mp-584 - Medical Policies - Alabama
Fecal Microbiota Transplantation
Policy Number: MP-584
Latest Review Date: November 2019
Policy Grade: B
The use of fecal microbiota transplantation for treatment of patients with recurrent Clostridium difficile infection may be considered medically necessary when:
- There have been at least three episodes of recurrent infection; AND
- Episodes are refractory to appropriate antibiotic regimens, including at least one regimen of pulsed vancomycin.
The use of fecal microbiota transplantation is considered not medically necessary and investigational in the absence of the conditions listed above.
DESCRIPTION OF PROCEDURE OR SERVICE:
Fecal microbiota transplantation (FMT) involves the infusion of intestinal microorganisms via the transfer of stool from a healthy person into a diseased patient, with the intent of restoring normal intestinal flora. Fecal transplant is proposed for treatment-refractory Clostridium difficile infection (CDI), and other conditions including inflammatory bowel disease (IBD).
Fecal microbiota transplantation (FMT), also called donor feces infusion, intestinal microbiota transplantation, and fecal bacteriotherapy, involves the infusion of intestinal microorganisms via the 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 ten 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.
Clostridium Difficile Infection
To date, the major potential clinical application of fecal microbiota transplantation is treatment of Clostridium difficile infection (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 the 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.
It is unclear what causes C difficile overgrowth, but disruption of the normal colonic flora and colonization by C difficile are major components. Disruption of the normal colonic flora occurs most commonly following the 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.
Other potential uses of fecal microbiota transplant include treatment of conditions in which altered colonic flora may play a role. These include inflammatory bowel disease, irritable bowel syndrome, idiopathic constipation and non-gastrointestinal diseases 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, Perof et al (2013) evaluated a synthetic stool product in two patients with recurrent CDI. The product is made from 33 bacterial isolates developed from culturing stool from a healthy donor.
The most recent literature review was updated through August 28, 2019.
Summary of Evidence
For individuals who have recurrent CDI refractory to antibiotic therapy who receive FMT, the evidence includes RCTs, multiple systematic reviews, and observational studies. The relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. The RCTs found that FMT was more effective than standard treatment or placebo for patients with recurrent CDI. Other RCTs did not find the superiority of any route of administration over another or the superiority of fresh versus frozen feces. Case reports and case series have reported high rates of resolution of recurrent CDI following treatment with FMT. Few treatment-related adverse events have been reported. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have IBD who receive FMT, a largescale systematic review and meta-analysis, the evidence includes two RCTs in patients with UC, as well as observational studies. The relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. Two small RCTs on FMT for treatment of ulcerative colitis were discontinued due to futility, and data analyzed for patients already enrolled. One trial found a statistically significant higher remission rate after active FMT than after a control intervention, but this trial had few patients in remission (n=11) and short follow-up (seven weeks). The other trial reported no difference in remission rates. Data on a small number of patients with Crohn disease are available; there are no controlled studies of FMT in this population. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have IBS who receive FMT, the evidence includes a systematic review and RCTs. The relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. The systematic review found mixed outcomes; in a pooled analysis of three RCTs utilizing autologous FMT as a placebo, the relative risk of IBS symptoms not improving decreased and was statistically superior compared to donor FMT. Few treatment-related adverse events have been reported. Data are limited by small study sizes and heterogeneity in utilized symptom severity measurement scales and definitions of treatment response. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have irritable bowel syndrome who receive FMT, the evidence includes a systematic review and RCTs. The relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. The systematic review found mixed outcomes; in a pooled analysis of three RCTs utilizing autologous FMT as a placebo, the relative risk of irritable bowel syndrome symptoms not improving decreased and was statistically superior compared to donor FMT. Few treatment-related adverse events have been reported. Data are limited by small study sizes and heterogeneity in utilized outcome measurement scales and definitions of treatment response. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have pouchitis, constipation, MDRO infection, or metabolic syndrome who receive FMT, the evidence includes a small number of case series and RCTs. The relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. Data are available for only small numbers of patients and there is a lack of comparative studies. Current comparative studies are small and either do not report clinical outcomes or fail to demonstrate a significant benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
PRACTICE GUIDELINES AND POSITION STATEMENTS
American College of Gastroenterology
The American College of Gastroenterology (2013) published a guideline on diagnosis, treatment, and prevention of CDIs. The guideline addressed fecal microbiota transplant for treatment of three 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 the treatment of one to two CDI recurrences, the guidelines 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)”.
The American College of Gastroenterology (2019) published guidelines on the management of adults with ulcerative colitis. The guidelines addressed fecal microbiota transplant as therapy for induction of remission, as follows:
"Fecal microbiota transplantation (FMT) requires more study and clarification of treatment before use as therapy for UC."
