Two FDA-Approved Fecal Microbiota Products

Fecal microbiota transplants (FMTs) have been used in clinical trials to treat a variety of health conditions for years. In November 2022, the Food and Drug Administration (FDA) approved the first product containing live microorganisms produced from stool (fecal matter) from healthy donors.[1],[2] This product, which is marketed under the brand name REBYOTA, is administered by enema. In April 2023, the FDA approved a second fecal microbiota product (VOWST) that can be taken orally. Both products are indicated only for adult patients who have a serious recurring infection called recurring Clostridioides difficile (C. difficile) infection (CDI) and are meant to help restore the gut microbiome of patients who have had this infection.[3]

FMTs may be a reasonable last resort for patients with recurrent C. difficile infections not responding to antibiotics, but it is crucial that FMT be performed using one of the two approved FMT products under the supervision of a health care professional.

What is the human microbiome?

The human body is home to trillions of microorganisms, such as bacteria and other microbial cells that make up the so-called human microbiome.[4] But because these organisms are so small, they only amount to about 1–3% of a person’s body mass. Most of these microbes live in the intestinal tract, or gut, and are referred to as the “gut flora” or “gut microbiome.” Although researchers estimate that there are over 1,000 types of gut microbes, a healthy person’s digestive tract tends to have a mix of at least 160 different species.

Generally, these microbes are not harmful to the human body. In fact, many are important for our overall health because they are helpful to digestion, are involved in producing vitamins that our bodies cannot produce by themselves and are necessary for the immune system to work well. Having many and diverse types of “good” organisms also can help to keep harmful pathogens in check. For example, researchers have found that patients suffering from diseases such as CDI, irritable bowel syndrome, ulcerative colitis or Crohn’s disease tend to have fewer and less diverse helpful microbes than do healthy individuals.[5]

The makeup of an individual’s gut flora changes over their lifetime depending on numerous factors including sex, age, race, lifestyle and diet.[6],[7] There are also several factors that can disturb the amount and balance of helpful microbes, including treatment with antibiotics, as discussed in more detail below.

What are fecal microbiota transplants?

Because many of the microbes that live in the gut also are found in fecal microbiota, fecal microbes of a healthy donor can be placed — or transplanted — into the gut of a patient.[8] This transfer is called a fecal microbiota transplant, sometimes also referred to as fecal microbiota or stool transplants.

However, since harmful microorganisms also can be transferred accidentally through FMTs, the donor and their stool donation must be screened and tested for different disease-causing bacteria and viruses.[9] The stool donations are then diluted, filtered and prepared for transplantation (via capsules that can be swallowed, enema or colonoscopy, or a tube inserted through the nose and into the stomach).

Researchers are not exactly sure yet how and why FMTs seem to work. It is most likely that the healthy microbes introduced into the patient’s gut help resolve the patient’s unhealthy balance by adding missing strains of gut microbes.[10] At the same time, it is not yet known whether there are possible undesirable long-term consequences of changing a person’s gut flora.

Overall, FMTs are considered relatively safe, with adverse effects largely restricted to mild, short-lived gastrointestinal disturbances, especially when the donor and their stool donation have been thoroughly screened and tested.[11],[12]

Yet more severe complications also have been reported, including some caused by the transplant’s delivery method (such as perforations of the intestine) but also bacterial or viral infections that can be life-threatening.[13] For example, several patients were hospitalized and two died after they received a FMT as part of a clinical trial because the transplant contained a rare type of Escherichia coli bacterium for which the donations had not been screened.[14],[15]

FMT for C. difficile infection

To date, most information on the safety and effectiveness of FMTs is available for the treatment of recurrent infection with the toxin-producing bacterium C. difficile.[16] CDI can cause abdominal pain, severe diarrhea and colitis (an inflammation of the colon). Every year, there are almost half a million of these infections in the United States, causing 15,000–30,000 deaths.[17],[18]

Although anyone can get CDI, older patients and those who have received antibiotic treatments are most at risk. In fact, according to the CDC, this infection is seven to 10 times more likely to occur during or after treatment with antibiotics because, in addition to killing the bacteria originally targeted by the antibiotic treatment, these antibiotics also can markedly change the gut flora. This, in turn, can enable harmful bacteria in the gut, such as C. difficile, to take over. Unfortunately, for about 10–30% of patients the infection recurs after the initial treatment, either once or several times (called recurrent CDI). Each recurrence also makes an additional subsequent recurrence more likely.

