Pending Policies - Surgery
Fecal Microbiota Transplantation (FMT)
Fecal microbiota transplantation (FMT) may be considered medically necessary for treatment of patients with recurrent Clostridium difficile infection under the following conditions:
• There have been at least 3 episodes of recurrent infection following initial treatment; AND
• Episodes are refractory to appropriate antibiotic regimens*, including at least 1 regimen of oral vancomycin.
*NOTE: Appropriate antibiotic regimens include oral vancomycin with tapered or pulse-tapered dosing, or standard doses of fidaxomicin, oral metronidazole, or rifaximin.
Fecal microbiota transplantation is considered experimental, investigational and/or unproven in all other situations.
Fecal microbiota transplantation (FMT) involves the infusion of intestinal microorganisms via transfer of stool from a healthy person into a diseased patient, with the intent of restoring normal intestinal flora. Fecal transplant is proposed for the treatment of treatment-refractory Clostridium difficile infection (CDI), as well as for other conditions including inflammatory bowel disease (IBD).
FMT, also called donor feces infusion, intestinal microbiota transplantation, and fecal bacteriotherapy, involves the infusion of intestinal microorganisms via transfer of stool from a healthy individual into a diseased individual to restore normal intestinal flora. The stool can be infused as a liquid suspension into a patient’s upper gastrointestinal tract though a nasogastric tube or gastroscopy, or into the colon through a colonoscope or rectal catheter.
The goal of FMT is to replace damaged and/or disordered native microbiota with a stable community of donor microorganisms. The treatment is based on the premise that an imbalance in the community of microorganisms residing in the gastrointestinal tract (i.e., dysbiosis) is associated with specific disease states, including susceptibility to infection.
The human microbiota, defined as the aggregate of microorganisms (bacteria, fungi, archaea) on and in the human body, is believed to consist of approximately 10 to 100 trillion cells, approximately 10 times the number of human cells. Most human microbes reside in the intestinal tract, and most of these are bacteria. In its healthy state, intestinal microbiota perform a variety of useful functions including aiding in the digestion of carbohydrates, mediating the synthesis of certain vitamins, repressing growth of pathogenic microbes, and stimulating the lymphoid tissue to produce antibodies to pathogens.
To date, the major potential clinical application of fecal microbiota transplantation is treatment of CDI. Infection of the colon with C difficile is a major cause of colitis and can cause life-threatening conditions including colonic perforation and toxic megacolon. C difficile occurs naturally in intestinal flora. The incidence of CDI in North America has increased substantially in the past decade. For example, according to hospital discharge diagnosis data, there were more than 300,000 cases of CDI in 2006, compared with fewer than 150,000 cases in 2000. Moreover, CDI causes an estimated 15,000 to 20,000 deaths per year in U.S. hospitals. (1, 2)
It is unclear what causes C difficile overgrowth, but disruption of the normal colonic flora in conjunction with colonization by C difficile are major components. Disruption of the normal colonic flora occurs most commonly following administration of oral, parenteral or topical antibiotics. Standard treatment for CDI is antibiotic therapy. However, symptoms recur in up to 35% of patients and up to 65% of patients with recurrences develop a chronic recurrent pattern of CDI. (3)
Other potential uses of fecal microbiota transplant include treatment of conditions in which altered colonic flora may play a role. These include IBD, irritable bowel syndrome, idiopathic constipation and non-gastrointestinal disease such as multiple sclerosis, obesity, autism, and chronic fatigue syndrome. However, for these conditions, the contribution of alterations in colonic flora to the disorder is uncertain or controversial.
There is interest in alternatives to human feces that might have the same beneficial effects on intestinal microbiota without the risks of disease transmission. A proof of principle study was published in 2013 that evaluated a synthetic stool product in 2 patients with recurrent CDI. (4) The product is made from 33 bacterial isolates that were developed from culturing stool from a healthy donor.
