FDA Licenses a Fecal Microbiota Product to Prevent Recurrent C. difficile Infection (2022)

Table of Contents

1. What the FDA Did on November 29 and 30, 2022
2. C. difficile Infection and Its Recurrence
3. The Enforcement Policy for Fecal Transplants
4. The Conditions in the Final Policy
5. The Licensed Product and How It Is Given
6. The Trial Evidence and How the FDA Weighed It
7. Side Effects and Label Warnings
8. The Advisory Committee Meeting of September 22, 2022
9. Safety Monitoring After Licensure
10. What the Two Actions Do Not Do
11. Dates and Legal Status as of October 18, 2026
12. How It Fits Other FDA Actions
13. Primary Documents
14. Key Research Papers
15. Connections
16. Featured Videos

1. What the FDA Did on November 29 and 30, 2022

November 29, 2022 — a final guidance. The FDA published a notice in the Federal Register, the U.S. government’s daily publication of rules and official notices, announcing a final guidance for industry titled “Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridioides difficile Infection Not Responsive to Standard Therapies” (87 FR 73313; Docket No. FDA-2013-D-0811). The notice states that “at this time, we intend to exercise enforcement discretion” with respect to the investigational new drug application requirements for the use of FMT to treat C. difficile infection not responding to standard therapies, “under limited circumstances described in the guidance.”

November 30, 2022 — a biologics license. The FDA’s Center for Biologics Evaluation and Research (CBER), the part of the FDA that reviews biological products, approved a Biologics License Application (BLA STN 125739) for fecal microbiota, live-jslm, under section 351(a) of the Public Health Service Act and U.S. License No. 2112. The approval letter gives the indication: “the prevention of recurrence of Clostridioides difficile infection (CDI) in individuals 18 years of age and older, following antibiotic treatment for recurrent CDI.” The letter authorizes the product’s introduction into interstate commerce under that license.

The two actions concern the same kind of material in different forms. The guidance covers fecal transplants prepared outside an FDA-licensed product, which remain investigational. The license covers one manufactured product that the FDA reviewed for safety and effectiveness.

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2. C. difficile Infection and Its Recurrence

The FDA’s Summary Basis for Regulatory Action, the review document that explains why the product was approved, describes Clostridioides difficile as “a spore-forming, rod-shaped, Gram-positive anaerobic bacterium that colonizes through the fecal-oral route.” It calls the bacterium “a common cause of antibiotic–associated diarrhea and colitis” and the infection “an urgent public health concern, associated with significant morbidity and mortality.” The organism itself is described on the site’s Clostridium difficile page.

The review gives these figures for the United States:

• “A half million C. difficile infections are reported in the United States each year.”
• According to the Centers for Disease Control and Prevention (CDC) 2019 report it cites, 223,900 estimated cases occurred in hospitalized patients, and 12,800 deaths were associated with the infection.
• The estimated burden of infection acquired in health care settings has decreased in recent years, while the rate of community-acquired infection “remains unchanged.”

Recurrence is the problem the licensed product addresses. The review defines recurrent infection as an episode occurring within eight weeks after symptoms of a previous episode have resolved. It states that approximately one in six patients will have a recurrence, that each recurrence increases the risk of further recurrences, and that a recurrence rate of 65% has been reported after three episodes. Complications it lists include dehydration, low blood pressure, kidney failure, severe diarrhea and, rarely, toxic megacolon, rupture of the colon, septicemia and death. It cites an estimated U.S. cost of $2.8 billion for recurrent infection.

On treatment, the review notes that practice guidelines list tapering or pulsed-dose vancomycin or a ten-day course of fidaxomicin for a first recurrence, that a monoclonal antibody (bezlotoxumab) is indicated to reduce recurrence in high-risk adults receiving antibacterial treatment, and that rifaximin is among the options after more than one recurrence. It concludes that “Prevention of recurrent CDI represents an unmet medical need.”

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3. The Enforcement Policy for Fecal Transplants

An investigational new drug application (IND) is the submission to the FDA under which a drug or biological product that is not approved for a use is studied in people for that use. Enforcement discretion means that the FDA states it does not intend, for now, to enforce a particular requirement in defined circumstances; the requirement itself stays on the books.

For fecal transplants, the FDA has had such a policy for years. The November 2022 notice states that the final guidance:

• finalizes a draft guidance with the same subject dated March 2016; and
• supersedes the guidance on the same subject dated July 2013.

The FDA’s review of the licensed product describes the practical effect of that policy. It states that FMT “has been recommended in various infectious diseases and gastroenterology practice guidelines and has been widely administered for this purpose under FDA’s investigational new drug application (IND) enforcement discretion policy for use of FMT to treat CDI not responding to standard therapies.” The same review lists, among the factors the FDA weighed in judging the trial evidence, “the challenges of enrolling placebo-controlled trials for FMT given availability of other FMT products under enforcement discretion” (section 6).

A Federal Register docket is the public file for an action, where the documents and public comments are kept on regulations.gov; this policy’s docket number is FDA-2013-D-0811.

