When performing medical treatment, there are quite strict laws in Japan and abroad.
What are the laws and regulations around FMT?
FMT was already in place before regulations began, and as the use of FMT became more widespread, countries began to regulate it later.
The method of implanting microbiome suspensions (bacterial fluid) derived from other people’s stool into patients is very unique and shows the individuality of each country in its handling.
The following list is a synthesis of the paper by Goldenberg et al. in the United Kingdom in 2020 (1) and the paper by Ianiro et al. in Italy in 2023 (2), plus additional research by the author.
Table of Contents
- U.S.A., Canada
- Australia
- France
- Italy, Netherlands, Belgium
- United Kingdom, Ireland, Germany, Switzerland
- Austria, Denmark, Sweden, Finland, etc.
- China, Korea, Taiwan, Japan and other Asian countries
- International Guidelines
The numbers in parentheses in the text refer to the reference numbers at the bottom of the article.
1. U.S.A., Canada
In the United States and Canada, FMT is strictly regulated as it should be performed for rCDI (recurrent Clostridioides difficile enteritis) or as a clinical trial for other diseases.
The U.S. Food and Drug Administration (FDA) issued a notice that FMT is the first-line treatment for patients with rCDI who do not respond to antimicrobial agents as soon as a Dutch randomized controlled trial article (3) was published in 2013 that found FMT to be effective in rCDI.
After this aggressive stance, the FDA issued a safety alert following an adverse event in which a donor-derived ESBL-producing strain was transferred to two immunocompromised patients and one died (4).
Then, in 2022, the FDA announced that it would impose stricter regulations (5) and would not allow FMT to be conducted on flights purchased from flight banks as so-called third-party organizations.
This could be due to concerns about the microbiome from a particular donor being implanted in multiple patients, or concerns that not all samples are rigorously tested in the stool bank.
Even Openbiome, which previously operated as the world’s largest stool bank, has now stopped collecting stool from donors.
However, Openbiome has not closed its doors and continues to provide donor flights in accordance with FDA guidelines by working with the University of Minnesota to register for clinical trials.
The drug discovery market is also thriving.
In 2022, Ferring’s biopharmaceutical REBYOTA® received the first FDA approval in the United States. Also in April 2023, Ceres Therapeutics’ VOWST (SER-109) was approved by the FDA as the first oral microbiome drug.
Other companies in the U.S., such as Ferring and Vedanta Biosciences, have filed drug applications, and it is possible that, at least at the market level, microbiome treatment will shift to drugs rather than general FMT.
2. Australia
Australia is one of the countries where FMT has been popularized under rather lax regulations, despite the fact that it is actively implemented.
In Australia, there is Thomas Borody, Ph. (Professor Thomas Borody – The Centre for Digestive Diseases)
He has been practicing MMT (Microbiota Transplant Therapy), an FMT developed by himself since the 1980s, and it is fair to say that he has played a central role in FMT in Australia.
MMT is also the method used in the FMT trial for children with autism spectrum disorder at the University of Arizona in the United States (6), and there is some confidence in its effectiveness.
It was only in January 2020 that the Australian Therapeutic Goods Administration (TGA) sat down to regulate FMT. A paper(7) was published a little later, but experts gathered to notify them about the regulations, etc., and the regulations officially began in July 2021.
Faecal microbiota transplant products regulation | Therapeutic Goods Administration (TGA)
この規制によると、
「院内実施や最低限の処理を行うのみの場合、FMTはリスクの低いクラス1か2に分類され、生物製剤として取り扱うこととする」とある。
この規制以降、FMTを実施する場合はTGAに登録し、有害事象などの報告を行うことが義務付けられた。
In November 2022, the TGA also approved BiomeBank’s BIOMICTRA as the world’s first microbiome drug.
3. France
In France, it seems that FMT is either to be performed as an investigational drug or by preparing donor stool in the hospital, or it is to be treated similar to a drug.
4. Italy, Netherlands, Belgium
The donor-derived stool suspension used in FMT contains not only microorganisms such as donor gut bacteria, viruses, and fungi, but also the donor’s own cells, water, mucopolysaccharides, and various metabolites, which vary from donor to donor.
In light of this, countries such as Italy, the Netherlands, and Belgium consider the microbiome a “human organ” and treat it as equivalent to an organ or cell transplant.