Infection Diseases Society of America
The Infectious Diseases Society of America and Society for Healthcare Epidemiology of America updated clinical practice guidelines (2019) for the diagnosis and treatment of CDI in children and adults. Recommendations were summarized as follows:
- "Consider fecal microbiota transplantation for pediatric patients with multiple recurrences of CDI following standard antibiotic treatments. (Weak recommendation, very low quality of evidence)"
- "Fecal microbiota transplantation is recommended for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments. (Strong recommendation, moderate quality of evidence)"
U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Fecal microbiota transplant, Donor feces infusion, Intestinal microbiota transplantation, Fecal bacteriotherapy, Fecal transplant
APPROVED BY GOVERNING BODIES:
In 2016, the U.S. Food and Drug Administration (FDA) issued updated draft guidance on investigational new drug requirements for the use of FMT to treat CDI not responsive to medication therapy. The draft guidance is similar to the 2013 guidance and states that the Food and Drug Administration is continuing to consider how to regulate FMT and that, during this interim period, the agency will use enforcement discretion regarding the use of fecal transplant to treat treatment-resistant CDI. The Food and Drug Administration requires that physicians obtain adequate informed consent from patients or their legal representative before performing the intervention. The document also noted that selective enforcement does not apply to the use of fecal transplant for treating conditions other than treatment-resistant CDI.
In 2019, the FDA issued a safety alert regarding the use of FMT due to the potential risk of serious or life-threatening infections caused by the transmission of multi-drug resistant organisms (MDROs). Two immunocompromised individuals received investigational FMT and developed invasive infections caused by the transmission of extended-spectrum beta-lactamase-producing Escherichia coli. One of the affected individuals died. The donor stool used in each patient's FMT procedures had not been tested for extended-spectrum beta-lactamase-producing gram-negative organisms prior to use. Follow-up testing verified donor stool was positive for MDROs identical to the organisms isolated from the two patients. Due to these events, the FDA has determined that the following additional protections are required for any investigational use of FMT:
- Donor screening that specifically addresses risk factors for colonization with MDROs and exclusion of individuals at higher risk of colonization with MDROs (eg, health care workers, persons who have recently been hospitalized or discharged from long-term care facilities, persons who regularly attend outpatient medical or surgical clinics, and persons who have recently engaged in medical tourism).
- MDRO testing of donor stool and exclusion of stool testing positive for MDROs. At a minimum, tests should include:
- extended-spectrum beta-lactamase-producing Enterobacteriaceae
- vancomycin-resistant enterococci
- carbapenem-resistant Enterobacteriaceae
- methicillin-resistant Staphylococcus aureus
- All FMT products currently in storage for future use must be quarantined until donor MDRO carriage risk can be assessed and FMT products are tested and found negative for MDROs.
- The informed consent process for FMT treatment subjects should describe the risk of MDRO transmission and infection and the measures being implemented for donor screening and stool testing.
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply.
FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
44705 Preparation of fecal microbiota for installation, including assessment of donor specimen
G0455 Preparation with instillation of fecal microbiota by any method, including assessment of donor specimen
- Aldrich AM, Argo T, Koehler TJ, et al. Analysis of treatment outcomes for recurrent Clostridium difficile infections and fecal microbiota transplantation in a pediatric hospital. Pediatr Infect Dis J. Mar 29 2018.
- American College of Gastroenterology (ACG). Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Available online at: gi.org/guideline/diagnosis-and-management-of-c-difficile-associated-diarrhea-and-colitis/.
- 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.
- Aziz I, Törnblom H, Palsson OS, et al. How the Change in IBS Criteria From Rome III to Rome IV Impacts on Clinical Characteristics and Key Pathophysiological Factors.. Am. J. Gastroenterol., 2018 Jun 9;113(7).
- Chapman BC, Moore HB, Overbey DM, et al. Fecal microbiota transplant in patients with Clostridium difficile infection: A systematic review. J Trauma Acute Care Surg. Oct 2016; 81(4):756-764.
- Costello SP, Hughes PA, Waters O, et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial.. JAMA, 2019 Jan 16;321(2).
- Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. Ann Intern Med. May 5 2015; 162(9):630-638.
- 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: www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformati on/Guidances/Vaccines/UCM361393.pdf. Accessed October 25, 2017.
- Food and Drug Administration (FDA). Fecal Microbiota Transplantation: Safety Communication - Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms. 2019; https://www.fda.gov/safety/medwatch-safety-alerts-human-medical-products/fecalmicrobiota-transplantation-safety-communication-risk-serious-adverse-reactions-due. Accessed September 23, 2019.
- Ford AC, Bercik P, Morgan DG, et al. Validation of the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care.. Gastroenterology, 2013 Sep 3;145(6).
- 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.
- 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.
- Holster S, Lindqvist CM, Repsilber D, et al. The Effect of Allogenic Versus Autologous Fecal Microbiota Transfer on Symptoms, Visceral Perception and Fecal and Mucosal Microbiota in Irritable Bowel Syndrome: A Randomized Controlled Study.. Clin Transl Gastroenterol, 2019 Apr 23;10(4).
- Huttner BD, de Lastours V, Wassenberg M, et al. A 5-day course of oral antibiotics followed by faecal transplantation to eradicate carriage of multidrug-resistant Enterobacteriaceae: a randomized clinical trial.. Clin. Microbiol. Infect., 2019 Jan 8;25(7).
