Exploring the challenges of regulating faecal microbiota transplants

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n the 4th century AD, a Chinese doctor called Ge Hong treated his diarrhoea patients with faeces from healthy individuals. Now known as a faecal microbiota transplant (FMT), this procedure involves introducing faeces from a healthy donor through an enema into an individual with a gastrointestinal (GI) disease to restore the correct balance of bacteria in their gut.

FMT continued to be employed throughout the following centuries, particularly in veterinary medicine. However, it wasn’t until the 1950s that it was first described in modern medicine, notes Guy’s and St Thomas’ NHS Foundation Trust consultant microbiologist and infection control doctor Dr Simon Goldenberg.

Over the following decades, FMT was increasingly explored by physicians as an alternative to antibiotics to treat and mitigate the severe and unpleasant symptoms of various GI diseases.

One standout indication for FMT was recurrent Clostridium difficile (C. difficile) infection, a bacterial disease that affects the bowel and causes diarrhoea, as well as other serious bowel issues. In 2013, researchers carried out the first randomised controlled trial of FMT in C. difficile; results were published in the New England Journal of Medicine.

The study compared FMT to antibiotic vancomycin and it was stopped after interim analysis because the superiority of FMT was so stark. This was a particularly noteworthy finding as it is well-known that the multiple courses of antibiotics previously required to treat recurrent C. difficile infection actually deplete the necessary good gut bacteria.

These promising results were replicated in future studies and clinical use; FMT is estimated to have an up to 90% success rate in recurrent C. difficile. This feat has led to the procedure being investigated for a range of other diseases – examples include ulcerative colitis, Crohn’s disease and inflammatory bowel disease, as well as depression and obesity.

Despite being widely accepted as an excellent treatment option, FMT still face multiple challenges that must be addressed to boost safety.

A central barrier is that the procedure relies on stool donations; however, attracting and recruiting suitable donors has proven to be difficult. A significant issue is ensuring that donation centres or stool banks are capable of adequately screening donors to make sure they do not have any diseases that could be transmitted in their stool sample.

The importance of adequate screening has been made clear through a number of recent safety alerts by the US Food and Drug Administration (FDA). One of these is related to the possible transmission of SARS-CoV-2, the virus which causes Covid-19, through FMT; there is evidence that Covid-19 is more than a respiratory disease and can be transmitted through the GI tract.

As a result, the FDA suggested that Covid-19 infection should therefore become part of the donor screening process. Goldenberg notes: “This is a timely reminder that we need to keep considering new and old risks, [as well as] our procedures for screening patients to ensure a high degree of safety.”

Another major barrier facing FMT is inconsistent global regulation, according to Goldenberg.

This is because there is disagreement about whether FMT should be regulated as a drug or like tissue or blood products that are involved in other transplants. This is linked to uncertainty about the definition and underlying mechanism of action of FMT, Goldenberg notes.

Although the EU decided FMT did not fall under the jurisdiction of the European Tissue and Cells Directive, Goldenberg explains that some European member states like the Netherlands, Belgium and Italy, have regulated it as a tissue.

Other countries, including the UK, France and Germany, regard FMT to be a drug, while the FDA has classified it as a biological product. There are also some countries, including Denmark and Slovenia, that have no regulations regarding FMT.

Goldenberg is clear that the regulatory confusion has a significant impact on patient access to FMT. A 2020 article Goldenberg co-authored in Infection Prevention in Practice noted: “Regulation seeks to improve quality and safety; however, lack of standardisation creates confusion, and overly restrictive regulation may hamper widespread access and discourage research using FMT.”

Lack of access as a result of regulation has led desperate patients to take matters into their own hands. There are many cases of desperate individuals performing dangerous at-home DIY FMTs where they rely on a family member’s faeces and a blender with the help of a YouTube tutorial.

Performing FMT without proper medical supervision is very unsafe, particularly because the donated faeces has not been screened, so there is no way of knowing if someone has a transmissible disease. In addition, there is always the risk of damaging the colon or rectum while performing the enema.

Because of concerns about the safety and efficacy of FMT, the FDA declared in 2013 FMT would be classed as a biological material and that the procedure can only be performed with an investigational new drug (IND) application.

This approach requires the biological product to be standardised, which is difficult in the case of faeces. Goldenberg explains: “The exact mixture of microorganisms from one donor may be significantly different from another, and also from donation to another even from the same donor.”

Since researchers have to jump through a lot of hoops to submit an IND and get approved, it is possible they will seek to price the FMT to recoup their investment and then capture additional profit. This would challenge the existing paradigm of stool research being carried out in the public domain by physicians, according to Alexandra Scheeler in a 2019 Journal of Law, Medicine and Ethics paper.

Therefore, the FDA decision caused consternation in the medical community as it was believed the IND requirement would severely delay and hamper both clinical research and patient access with potentially disastrous consequences.

Therefore, the FDA decided to allow enforcement discretion in limited scenarios and where physicians have consent from the patient. Unfortunately, this means the use of FMT in the US remains at the discretion of the FDA, as Verbeke et al argue in a 2017 paper.

In a slightly different vein, the UK and other countries decided that FMT falls under the definition of a medicinal product. Scheeler wrote this is often a provisional classification while figuring out the final classification or awaiting someone to submit a marketing application.

The implementation of this drug-focused regulatory approach has also been implemented inconsistently globally, according to Scheeler. For instance, Switzerland limits the use of FMT to an approved clinical trial, while Australia has many schemes that allow patients access to unapproved therapies, leading to a high number of stool banks that treat not only C. difficile, but other GI conditions.

Rather than being regulated as a biological product or a medicine, many researchers that argue FMT fits better with the properties of human cell and tissue-based products, and therefore should be regulated in this manner. This view centres around the fact that FMT is derived from humans, notes Goldenberg. 

Scheeler explained that the human and cell tissue product classification is right for FMT because it allows for “robust oversight of the critical process elements of donor selection and stool preparation while permitting flexibility in indication of use”. 

She continued that this approach “adapts oversight to maximise safety while acknowledging that human-derived products are not produced in a lab, and therefore defy some typical drug requirements like batch uniformity”. 

However, Goldenberg explains that the issue with viewing FMT as a tissue or cell product is that the active ingredient is a bacterial microorganism in the faeces, rather than the faeces itself, and therefore not of human origin. In this respect, FMT differs from blood transfusions or stem cell transplants.

This was the view taken by both the UK’s Medicines and Healthcare products Regulatory Agency and the EU’s European Commission. However, the EU allowed individual member states their own discretion in regulating FMT, meaning some countries in Europe do view it as a human cell and tissue product.

A particularly noteworthy example of a country regulating FMT as a human cell or tissue product is Belgium. To do this, in 2018, Belgian legislators amended a 2008 law defining human body material to include stool.

Scheeler called on the US FDA to follow suit and adjust its definition to include stool. Verbeke et al echoed this saying FMT could be included in an extended definition of cell, gene and tissue therapeutics, particularly in Europe.

However, some researchers go further and suggest that proper regulation of FMT may require the development of entirely new regulatory categories.

Goldenberg notes: “There are aspects of each of the product classes that are rational for FMT; perhaps those aspects could be combined to form a new regulatory grouping.”

No matter the solution, it is clear that this mixed picture of regulation cannot continue. As FMT becomes increasingly studied and used for a range of GI and other conditions, it is imperative that the lack of regulation and access issues do not force any more patients to perform incredibly risky at-home FMT procedures.