The EU as a whole seems to have adopted a similar view.（New EU rules on substances of human origin – European Commission）
5. United Kingdom, Ireland, Germany, Switzerland
In contrast, countries such as the United Kingdom, Ireland, Germany, and Switzerland do not treat FMT as a biologic transplant, but as a nonbiologic drug.
It is not that there are no regulations, but that they try to treat it like any other drug with a clear mechanism and defined rules for taking it.
6. Austria, Denmark, Sweden, Finland, etc.
In the rest of Europe, there seems to be no clear regulation.
Although FMT is considered a common medical procedure, rules for donor selection and stool disposal are often left to individual medical facilities.
The reporting of adverse events is also done on a voluntary basis by each facility.
7. Asian countries such as China, Korea, Taiwan and Japan
No clear regulation is underway for the Asian region as well.
China has a background where FMT has been commonly implemented since ancient times, and the establishment of donor banks and the spread of FMT has been rather smooth.
Experts seem to have come up with a consensus document (8) for donor selection and management, which they use as a guideline.
Similarly, guidelines (9) have been issued in Korea.
In Taiwan, the Ministry of Health and Welfare allowed FMT by special law in 2018.
In Japan, the number and severity of CDI cases, for which FMT is most effective, are not as severe as in Europe and the U.S. Furthermore, FMT as an unrestricted medical treatment is not as widespread as in the U.S., since medical treatment has been mainly based on insurance for a long time.
For this reason, there are no clear regulations as yet, but with several clinical trials underway and registration as an advanced medical treatment in 2023, it is possible that regulations or some kind of guidelines will be issued in the future.
8. International Guidelines
Against the backdrop of regulations and guidelines published by various countries, there is a movement to create guidelines across countries.
Europe, thanks to the existence of the European Union, facilitates cross-border dialogue.
In 2017, 28 experts from 10 European countries met to publish guidelines (10) for performing FMT in clinical practice.
This section provides detailed guidelines for each medical facility to perform FMT, including donor selection, transplant suspension preparation, and stool management.
Target diseases are formulated with CDI in mind.
However, it is not easy for each medical facility to find donors, conduct tests, and prepare transplant suspensions. If there were a donor bank in the stool, like blood banks and bone marrow banks, the hurdles for safety assurance and treatment implementation would be lowered.
In 2019, at a time when stool banks were starting up in many countries, experts from Europe, North America, and Australia gathered to develop an international consensus document (11) for donor bank operations.
However, the actual operation is left to the laws and policies of each country.
This section includes guidelines for interviewing donors, blood tests for donors, and stool test items, as well as how to store and thaw donor stool.
Japanbiome®, a stool bank affiliated with the Intestinal Flora Transplant Clinical Research Foundation in which we are involved, has been conducting strict inspections of donors since its establishment in 2017.
Referencing the inspection items of Openbiome, which was the largest stool bank in the U.S. at that time, we have established even stricter inspection items than those in the international agreement document released in 2019.
In March 2020, when a worldwide pandemic of a new coronavirus occurred, the U.S. FDA issued a safety warning (12), and in September of the same year, Italian researchers published a paper (13) showing that FMT could be safely performed even during a pandemic.
It is expected that similar measures will be adopted in the future in the event of a significant infectious disease outbreak.
It is not only FMT for CDI for which guidelines are being developed.
In 2023, experts from European countries, the United States, Australia, and Israel gathered to create a document (14) to guide FMT for inflammatory bowel disease (IBD).
In addition, in May 2024, the American Gastroenterological Association (AGA) published more comprehensive FMT guidelines (15) that expanded the scope to include ileocolitis and irritable bowel syndrome (IBS).
FMT has only recently burst onto the stage of Western medicine, and it is expected that each country will proceed with both regulations and guidelines.
どの国にも共通するのは、FMTは医師の管理下で行われる医療行為として扱われているということだ。
医師でもない者が患者に実施するのはもちろん違法だが、親しい家族に便を提供してもらって自宅で行うことは、感染症の問題などもあり大変危険な行為である。（でも気持ちは痛いほどわかる。今のところFMTは自由診療のため費用が高いか、対象疾患が限られた治験・先進医療などの臨床研究しかない。）
It is expected that regulations and guidelines will be developed in Japan in the future.
