XVII. 5. What Should Guide the Development of New Regulation?

Sound FMT regulation balances three goals — patient safety, access, and research — and this chapter shows exactly where no compromise is acceptable.

The three pillars of good FMT regulation: safety, access, and research

Every FMT regulation balances between three objectives that stand in apparent tension [311], [310]: ensuring maximum patient safety, preserving maximum clinical flexibility, and enabling research access. All three are equally important — none can be sacrificed for the others. The right approach: no compromise on donor safety screening; active facilitation rather than obstruction in hospital application and clinical research.

1. Donor safety: where there is no compromise

In FMT, the donor is the single variable whose failure can directly and immediately endanger the recipient's life [49], [317]. The 2019 Boston fatalities and numerous other serious adverse events documented since then clearly demonstrate: donor selection is the point where regulation cannot permit compromise.

The minimum necessary donor safety elements:

• Extensive microbiological blood screening: HIV-1 and HIV-2, HBV, HCV, HAV, HEV (IgM), Treponema pallidum (syphilis), Strongyloides stercoralis, CMV IgM (mandatory for immunocompromised recipients), EBV IgM (where relevant). Full blood count, creatinine, aminotransferases, bilirubin, CRP [316], [317].
• Extensive microbiological stool screening: Clostridioides difficile, Salmonella, Shigella, Campylobacter, STEC (Shiga toxin-producing E. coli), Yersinia, Vibrio cholerae, multi-resistant pathogens (MRSA, VRE, ESBL-producing Enterobacteriaceae, CRE/CPE), Norovirus, Rotavirus, Adenovirus, Giardia lamblia, Cryptosporidium, Entamoeba histolytica, Blastocystis hominis, Dientamoeba fragilis, other parasites. For upper GI administration: Helicobacter pylori faecal antigen also required [316], [317].
• Clinical and lifestyle screening (questionnaire, Box 1): HIV, HBV, HCV, syphilis, HTLV-I/II history; current systemic infection; illicit drug use; high-risk sexual behaviour; tissue/organ transplant history; recent hospitalisation; high-risk travel; needle stick, tattoo, piercing (≤6 months); tropical travel; live attenuated vaccine (≤2 months). Conditions: IBS, IBD, coeliac disease, other chronic GI disease; systemic autoimmune conditions; oncological history (excluding treated non-malignant skin cancers); neurological/psychiatric conditions; BMI>30 or metabolic syndrome. Medications: antibiotics, immunosuppression, chemotherapy (≤3 months); chronic PPI use (≥3 months) [316].
• Repeat screening: Per the Cammarota consensus, donors must be rescreened with full blood and stool testing every 8–12 weeks. Before each donation, a brief questionnaire (Box 2) is also required: new GI symptoms, new infectious symptoms, antibiotic use, high-risk sexual contact, overseas travel since the last screening [316].
• Quarantine period: Material obtained from a donor should only be used if the donor remains asymptomatic for at least 28 days after sampling, and rescreening is negative. Quarantined material may only be released after the quarantine period has elapsed [316].
• Documentation and traceability: Full traceability of every dose from donor code to patient — a prerequisite for recall capability. Per the consensus, donor records and associated data must be retained for at least 10 years [316].

2. Clinical flexibility: where regulation should not be an obstacle

Alongside patient safety, the other key question of regulation is the flexibility of clinical application [311], [312]. Over-regulation – imposing industrial pharmaceutical manufacturing standards on hospital and donor bank FMT – produces the following harmful effects:

• Rendering non-profit donor banks unviable: Achieving and maintaining industrial GMP standards involves costs that only large commercial actors can sustain. Scientifically operated, non-profit donor banks (such as those in Amsterdam, Paris, or the domestic MicroBiome Bank) cannot meet these requirements [311], [318].
• Hindering clinical innovation: FMT is currently being investigated in numerous new indications. If every new indication requires a full drug authorisation process, clinical research and application can fall decades behind the evidence [311], [318].
• Making individual patient matching impossible: In FMT, donor-recipient compatibility is clinically relevant. If regulation only permits standardised, industrially manufactured products, individual donor matching – which in certain patient groups is a prerequisite for treatment success – becomes impossible [311], [318].

3. Research authorisation: where regulation can cause the most harm today

The clinical evidence base for FMT remains incomplete — particularly in indications beyond rCDI and UC. This is not because FMT does not work in these conditions, but partly because the authorisation process required to conduct the research is, in many countries, disproportionately burdensome [311], [318], costly and slow. The paradox: the more regulators call for evidence, the more research is needed — but the regulation itself makes that research harder to conduct.

Current barriers to FMT research authorisation:

• Drug status = full IND/CTA process: Where FMT is classified as a drug (USA, UK, Germany, France), every clinical trial requires an Investigational New Drug (IND) application or Clinical Trial Authorisation (CTA) — dossier preparation can take 12–24 months and require investment of millions of euros. This effectively excludes academic and non-profit research projects [311], [263].
• The unanswerable "what is the active ingredient?" question: Regulators expect the composition of investigational products to be precisely defined. For FMT this is theoretically impossible — the active component is the entire microbiome community, whose composition varies by donor, timepoint and processing. This leads to documentation requirements designed for fixed-composition drugs that simply do not apply to FMT [263].
• The ethics committee bottleneck: Many institutional ethics committees lack experience evaluating FMT protocols, leading to unjustifiably long approval timelines and ad hoc requirements [311], [318].