- Ianiro G, Eusebi LH, Black CJ, et al. Systematic review with meta-analysis: efficacy of faecal microbiota transplantation for the treatment of irritable bowel syndrome.. Aliment. Pharmacol. Ther., 2019 May 29;50(3).
- Johnsen PH, Hilpüsch F, Cavanagh JP, et al. Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial.. Lancet Gastroenterol Hepatol, 2017 Nov 5;3(1).
- Kachrimanidou M, Malisiovas N. Clostridium difficile infection: a comprehensive review. Crit Rev Microbiol 2011; 37(3):178-87.
- Kelly CR, Khoruts A, Staley C, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial. Ann Intern Med. Aug 23 2016.
- Khan MY, Dirweesh A, Khurshid T, et al. Comparing fecal microbiota transplantation to standard-of-care treatment for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. Nov 2018;30(11):1309-1317.
- Kronman MP, Nielson HJ, Adler AL, et al. Fecal microbiota transplantation via nasogastric tube for recurrent clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr. Jan 2015; 60(1):23-26.
- 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.
- Lee CH, Chai J, Hammond K, et al. Long-term durability and safety of fecal microbiota transplantation for recurrent or refractory Clostridioides difficile infection with or without antibiotic exposure.. Eur. J. Clin. Microbiol. Infect. Dis., 2019 Jun 6;38(9).
- Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile Infection: a randomized clinical trial. JAMA. Jan 12 2016; 315(2):142-149.
- Mamo Y, Woodworth MH, Wang T, et al. Durability and long-term clinical outcomes of fecal microbiota transplant treatment in patients with recurrent Clostridium difficile infection. Clin Infect Dis. May 17 2018;66(11):1705-1711.
- McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).. Clin. Infect. Dis., 2018 Feb 21;66(7).
- Meighani A, Hart BR, Bourgi K, et al. Outcomes of fecal microbiota transplantation for Clostridium difficile infection in patients with inflammatory bowel disease. Dig Dis Sci. Oct 2017;62(10):2870-2875.
- Moayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. Jul 2015; 149(1):102-109 e106.
- Nelson RL, Kelsey P, Leeman H et al. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database Syst Rev 2011; (9):CD004610.
- Paramsothy S, Paramsothy R, Rubin DT, et al. Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis. Oct 1 2017;11(10):1180-1199.
- 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.
- Quraishi MN, Widlak M, Bhala N, et al. Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Aliment Pharmacol Ther. Sep 2017; 46(5):479-493.
- Rossen NG, Fuentes S, van der Spek MJ, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology. Jul 2015; 149(1):110-118 e114.
- Rossen NG, MacDonald JK, de Vries EM, et al. Fecal microbiota transplantation as novel therapy in gastroenterology: A systematic review. World J Gastroenterol. May 7 2015; 21(17):5359-5371.
- Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG Clinical Guideline: Ulcerative Colitis in Adults.. Am. J. Gastroenterol., 2019 Mar 7;114(3).
- Sha S, Liang J, Chen M, et al. Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children. Aliment Pharmacol Ther. May 2014; 39(10):1003-1032.
- 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.
- Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. Apr 2013;108(4):478-498; quiz 499.
- Tariq R, Pardi DS, Bartlett MG, et al. Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis.. Clin. Infect. Dis., 2019 Apr 9;68(8).
- 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.
- Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. Oct 2012; 143(4):913-916 e917.
- Wang S, Xu M, Wang W, et al. Systematic review: adverse events of fecal microbiota transplantation. PLoS One. 2016; 11(8):e0161174.
- 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.
Medical Policy Panel, February 2014
Medical Policy Group, February 2015 (3): Newly adopted policy
Medical Policy Administration Committee, March 2015
Medical Policy Panel, April 2015
Medical Policy Group, May 2015 (3): 2015 Updates to Key Points & References; no change in policy statement.
Medical Policy Panel, November 2015
Medical Policy Group, December 2015 (3): 2015 Updates to Key Points and References; no change in policy statement.
Medical Policy Panel, November 2016
Medical Policy Group, November 2016 (3): 2016 Updates to Key Points and References; no change in policy statement.
Medical Policy Panel, November 2017
Medical Policy Group, November 2017 (3): 2017 Updates to Description, Key Points & References; no change in policy statement.
Medical Policy Panel, November 2018
Medical Policy Group, December 2018 (4): Updates to Key Points, Approved by Governing Bodies, and References. No change to policy statement.
Medical Policy Panel, November 2019
Medical Policy Group, November 2019 (5): Updates to Description, Key Points, Practice Guidelines, Approved by Governing Bodies, and References. No change to Policy Statement.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.
The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.
As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.
The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:
1. The technology must have final approval from the appropriate government regulatory bodies;
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.
Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:
1. In accordance with generally accepted standards of medical practice; and
2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and
3. Not primarily for the convenience of the patient, physician or other health care provider; and
4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.