In July 2013, the U.S. Food and Drug Administration (FDA) issued guidance regarding investigational new drug requirements for use of fecal microbiota transplant to treat CDI not responsive to medication therapy. (5) The document states that FDA is continuing to consider how to regulate fecal microbiota transplant and that, during this interim period, the agency will use enforcement discretion regarding use of fecal transplant to treat treatment-resistant CDI infections. FDA requires that physicians obtain adequate informed consent from patients or their legal representative before performing the intervention. The document also states that selective enforcement does not apply to use of fecal transplant for treating conditions other than treatment-resistant CDI.
The available literature consists of two randomized controlled trial (RCTs) and numerous case series or case reports. Other than a few case reports of patients with acute Clostridium difficile (CDI), studies treated patients with recurrent infection.
The first RCT that evaluated fecal microbiota transplantation was published in 2013. (6) This non-blinded study, by van Nood et al. in the Netherlands, included 43 patients 18 years and older with at least one recurrence of CDI. Exclusion criteria included prolonged compromised immunity, admission to an intensive care unit, and need for vasopressor medication.
Patients were randomized to 1 of 3 treatment groups: (1) fecal microbiota transplantation (FMT, here called donor feces infusion) (n=17); (2) antibiotic therapy (n=13); or (3) antibiotics and bowel lavage (n=13). The FMT intervention involved collecting feces from healthy screened donors on the day of infusion, diluting the feces with 500 mL of sterile saline and infusing the solution (mean, 141 g) through a nasoduodenal tube. Patients assigned to the FMT group also received a modified course of vancomycin (500 mg orally 4 times a day for 4-5 days) and bowel lavage before infusion. A second infusion was given to patients in the FMT group who had a relapse after the first treatment. Potential donors underwent an evaluation process that included completing a questionnaire on potential risk factors for transmissible diseases, screening feces for parasites, and screening blood for antibodies for viruses. The study was initially designed to include 120 patients (40 per group), but, because of the high relapse rate in the control groups, the data and safety monitoring group recommended early termination of the trial.
The primary efficacy outcome was cure without relapse within 10 weeks of initiating treatment. Cure was defined as absence of diarrhea that could not be explained by other causes and 3 consecutive negative tests for CDI toxin. Relapse was defined as diarrhea with a positive stool test for CDI toxin during this 10- week period. For the 3 patients who received a second infusion, follow-up was extended to 10 weeks after the second treatment. Patients were questioned about symptoms of diarrhea, and stool tests were performed on days 14, 21, 35, and 70 and when diarrhea was reported. One patient in the FMT group was excluded from analysis.
A total of 15 of 16 patients (94%) of analyzed patients in the FMT group were cured: 13 after a single infusion and another 2 after a second infusion from a different donor. In contrast, only 4 of 13 patients (31%) in the antibiotics-only group and 3 of 13 patients (23%) in the antibiotics and bowel lavage group were cured. The overall cure rate was significantly higher in the FMT group compared with the other 2 groups (p<0.001). Most patients in the FMT group experienced short-term adverse events (i.e., diarrhea in 94%, cramping in 31%, belching in 19%) that resolved within 3 hours.
Data on the diversity of fecal microbiota were available for 9 patients in the FMT group. Diversity was measured on a scale ranging from 1 to 250, with higher values indicating more diversity. Before infusion, mean microbiota diversity was low (mean, 57, SD=26). Within 2 weeks of infusion, diversity increased to a mean of 179 (SD=42), a level similar to the diversity levels in the donors (mean=172, SD=54).
A second RCT, published by Youngster et al. in 2014, compared infusion of donor stools by colonoscopy or nasogastric tube. (7) A total of 20 patients with relapsing and recurrent CDI were included. Patients needed to have a relapse of CDI following at least 3 episodes of mild-to-moderate CDI and failure of a course of vancomycin or at least 2 episodes of severe CDI that resulted in hospitalization and was associated with significant morbidity. All patients underwent FMT and were randomized to 1 of 2 infusion routes, colonoscopy or a nasogastric tube. Both groups had 90 mL thawed inoculum. Stool donors were healthy nonrelatives who successfully completed an extensive screening process. Stool was frozen up to 156 days before use. Patients could receive a second FMT if symptoms did not resolve following the initial transplant.