CDI and recurring CDI are treated with antibiotics.[19] However, several case studies[20] and clinical trials[21] have shown that transplanted fecal microbiota can be an effective treatment alternative for patients with recurring CDI.

The approval of the fecal microbiota product RBX2660 (Rebyota) was based on data from six clinical trials.[22] The product’s safety was demonstrated by a combined analysis of five of these studies and showed that 23% of patients who received the fecal microbiota product experienced treatment-emergent adverse events, compared with 19% in the placebo group. These adverse effects were mainly mild or moderate and included abdominal pain, diarrhea, bloating, gas and nausea.[23] However, twice as many patients taking RBX2660 (14%) than those who received a placebo (7%) experienced serious adverse events. It is also important to note that participants across these studies were mainly women (67%) and White (94%), which reduces what we know about the safety of this treatment for other patient groups.

The data about the effectiveness of this product come only from a subset of these studies, which showed that treatment with RBX2660 was considered a success for significantly more patients (71%) than treatment with a placebo (58%).[24] Although the experts on the committee that advised the FDA in this approval decision considered this effect to be only “modest,” they noted that “even a modest treatment effect could be clinically meaningful for patients with recurrent CDI that have not responded to other available treatment options.”

The safety and efficacy of the oral product fecal microbiota spores, live-brpk (Vowst), was based on one clinical trial. Fewer patients who had received the FMT (12.4%) than those who had received the placebo treatment (39.8%) experienced a recurrence.

Patients who did experience a recurrence of CDI during the eight-week trial also were able to enroll in a second safety study. Across both safety studies, more patients in the treatment arm experienced adverse events such as abdominal bloating, fatigue, constipation and diarrhea than did those who received a placebo. However, all adverse events were considered mild to moderate and resolved after a few days.

What do these approvals mean for patients?

To date, the product administered by enema and the oral product are indicated only to reduce the recurrence of CDI in adult patients who have previously been treated with antibiotics for CDI.[25] However, because they are fecal microbiota products, they contain microbes and can therefore transmit infectious agents.

Although there are clinical trials that test FMTs for a range of other conditions, including inflammatory bowel disease, obesity, Crohn’s disease and autism, there is no conclusive evidence yet on the safety or efficacy of this type of treatment for these conditions.[26]

For this reason, any treatment with FMTs for any condition other than recurring CDI is considered investigational by the FDA and should only be done as part of a clinical trial.[27],[28]

What You Can Do

Patients should only consider these treatments after speaking with their health care professional and by using either Rebyota or Vowst under medical supervision. Despite the restrictions of receiving FMTs in a health care setting, especially for those who suffer from conditions other than recurrent CDI, this procedure should not be performed at home without oversight from a health care professional. Do-it-yourself fecal transplants can be very dangerous, especially if the donated stool is not adequately screened.

Moreover, it is important to remember that until reliable clinical data for conditions other than recurrent CDI become available, the true short- and long-term benefits and risks of this treatment remain unknown.
 

References

[1] Food and Drug Administration. FDA approves first fecal microbiota product. November 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-fecal-microbiota-product. Accessed May 8, 2023.

[2] Ferring Pharmaceuticals. Label: REBYOTA (donor human stool suspension). November 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=7af8a7f6-a441-4dc6-a151-138a89166fbb&type=display. Accessed May 8, 2023.

[3] Food and Drug Administration. Fecal microbiota products. November 2022. https://www.fda.gov/vaccines-blood-biologics/fecal-microbiota-products. Accessed May 8, 2023.

[4] National Institutes of Health Human Microbiome Project. About the human microbiome. https://hmpdacc.org/hmp/overview/. Accessed May 8, 2023.

