Faecal microbiota transplantation
Faecal microbiota transplantation moves stool from a healthy donor into a patient's gut to change its microbiota. It is part of conventional practice for Clostridioides difficile infection and experimental in other conditions. Hospitals can prepare it themselves, from donors screened under rules like those for blood and tissue donation. Regulators have not agreed whether it is a drug or a transplant, and a medical writer needs that classification to choose the writing guidelines and templates for the regulatory documents.
Definition and history
Faecal microbiota transplantation (FMT) is the transfer of biological material containing faecal microorganisms from a human donor to a recipient's gastrointestinal tract to change the composition of the gut microbiota. Preprocessed stool from a healthy donor, in a capsule or in liquid form, is transplanted into the colon of a person with a disease. The aim is to restore the balance of an unbalanced gut microbial population in an unhealthy person with gut microbiota from a healthy one. Human faeces are a base for an entirely new class of biotechnology product, microbiome-based medicines.
Humankind has always used faecal matter to treat diseases, and it has never stopped. Ancient Egyptian healers used hippopotamus and human excrement to treat gynaecological problems. In ancient China, "golden juice" from human faeces brought fever down, and ox excrement served the same purpose in medieval Britain. The mixtures were applied to the skin and mucosae or even ingested.
What a transplant contains
Healthy human stool consists not only of living or dead microorganisms, such as bacteria, fungi and archaea, but also of bacteriophages and other viruses, human cells, mucus, enzymes, bile acids, metabolites and undigested food remnants. A gram of healthy wet stool holds about 10^11 bacteria, 10^8 to 10^9 viruses, 10^8 archaea, 10^7 colonocytes and 10^6 fungi. Besides the microbiota, a transplant carries vitamins, short-chain fatty acids and bile salts.
How it acts
FMT increases the diversity of microbes in the recipient's dysbiotic gut and their quantity. Its mechanism of action is more complex, however: FMT starts multiple interactions between the microbiota and the recipient's intestinal environment and immunity. One opinion in the expert community suggests that the effect of FMT cannot be reduced to living bacteria. Dead bacterial cells, bacteriophages and microbial metabolic products have biological and immunological activity as well, and they may contribute to the clinical effect. This "whole stool" approach will benefit from the continuing development of certified non-profit stool banks and from efforts to standardise the method internationally.
Where it is used
FMT is a potent tool to improve gut health and to influence diseases associated with an impaired community of gut microorganisms. In conventional practice, FMT treats Clostridioides difficile infection. This severe hospital-acquired enterocolitis can be fulminant, and it develops frequently in immunocompromised patients and after the use of broad-spectrum antibiotics. Randomised controlled trials and observational studies have confirmed that FMT is highly effective in treating the infection and preventing its recurrence. European and American clinical guidelines make FMT an option for recurrent infection or for infection refractory to standard therapy. Compared with the standard therapy of recurrent infection, FMT proved the most cost-effective method. It is a lifesaving treatment, but it can be life-threatening if it is not performed in a controlled way.
FMT is widespread, and more than 1,800 hospital-based procedures were estimated to have been performed in Europe in 2019. Many countries have clinical guidelines for its rational and safe use, Australia, Austria, Canada, Czechia, Denmark, Poland, Romania, South Korea and the United Kingdom among them. These guidelines, however, are mostly an expert consensus of medical societies without the point of view of the regulatory authorities.
The evidence for the efficacy of FMT in autoimmune diseases, liver pathologies, obesity and neurological disorders is not yet strong, so in those indications FMT is considered experimental and used only in the controlled environment of clinical trials. In mid-July 2022, more than 400 academic or industry-sponsored trials registered at ClinicalTrials.gov declared the use of FMT. Their indications spanned C. difficile infection and other infectious diseases, irritable bowel syndrome, obesity, insulin resistance and diabetes, oncologic indications including adverse effects, gut decolonisation and antibiotic-induced adverse effects, neurological and psychiatric disorders, diseases of the liver, pancreas and bile ducts, other diseases of the intestine and colon, non-gastrointestinal autoimmune diseases, cell and organ transplantation including graft-versus-host disease, and other conditions. By 2024, FMT had shown promise in neurological conditions such as autism spectrum disorder and Parkinson disease, in obesity, and in gastrointestinal disorders, blood disorders, diabetes and liver diseases.
Donor selection and screening
The selection of the donor is the most critical element of FMT. The quality of the donor microbiome is an acknowledged risk of FMT. Resident pathogens, multidrug-resistant bacteria or infection can be transferred through it, especially to immunocompromised patients. Candidates must be examined extensively, including their medical history and laboratory testing. Their stool must be free of gastrointestinal pathogens, parasites included, and of drug-resistant bacteria, so that no undesirable germs or drug resistance genes are transmitted. Donor selection also depends on factors such as type of birth (caesarean or vaginal), smoking history and prior antibiotic exposure. Healthcare professionals should not donate stool, because they are often colonised with multidrug-resistant microbiota. The microbiological safety of a stool sample is fundamental, since transmission of antibiotic-resistant E. coli and subsequent serious adverse reactions to FMT have been reported. Altogether, it is easier to donate blood than stool.