*Click here for an article with links to articles about FMT.
1. Merrick B, Allen L, Masirah M Zain N, Forbes B, Shawcross DL, Goldenberg SD. Regulation, risk and safety of Faecal Microbiota Transplant. Infect Prev Pract. 2020;2(3):100069. doi:10.1016/j.infpip.2020.100069
2. Porcari S, Benech N, Valles-Colomer M, et al. Key determinants of success in fecal microbiota transplantation: From microbiome to clinic. Cell Host Microbe. 2023;31(5):712-733. doi:10.1016/j.chom.2023.03.020
3. van Nood Els, Vrieze Anne, Nieuwdorp Max, et al. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415. doi:10.1056/NEJMoa1205037
4. Research C for BE and. Important Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms. FDA. Published online April 12, 2020. Accessed June 26, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/important-safety-alert-regarding-use-fecal-microbiota-transplantation-and-risk-serious-adverse
5. Research C for BE and. Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. Published November 29, 2022. Accessed June 26, 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-regarding-investigational-new-drug-requirements-use-fecal-microbiota
6. Adams JB, Borody TJ, Kang DW, Khoruts A, Krajmalnik-Brown R, Sadowsky MJ. Microbiota transplant therapy and autism: lessons for the clinic. Expert Rev Gastroenterol Hepatol. 2019;13(11):1033-1037. doi:10.1080/17474124.2019.1687293
7. Haifer C, Kelly CR, Paramsothy S, et al. Australian consensus statements for the regulation, production and use of faecal microbiota transplantation in clinical practice. Gut. 2020;69(5):801-810. doi:10.1136/gutjnl-2019-320260
8. Society of Parenteral and Enteral Nutrition, Chinese Medical Association, Microecology Professional Committee of Shanghai Preventive Medicine Association. [Chinese expert consensus on screening and management of fecal microbiota transplantation donors (2022 edition)]. Zhonghua Wei Chang Wai Ke Za Zhi Chin J Gastrointest Surg. 2022;25(9):757-765. doi:10.3760/cma.j.cn441530-20220606-00246
9. Gweon TG, Lee YJ, Kim KO, et al. Clinical Practice Guidelines for Fecal Microbiota Transplantation in Korea. J Neurogastroenterol Motil. 2022;28(1):28-42. doi:10.5056/jnm21221
10. Cammarota G, Ianiro G, Tilg H, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017;66(4):569-580. doi:10.1136/gutjnl-2016-313017
11. Cammarota G, Ianiro G, Kelly CR, et al. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019;68(12):2111-2121. doi:10.1136/gutjnl-2019-319548
12. Research C for BE and. Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Additional Safety Protections Pertaining to SARS-CoV-2 and COVID-19. FDA. Published online September 4, 2020. Accessed April 12, 2023. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/safety-alert-regarding-use-fecal-microbiota-transplantation-and-additional-safety-protections
13. Ianiro G, Bibbò S, Masucci L, et al. Maintaining standard volumes, efficacy and safety, of fecal microbiota transplantation for C. difficile infection during the COVID-19 pandemic: A prospective cohort study. Dig Liver Dis. 2020;52(12):1390-1395. doi:10.1016/j.dld.2020.09.004
14. Lopetuso LR, Deleu S, Godny L, et al. The first international Rome consensus conference on gut microbiota and faecal microbiota transplantation in inflammatory bowel disease. Gut. 2023;72(9):1642-1650. doi:10.1136/gutjnl-2023-329948
15. Peery AF, Kelly CR, Kao D, et al. AGA Clinical Practice Guideline on Fecal Microbiota-Based Therapies for Select Gastrointestinal Diseases. Gastroenterology. 2024;166(3):409-434. doi:10.1053/j.gastro.2024.01.008
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シンバイオシス株式会社微生物事業部の研究員が
noteにて作成した記事を一部変更しております。
The original post can be found here.
Article Title: Handling of FMT (Fecal Microbiota Transplantation) and Summary of Regulations and Guidelines in Each Country
Article Link:https://note.com/symbiosis17/n/n02bc61980e7e#0a56a313-dd75-4dc5-87f9-1f7adb612ba5