The primary efficacy outcome was clinical cure, defined as resolution of diarrhea (i.e., <3 bowel movements per 24 hours) while off antibiotics for CDI, without relapse for 8 weeks. Fourteen patients were cured after the first FMT, 8 in the colonoscopy group and 6 in the nasogastric tube group; the difference between groups was not statistically significant (p=0.628). Of the remaining 6 patients, 1 refused additional treatment and the other 5 underwent a second transplant. According to the study protocol, patients could choose the route of administration for the second procedure, and all of them chose the nasogastric tube. Four additional patients were cured after the second transplant, for an overall cure rate of 18 of 20 (90%). This study did not find that either route of administration of donor feces was superior to the other, but patients preferred use of a nasogastric tube.
Several systematic reviews of uncontrolled studies on fecal microbiota transplantation for treating CDI have been published. (3, 9, 10) Of these, only Sofi et al. conducted a pooled data analysis. (10) The investigators searched the literature through April 2012. The authors did not identify any RCTs that evaluated FMT (their literature search was conducted before publication of a 2013 RCT, discussed next). A total of 25 observational studies (10 case reports, 15 case series) provided data on 239 adult patients treated with fecal microbiota transplants for CDI. All of the case series were retrospective, and sample sizes ranged from 4 to 70 patients; only 4 studies included more than 25 patients. Most studies included recurrent CDI, but several case reports treated patients who were severely ill due to acute CDI. Fecal transplants were performed by the gastroduodenal route in 91 patients (32%) and by the colonic route in 198 (68%) patients. Treatment success was defined as resolution of CDI symptoms at follow-up. Mean follow-up posttransplant ranged from 10 days to 65 months. In a pooled analysis of individual patient data, the overall treatment success rate was 91.2%. Subanalyses revealed a significantly higher treatment failure rate in patients treated by the colonic versus the duodenal route and patients with symptoms for at least 60 days versus less than 60 days.
A 2014 retrospective case series included 94 patients with refractory or recurrent CDI who underwent 1 or more FMT via retention enema. (11) Cure was defined as no recurrence of diarrhea in the 6 months after treatment. A total of 45 of 94 patients (48%) were cured following a single FMT. When 4 or more FMTs were administered, the cure rate was 86.2%, and this increased further to 91.5% when antibiotics were administered between FMTs.
One small RCT, which enrolled patients who had failed at least one course of antibiotic treatment, reported a large increase in resolution of C difficile with FMT plus antibiotics compared with antibiotics alone with or without bowel lavage. A second RCT compared different modes of administration and did not find a significant difference in fecal transplantation via colonoscopy or nasogastric tube. This study also reported a high overall CDI cure rate, but did not have a medical treatment control group. Case reports and case series report a high rate of resolution of CDI following treatment with FMT. Further studies are needed to determine the optimal patient selection criteria and treatment protocol for this therapy.
Inflammatory Bowel Disease
In 2012, Anderson et al. published a systematic review of the available literature on fecal microbiota transplant for treatment of inflammatory bowel disease (IBD). (12) The investigators searched for published studies and conference abstracts in any language reporting on patients with IBD treated with fecal transplants for IBD symptoms or infectious diarrhea. A total of 17 studies with 41 patients met the review’s inclusion criteria. None of the studies were controlled; all were case reports or case series. Nine articles reported on 26 patients (18 with ulcerative colitis, 6 with Crohn disease, 2 with undefined IBD) who received fecal microbiota transplants because their IBD was resistant to standard management. The other 8 articles included 15 patients (9 with ulcerative colitis, 6 with Crohn disease) whose primary indication for fecal transplant was recurrent CDI.