[5] Mayo Clinic. The microbiome, fecal microbiota transplants and inflammatory bowel disease. June 2019. https://www.mayoclinic.org/medical-professionals/digestive-diseases/news/the-microbiome-fecal-microbiota-transplants-and-inflammatory-bowel-disease/mqc-20463208. Accessed May 8, 2023.

[6] Valles-Colomer M, Blanco-Míguez A, et al. The person-to-person transmission landscape of the gut and oral microbiomes. Nature. 2023; 641 (7946):125-135.

[7] Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Therap Adv Gastroentero. 2016;9(2):229-239.

[8] Food and Drug Administration. Fecal microbiota products. November 2022. https://www.fda.gov/vaccines-blood-biologics/fecal-microbiota-products. Accessed May 18, 2023.

[9] Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Therap Adv Gastroentero. 2016;9(2):229-239.

[10] Borody, T., Ramrakha, S. Fecal microbiota transplantation for treatment of Clostridioides difficile infection. UpToDate. Updated January 03, 2023.

[11] Fecal transplants for c. difficile diarrhea gain wider use. Worst Pills, Best Pills News. August 2016. https://www.citizen.org/news/fecal-transplants-for-c-difficile-diarrhea-gain-wider-use/. Accessed May 8, 2023.

[12] Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Therap Adv Gastroentero. 2016;9(2):229-239.

[13] Johns Hopkins Medicine. Fecal Transplant. https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/fecal-transplant. Accessed May 8, 2023.

[14] Food and Drug Administration. Safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse events likely due to transmission of pathogenic organisms. March 2020. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/safety-alert-regarding-use-fecal-microbiota-transplantation-and-risk-serious-adverse-events-likely. Accessed May 8, 2023.

[15] Borody, T., Ramrakha, S. Fecal microbiota transplantation for treatment of Clostridioides difficile infection. UpToDate. Updated January 03, 2023.

[16] Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Therap Adv Gastroentero. 2016;9(2):229-239.

[17] Centers for Disease Control and Prevention. C. diff infection – am I at risk? https://www.cdc.gov/cdiff/pdf/FS-Cdiff-PatientsFamilies-508.pdf. Accessed May 8, 2023.

[18] Food and Drug Administration. FDA briefing document for RBX2660 (fecal microbiota suspension for rectal enema). September 2022. https://www.fda.gov/media/161679/download. Accessed May 8, 2023.

[19] Infectious Diseases Society of America. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused update guidelines on management of Clostridioides difficile infection in adults. June 2021. https://www.idsociety.org/practice-guideline/clostridioides-difficile-2021-focused-update/#null. Accessed May 8,2023.

[20] Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Therap Adv Gastroentero. 2016;9(2):229-239.

[21] Fecal transplants for c. difficile diarrhea gain wider use. Worst Pills, Best Pills News. August 2016. https://www.citizen.org/news/fecal-transplants-for-c-difficile-diarrhea-gain-wider-use/. Accessed May 8, 2023.

[22] Food and Drug Administration. FDA briefing document for RBX2660 (fecal microbiota suspension for rectal enema). September 2022. https://www.fda.gov/media/161679/download. Accessed May 8, 2023.

[23] Ferring Pharmaceuticals. Label: REBYOTA (donor human stool suspension). November 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=7af8a7f6-a441-4dc6-a151-138a89166fbb&type=display. Accessed May 8, 2023.

[24] Food and Drug Administration. Center for Biologics Evaluation and Research. Summary minutes. September 2022. https://www.fda.gov/media/162485/download. Accessed May 8, 2023.

[25] Ferring Pharmaceuticals. Label: REBYOTA (donor human stool suspension). November 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=7af8a7f6-a441-4dc6-a151-138a89166fbb&type=display. Accessed May 8, 2023.

[26] Johns Hopkins Medicine. Fecal transplant. https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/fecal-transplant. Accessed May 8, 2023.

[27] Food and Drug Administration. Enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat clostridioides difficile infection not responsive to standard therapies. November 2022. https://www.fda.gov/media/86440/download. Accessed May 8, 2023.

[28] Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Therap Adv Gastroentero. 2016;9(2):229-239.