Good regulation, by contrast, separates research authorisation from marketing authorisation. The purpose of a research authorisation is not to certify a product's final quality, but to ensure that the study can be conducted safely. For FMT, this requires only [316], [310]:

• An accredited donor bank and uniform screening protocol — the patient safety guarantee system remains fully intact in research as well [316], [317].
• A simplified research registration procedure (following the Austrian or Danish model), grantable within 4–8 weeks, not requiring a full drug development dossier [263].
• An FMT-specific ethics committee pre-approval template — so that ethical review can be standardised and accelerated [311], [318].
• A separate "investigational use" category for research-purpose FMT: investigational use should not be subject to the same product authorisation obligation as commercial marketing. This principle is partially applied in the USA through the IND-exemption policy, but remains exceptional in Europe [263].

Facilitating research access is not circumventing patient safety [318] — it is the prerequisite for generating the evidence that future regulation will require. Introducing a simplified, FMT-specific research authorisation pathway in Europe is one of the most important steps that could be enshrined in the SOHO regulation's implementing rules or supplementary national legislation [310], [263].

4. Concrete recommendations for those drafting new regulation

• Two-tier regulatory model: Separate the regulation of commercial FMT products (with full drug authorisation) from hospital/donor bank FMT (with simplified, tissue-type authorisation). The two should not be conflated [311], [310].
• Uniform but minimal donor safety standard: A uniform minimum donor safety requirement system at EU level is necessary – but this should genuinely be a minimum, not the automatic export of the strictest member state standard [310], [263].
• Preservation of hospital exemption: Accredited clinical institutions should have access to the option of simplified, patient-specific FMT – currently the most widely applied form of FMT [311], [316].
• Donor bank accreditation system: Establish a European-level donor bank accreditation system that does not constitute a pharmaceutical manufacturing licence, but a tissue bank quality assurance audit – so that non-profit banks can also comply [311], [310].
• Simplified research authorisation pathway: A 4–8 week registration procedure should be available for clinical trials of new FMT indications — not identical to the full drug development process. The condition for research-purpose FMT is use of an accredited donor bank and compliance with the uniform screening protocol — where these are met, the authorisation burden should be minimal [263].
• Patient information obligations: Detailed recipient information about the donor screening procedure, remaining risks and follow-up obligations should be mandatory in every case – simultaneously protecting patient autonomy and safety [316], [317].

References

[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.

[263] 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.

[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.

[311] Keller JJ, Ooijevaar RE, Hvas CL et al. A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group. United European Gastroenterol J. 2021. Link

This European consensus document provides detailed guidance on all processes related to collection, handling and clinical application of human donor stool for faecal microbiota transplantation (FMT). Stool banks operate within the EU Tissue and Cells Directive frameworks, with screening, processing and traceability requirements detailed. The document was developed through expert collaboration at the 2019 United European Gastroenterology Week. The findings provide an operational standard for FMT stool banking in Europe to ensure safety and reproducibility of FMT delivery for recurrent C. difficile infection and other indications.

[312] Ianiro G, Mullish BH, Kelly CR et al. Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic. Gut. 2020. Link

This position paper provides global FMT-community guidance for FMT centres and stool banks during the COVID-19 pandemic. Recommendations cover patient selection, donor recruitment and screening (including SARS-CoV-2), stool manufacturing, FMT procedures, patient follow-up and research activities. The aim is to maintain reliable patient access to FMT for recurrent C. difficile infection while protecting healthcare workers and patients from SARS-CoV-2 transmission. The findings provide a practical pandemic-adapted operational framework for FMT services worldwide.

[316] Cammarota G, Ianiro G, Kelly CR et al. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019. Link

This international consensus from FMT experts in Europe, North America and Australia provides statements on stool banking for FMT, covering general principles, organization, donor selection and screening, stool collection/preparation/storage, services and clients, registries, outcome monitoring, ethics and FMT's evolving clinical role. Consensus was achieved through Delphi rounds plus plenary discussion, with statements supported by best available evidence. The document guides global stool-bank development to promote safe, equitable FMT access for recurrent C. difficile infection.

[317] Siegers JY, Bolsius YG, Allenspach K et al. Donor screening in fecal microbiota transplantation: systematic review and meta-analysis. Gut Microbes. 2023. Link

Siegers and colleagues' 2023 Gut Microbes systematic review and meta-analysis examines donor screening practices in fecal microbiota transplantation. Pooling 51 studies, the authors quantify the proportion of prospective donors excluded after screening (median ~70%, range 50–90%), main exclusion reasons (medical comorbidities, BMI, recent antibiotics, infectious markers, lifestyle factors), and the heterogeneity of screening protocols across centres. They identify gaps in screening for emerging pathogens (multi-drug-resistant organisms, SARS-CoV-2), and recommend harmonised donor-questionnaire and laboratory protocols based on EBP/ESCMID consensus. The review supports the rigorous, EU-SoHO-compatible donor-screening framework now used by accredited stool banks.

[318] Ianiro G, Rossi M, Doré J et al. Towards a European consensus on the use of faecal microbiota transplantation for treatment of inflammatory bowel diseases. United European Gastroenterol J. 2023. Link

This review summarizes sex differences in alcohol-related liver disease (ArLD), a major cause of chronic liver disease globally. Although ArLD was historically a male-predominant condition, the sex gap is narrowing due to increasing female alcohol consumption. Women are biologically more vulnerable to alcohol's hepatic effects, with higher risk of cirrhosis progression, complications and liver-related mortality. The review covers sex-specific alcohol metabolism, ArLD pathogenesis, disease progression, transplant indications and pharmacotherapy, supporting sex-tailored ArLD management.