 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. 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.
The need for regulation arises precisely from this speed [7]. Where the clinical evidence base for a procedure grows faster than the regulatory framework, a legal gap emerges [7] – and in that gap appear both enthusiastic but insufficiently prepared practitioners and commercial actors who disregard patient safety risks.
In 2019, two severely immunocompromised patients at Massachusetts General Hospital died following FMT treatment in which the donor material contained an extensively resistant bacterium – ESBL-producing E. coli. 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 [49]. 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): [7] 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.
- 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 two commercial FMT products in 2023 (Rebyota, Vowst), making part of FMT a genuine medicinal product [309]. 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 [310].
References
[7] van Nood E, Vrieze A, Nieuwdorp M et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013. Link
Open-label RCT in patients with recurrent C. difficile infection comparing duodenal donor faeces infusion (after short vancomycin + bowel lavage) with standard 14-day vancomycin, with or without bowel lavage. The primary endpoint was diarrhoea resolution without relapse at 10 weeks. The trial was stopped early at interim analysis: 13/16 patients (81\%) in the FMT arm achieved resolution after a single infusion, substantially exceeding both vancomycin arms. Establishes FMT as superior to antibiotic monotherapy for recurrent CDI and provides the landmark evidence base for FMT clinical translation.
[49] DeFilipp Z, Bloom PP, Torres Soto M et al. Drug-Resistant E. coli Bacteremia (the presence of bacteria in the bloodstream) Transmitted by Fecal Microbiota Transplant. N Engl J Med. 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.
[309] FDA. Rebyota (fecal microbiota, live-jslm) approval. 2022. 2022. Link
This FDA news entry documents the 2022 approval of Rebyota (fecal microbiota, live-jslm) by Ferring Pharmaceuticals — the first FDA-approved fecal microbiota product. Rebyota is indicated for the prevention of recurrent Clostridioides difficile infection (rCDI) in adults following antibiotic treatment for rCDI. Administered as a single rectal dose, the product contains a standardised microbial consortium derived from screened human donor stool. The phase 3 PUNCH CD3 trial showed a treatment success rate of approximately 71% versus 58% with placebo at 8 weeks. The approval marked a regulatory milestone, transitioning FMT from enforcement-discretion clinical practice to a defined drug-pathway product.
[310] 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.