Outcome data were reported for 17 of the 26 patients being treated for IBD. Thirteen of 17 (76%) patients stopped IBD medications within 6 weeks. Data on IBD symptoms before and after the procedure were available for 16 patients. All of these reported a reduction or resolution of IBD symptoms within 4 months of receiving fecal transplants, and 15 reported complete resolution of symptoms within a year. Three of 13 patients reported no disease recurrence at long-term follow-up (which was 3-6 months in 15 patients and 1-13 years in 12 patients).
Data are available on only a small number of patients with IBD treated with fecal microbiota transplant and there is a lack of controlled studies. Improvements in IBD symptoms have been reported, but further controlled studies in larger numbers of patients are needed to establish efficacy,
Ongoing clinical trials
A search of online clinicaltrials.gov database in March 2014 found a number of ongoing RCTS evaluating fecal microbiota transplant. These trials can be grouped into several categories, as follows:
Evaluating fecal microbiota transplant as a treatment for recurrent CDI:
Stool Transplant in Pediatric Patients with Recurring C Difficile Infection (NCT01972334): Double-blind RCT comparing fecal transplant to a placebo procedure in children (age 8-18 years) with recurrent CDI. Estimated enrollment is 46 patients.
Oral Vancomycin Followed by Fecal Transplant Versus Tapering Oral Vancomycin (NCT01226992): Nonblinded RCT to compare 2 weeks of oral vancomycin treatment followed by single-dose fecal transplant via rectal enema with 2 weeks of oral vancomycin treatment followed by tapering of vancomycin. Estimated enrollment is 146 patients.
Evaluating fecal microbiota transplant as a treatment for other conditions:
Fecal Biotherapy for the Induction of Remission in Active Ulcerative Colitis (NCT01545908): Double-blind RCT to compare 6 weekly fecal transplant enemas with placebo enemas in patients with ulcerative colitis. Estimated enrollment is 130 patients.
Standardized Fecal Microbiota Transplantation for Crohn Diseases (NCT01793831): Nonblinded RCT to compare a single fecal transplant procedure with standard medical care in patients with ulcerative colitis or Crohn disease. Estimated enrollment is 30 patients.
Evaluating technical aspects of the transplant procedure:
Multi-Centre Trial of Fresh vs. Frozen-and-Thawed HBT (Fecal Transplant)for Recurrent CDI (NCT01398969): Double-blind RCT to compare an enema of fresh human fecal bacteriotherapy and frozen-and-thawed fecal bacteriotherapy. The study includes patients with recurrent CDI. Estimated enrollment is 136 patients.
Fecal microbiota transplantation (FMT) is proposed as a treatment of recurrent C difficile infection (CDI) unresponsive to standard therapy and other conditions that are potentially associated with disruption of normal intestinal flora. Two small randomized controlled trials (RCTs) evaluating fecal microbiota transplantation for CDI has been published. Findings of the trial that compared FMT with standard treatment suggest that FMT is more effective than currently used treatments of recurrent CDI. However, the study had limitations including a small sample size and open-label design. The other RCT did not find a significant difference in efficacy when donor feces was administered via colonoscopy or nasogastric tube. Although published evidence is limited and questions remain e.g., about safety, patient selection criteria and optimal FMT protocol, due to support from the available evidence and clinical reviewers, FMT may be considered medically necessary for treatment of patients with 3 or more recurrences of CDI.
There is insufficient published evidence on the safety and efficacy of fecal transplant for treating conditions other than CDI, such as IBD. Thus, fecal microbiota transplantation is considered experimental, investigational and/or unproven for all conditions other than recurrent CDI.