Many measures typical of blood, tissue and cell donation must be observed in FMT: screening of candidates by questionnaire, medical examinations, blood, urine and stool tests and an interview with a healthcare professional; healthy donors who are not anonymous to the donation facility; altruistic donation without direct payment; informed consent from donor and recipient; the donor's identity withheld from the recipient; traceability of the material from donation through preparation to administration; and written or electronic records kept long enough for vigilance.
Preparation and administration
The exact preparation method is not standardised, and facilities adapt it according to their own experience. The product is prepared from a portion of a healthy donor's stool. In the common method, the stool is mashed with sterile saline in a blender and sieved through gauze to remove most of the undigested material. The suspension is filled into sterile large-volume syringes or bags. The liquid product is given into the lower gut by enema or endoscopy, or into the upper gut through a nasogastric or nasojejunal tube. The suspension can also be freeze-dried into a loose solid, which is filled into conventional or acid-resistant capsules taken by mouth. The European Medicines Agency (EMA) distinguishes extemporaneous preparation, which processes the stool minimally in the healthcare facility, from manufacture in dedicated facilities through multiple steps and more sophisticated technology.
Classification as a drug or a transplant
The regulation of products that influence human health often falls behind clinical practice. The first modern scientific article on FMT was published in 1958, and in 2022 there was still no internationally agreed classification of FMT products. The US Food and Drug Administration (FDA) made the first attempt to define the product in regulatory terms in May 2013, when it classified FMT as a drug and an investigational new drug. That decision generally ruled out its use outside clinical trials. A few months later, after the expert community objected, the FDA declared enforcement discretion for FMT in C. difficile infection not responding to standard therapies. In 2022, FMT in other indications was still regarded as an investigational new drug.
In 2014 the European Commission declared that FMT falls outside the EU tissues and cells legislation and every other legislative framework, so EU member states were free to regulate it nationally. Since then, a significant tendency to classify FMT as a medicinal product has emerged across the EU. An EMA survey found it treated as a medicinal product in Croatia, Czechia, France, Germany, Ireland, Portugal, Spain and Sweden; as tissues and cells in Belgium and Italy; as a therapeutic intervention in Finland; and case by case or undetermined in Austria, Denmark and the Netherlands. The resemblance to blood and tissue donation has led several countries to base their FMT rules on national tissues and cells legislation. In other countries the classification is decided case by case, by indication, preparation process and the facilities involved.
The classification influences many practical aspects of FMT use, and the medicinal-product status in particular challenges clinicians, facilities and regulators. Treating FMT as a medicinal product raises questions that are not yet sufficiently answered: what the active ingredient or drug substance is, how to test its potency, whether good manufacturing practice is necessary for a product prepared extemporaneously in the hospital, and how to achieve batch-to-batch similarity when stool from even the same healthy donor varies in composition.
Development and approval
The development of FMT rushes forward despite the regulatory ambiguity. Researchers are hunting for the microbial species responsible for the main effect in C. difficile infection, inflammatory bowel diseases and other conditions. Companies are developing "purified" FMT-based products from defined bacterial strains cultivated from stool, an approach that would largely reduce the safety concerns of administering an extemporaneously prepared suspension. The future should bring deeper knowledge of the mechanism of action of FMT and measures to increase its efficacy, safety, quality and availability for patients worldwide.
A December 2022 account states that no FMT-based medicinal product had a marketing authorisation, but that several were being tested in phase III trials with encouraging preliminary results. A 2024 account dates the FDA's approval of FMT to treat Clostridioides (formerly Clostridium) difficile colitis to September 2022 and names two additional approved therapies: Vowst, an oral drug containing faecal microbiota spores, and Rebyota, a live microbiota-based FMT. The same account states that FMT is the only FDA-approved microbiome therapy for C. difficile colitis infections.
The medical writer's role
In the clinical research of FMT, non-commercial sponsors, such as universities and university hospitals, research centres, medical societies or patients' organisations, prevail over companies. Many of these sponsors have established a clinical trials department that handles the trials' administration and communication with the regulatory authorities. Medical writers have started to appear there, but they have often had to take on several roles in the team.
A medical writer on an FMT project needs its regulatory status to choose the appropriate writing guidelines and templates for the required regulatory documents. Consultations with the national regulatory authority are necessary and valuable, especially where there is no specific position statement on FMT. A medical writer well acquainted with the preparation process and facility, the clinical aspects of the project and the relevant legislation can be an excellent leader in these consultations.
Presenting FMT neutrally and informatively to a lay audience is also a challenge. Inappropriate language or humour alone can easily repel potential donors and patients. Cultural attitudes to human waste differ enormously: what is acceptable to most Europeans, for instance, could be totally unacceptable to the Japanese. Presenting FMT to a lay audience is a task for a communication expert.