Ferring Pharmaceuticals has had editorial planning involvement, including suggestions of content and topics, as well as proposal of experts for articles. The final educational content was independently developed and approved by the GMFH publishing team and editorial board.
This is the sixth article in a special collection that focuses on the epidemiology, diagnosis and management of C. difficile infection, which is of relevance to gastroenterologists. See the first article on C. difficile infection prevalence and risk factors here, the second article on diagnosing and managing primary and recurrent C. difficile infection here, the third article on the pros and cons of fecal transplants and defined commensal consortia for recurrent C. difficile infection here, the fourth article on C. difficile infection from clinicians’ and patients’ perspectives here and the fifth article on C. difficile complications here.
The evolution of fecal microbiota transplants, one of the most advanced microbiome-based treatments
While fecal microbiota transplants (FMTs) have been practiced since the 1950s, it was not until recently that they were re-discovered as a therapeutic approach for restoring an altered gut microbiota composition and function. Current European and American guidelines recommend FMTs for treating patients with recurrent Clostridioides difficile infections.
Initially, FMT was performed after little processing of the original fecal material. Yet as key microbes or functions involved in its efficacy have been characterized, companies have developed products consisting of defined consortia of microorganisms (namely investigational microbiome biotherapeutics).
The approval of other therapeutic candidates for the microbiome is also expected in early 2023 and will open the door to future biologics license applications (a formal documentation required by the FDA to commercialize a new drug).
Challenges that hinder fecal microbiota transplants’ access to market
While establishing stool banks has enabled a centralization of ready-to-use feces suspensions to meet the needs of patients, some challenges still hinder access to the treatment for severely ill patients. A definition of quality standards for FMT is of utmost importance due to safety concerns around the transmission of multi-drug resistant organisms through FMT. Standardization of preparation processes best suited to preserve functionalities of the intestinal ecosystem, development of appropriate tools to finely assess engraftment and documentation of compatibility between FMT drug and the recipient are major scientific challenges that this treatment modality needs to overcome in order to move from the bench to the bedside according to Joël Doré, a trained gut microbial ecologist with 40 years’ experience in both basic and translational developments in microbiome-based therapies. In the current post-COVID-19 era, screening donors and recipients to ensure the efficacy and safety of FMT is also relevant.
Despite products based on FMT being among the most advanced microbiome-based treatments, the lack of consistency in regulatory standards and scientific guidelines derived from those standards hinders its ready-to-use application for patients. The United States has the longest history in taking the lead in the microbiome field. In 2013, the FDA positioned FMT for recurrent CDI as a therapeutic intervention that only needs the informed consent of the patient, while for other indications it is considered a drug and thus requires an investigational new drug application to be made. In November 2022, a product composed of a defined consortium of microorganisms was the first-ever microbiome therapeutic approved by the FDA for preventing the recurrence of C. difficile infection in adults after standard-of-care antibiotic treatment.
When making FMT readily available to severely ill patients, Doré states that: “Production of the drugs should not be a limiting factor, but it still is in many countries. The false perception that the academic/hospital structures will be able to fulfill the need is probably at stake. It has to become the routine job of pharma companies to condition the FMT drugs and make them readily available.”
Australia has facilitated access to fecal transplants for treating not only C. difficile but other digestive conditions. Last November, it became the first country in the world to receive regulatory approval for fecal transplants as a biological drug for restoring the gut microbiota in the management of gastrointestinal disorders.
In Europe, there is a long way to go before marketing authorizations of FMT are granted. And even though the EU Innovation Network published a recent report with an update of the regulatory situation of FMT in Europe, the quality and safety requirements of FMT is defined by individual countries.
Most EU countries have regulated FMT as a drug, while Finland regulates it as a therapeutic intervention and Italy as tissue. The United Kingdom also regulates FMT as a drug and Canada classifies it as a biological drug. When FMT is classified as a pharmaceutical drug or biological product, it is subject to more stringent requirements and legislation. In addition, the degree of processing of the fecal material or its indication also determines how FMT is regulated. Despite FMT being a widespread treatment in Europe, there is a significant underuse of FMTs (covering only 10% of patients with recurrent CDI).
Raising clinical awareness, adjusting regulatory frameworks for FMT and collaboration between scientists, clinicians and regulatory agencies are suggested as steps that will help move the field forward.
According to Doré: “By far the general consensus in Europe is to consider FMT products as drugs, which is probably the best for the patients. A harmonized regulation for all countries considering FMT products as drugs could be promoted. C. difficile infection it is the only ecological disease for which FMT as an ecological treatment does not seem extremely demanding: the barrier function that eliminates the pathogen can be restored with a preparation that does not attempt to preserve all functionalities of the intestinal ecosystem.”
Beyond regulatory issues, another challenge is FMT application in vulnerable populations, such as children. The pediatric population will be less likely to benefit from the treatment given the lack of clinical trials in children and the limitations of available tests to differentiate infection from colonization in children, which obstructs clinical decisions on the best time to start FMT therapy. As for any other drug, FMT may not be recommended for specific vulnerable populations, until proven safe.
The future of fecal microbiota transplants
While infectious diseases are the field in which applications of FMT are most widely researched, scientists have also started exploring its role for preserving the gut microbiome damaged after cancer treatments and also for inflammatory bowel diseases, due to its immune-modulating properties. Examples of diseases in which FMT could become an accepted treatment option in the future are irritable bowel syndrome, liver disorders, decolonization of multidrug-resistant bacteria, metabolic disorders, some neurological disorders and even as add-on to cancer therapy.
According to Doré: “The current scientific literature indicates that fecal microbiota transfer will be much more potent than most if not any of the single strain or small consortia tested in line with the probiotic concept. It will nevertheless most likely be add-on therapies in the many contexts for which standard of care is not providing a cure but also is only efficient in a fraction of patients. Scientific evidence has been building for ulcerative colitis, for cancer therapy with immune checkpoint inhibitors or possibly chimeric antigen receptor (CAR) T-cells, and possibly for therapeutic dead-ends such as steroid-resistant acute graft versus host disease, acute-on-chronic liver failure or amyotrophic lateral sclerosis.”
- While fecal microbiota transplants are commonly used for medically refractory or recurrent difficile infections, questions remain about its effectiveness, safety, regulation and best practice.
- The US and Australia have approved FMT for recurrent difficile infection, while in Europe, regulation of the procedure hinders its widespread use, especially among high-risk patients for whom the treatment might be lifesaving.
- Beyond gastrointestinal conditions, immune-mediated diseases and oncology are areas of potential interest for fecal microbiota transplants and their application in those contexts may take place in the near future.
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