Practice Guidelines and Position Statements
In April 2013, the American College of Gastroenterology published a guideline on diagnosis, treatment, and prevention of CDIs. (8) The guideline addressed fecal microbiota transplant for treatment of 3 or more CDI recurrences, as follows: “If there is a third recurrence after a pulsed vancomycin regimen, fecal microbiota transplant (FMT) should be considered. (Conditional recommendation, moderate-quality evidence)”
For treatment of 1 to 2 CDI recurrences, the guideline recommended: “The first recurrence of CDI can be treated with the same regimen that was used for the initial episode. If severe, however, vancomycin should be used. The second recurrence should be treated with a pulsed vancomycin regimen. (Conditional recommendation, low-quality evidence)”
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The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
1. Kachrimanidou M, Malisiovas N. Clostridium difficile infection: a comprehensive review. Crit Rev Microbiol 2011; 37(3):178-87.
2. Nelson RL, Kelsey P, Leeman H et al. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database Syst Rev 2011; (9):CD004610.
3. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011; 53(10):994-1002.
4. Petrof EO, Gloor GB, Vanner SJ et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: 'RePOOPulating' the gut. Microbiome 2013; 1(1):3.
5. Food and Drug Administration (FDA). Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. July 2013. Available online at: <http://www.fda.gov>. Last accessed March, 2014.
6. van Nood E, Vrieze A, Nieuwdorp M et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013; 368(5):407-15.
7. Youngster I, Sauk J, Pindar C et al. Fecal Microbiota Transplant for Relapsing Clostridium difficile Infection Using a Frozen Inoculum From Unrelated Donors: A Randomized, Open-Label, Controlled Pilot Study. Clin Infect Dis 2014.
8. American College of Gastroenterology (ACG). Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Available online at: <http://gi.org>. Last accessed March, 2014.
9. Guo B, Harstall C, Louie T et al. Systematic review: faecal transplantation for the treatment of Clostridium difficile-associated disease. Aliment Pharmacol Ther 2012; 35(8):865-75.
10. Sofi AA, Silverman AL, Khuder S et al. Relationship of symptom duration and fecal bacteriotherapy in Clostridium difficile infection-pooled data analysis and a systematic review. Scand J Gastroenterol 2013; 48(3):266-73.
11. Lee CH, Belanger JE, Kassam Z et al. The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema. Eur J Clin Microbiol Infect Dis 2014.
12. Anderson JL, Edney RJ, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther 2012; 36(6):503-16.
13. Fecal Microbiota Transplantation. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (February 2015) Medicine 2.01.92.
|4/15/2018||Reviewed. No changes.|
|2/1/2015||Document updated with literature review. The following change was made to coverage: Fecal microbiota transplantation (FMT) may be considered medically necessary for treatment of patients with recurrent Clostridium difficile infection under the following conditions: There have been at least 3 episodes of recurrent infection following initial treatment; AND Episodes are refractory to appropriate antibiotic regimens*, including at least 1 regimen of oral vancomycin. *NOTE: Appropriate antibiotic regimens include oral vancomycin with tapered or pulse-tapered dosing, or standard doses of fidaxomicin, oral metronidazole, or rifaximin.|
|1/1/2013||New medical document. Fecal microbiota transplantation (FMT) is considered experimental, investigational and unproven for the treatment of intestinal dysbiosis (such as, inflammatory bowel disease [IBD], ulcerative colitis [UC], constipation, diarrhea, and Clostridium difficile infection [CDI]); neurological disorders (such as, anxiety or depression); autoimmune disorders; or obesity.|
|Title:||Effective Date:||End Date:|
|Fecal Microbiota Transplantation (FMT)||04-15-2018||03-31-2019|
|Fecal Microbiota Transplantation (FMT)||04-15-2017||04-14-2018|
|Fecal Microbiota Transplantation (FMT)||04-01-2016||04-14-2017|
|Fecal Microbiota Transplantation (FMT)||02-01-2015||03-31-2016|
|Fecal Microbiota Transplantation (FMT)||01-01-2013||01-31-2015|