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4. The Conditions in the Final Policy

The Federal Register notice describes the circumstances under which the FDA intends to exercise enforcement discretion when the FMT product is not obtained from a stool bank. Taken together, they are:

• Consent. The licensed health care provider treating the patient obtains appropriate consent from the patient or the patient’s legally authorized representative. In the notice’s words, the consent should include, at a minimum, “a statement that the use of FMT products” to treat C. difficile is investigational, together with a discussion of its reasonably foreseeable risks.
• Donor and stool qualification. The stool donor and the stool are qualified by screening and testing performed under the direction of that licensed health care provider.
• No reported safety concerns. The use does not raise reported safety concerns.

The policy applies only to C. difficile infection that is not responding to standard therapies. The notice describes these as “limited circumstances”; outside them, the ordinary IND requirements apply. This page reports only the conditions the notice’s published text states; the full guidance document is the authority on the details.

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5. The Licensed Product and How It Is Given

The package insert and the review describe the product as follows:

• Source. It is “manufactured from human fecal matter sourced from qualified donors.” Donors are screened by questionnaire and physical examination, and blood and stool are tested for potentially transmissible pathogens. The finished product stays in quarantine until donor test results are acceptable.
• Contents. Each 150 mL dose contains between 1×10⁸ and 5×10¹⁰ colony-forming units per mL of fecal microbes, including more than 1×10⁵ colony-forming units per mL of Bacteroides, in a solution of polyethylene glycol 3350 (no more than 5.97 grams) and saline. A colony-forming unit is a count of live microbes able to grow in the laboratory.
• Dose and route. “For rectal administration only.” A single dose of 150 mL is given 24 to 72 hours after the last dose of antibiotics for C. difficile, through a rectal tube by gravity flow. The patient is kept on the left side or in the knee-chest position for up to 15 minutes afterward to reduce cramping.
• Storage. The product contains live microorganisms. It is stored in an ultracold freezer (−60°C to −90°C), thawed in a refrigerator for about 24 hours, used within 5 days including thawing time, and not refrozen. Its dating period is 36 months from the date of manufacture when stored at −80°C.
• How it works. Both the label and the review state: “The mechanism of action … has not been established.”

The review also records that the product is a combination product (the suspension plus an administration set) and that it is not subject to CBER lot release testing, meaning the manufacturer does not have to send samples of each batch to the FDA before release; the approval letter says the FDA will continue to monitor compliance with the required tests. The proper name’s four-letter suffix, “-jslm,” was supplied by the FDA on June 3, 2022, after the suffixes the applicant proposed were found unacceptable.

The review’s regulatory history lists development under an IND from March 2013, Fast Track designation (May 21, 2013), Orphan Drug designation (March 10, 2014, amended November 9, 2017) and Breakthrough Therapy designation (October 8, 2015). The application was submitted in parts between May 3, 2021 and November 30, 2021, filed on January 28, 2022, and acted on by its due date of November 30, 2022. Because the product has an orphan designation for this use, the approval letter states that the application is exempt from the Pediatric Research Equity Act requirement to study children.

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6. The Trial Evidence and How the FDA Weighed It

The review lists three Phase 2 studies, two Phase 3 studies and one retrospective study, conducted in the United States and Canada. A total of 978 adults with documented recurrent C. difficile infection received at least one dose across the five prospective studies; 67.2% were female, 93.8% were white, and 78.5% had had at least three previous episodes. The package insert adds that the median age was 64 years and that 48.8% were 65 or older.

The main analysis. Because of enrollment difficulties, the review explains, the applicant ran a single placebo-controlled Phase 3 trial and analyzed it with a Bayesian statistical model that formally borrowed information from an earlier placebo-controlled Phase 2 trial. A Bayesian analysis expresses its result as a probability that the treatment is better than placebo, given the data. In the Phase 3 trial, 262 adults were randomized and treated: 177 received one dose of the product and 85 received placebo. Treatment success was defined as no C. difficile diarrhea for 8 weeks after treatment.

The package insert reports the result:

• Estimated treatment success: 70.6% with the product and 57.5% with placebo.
• Difference: 13.1 percentage points (95% credible interval 2.3 to 24.0).
• Posterior probability that the product is superior to placebo: 0.991, against a pre-defined threshold of 0.975.

Which bar it cleared. The trial had two pre-specified success thresholds, a stricter posterior probability of 0.9993 and a less strict one of 0.9750. The review states that the results “met the second success threshold” but “did not meet the more stringent first success threshold.” It records that before the analysis, the FDA had concluded that meeting the first threshold would be sufficient to show substantial evidence of effectiveness. When only the second was met, the FDA considered whether the trial and the supporting open-label studies were still enough, weighing four points: recurrent infection is a serious condition; treatment options are limited; placebo-controlled FMT trials were hard to enroll while other FMT products were available under enforcement discretion; and the success rate seen was similar to that in the open-label studies and in randomized trials of other FMT products. After the advisory committee meeting (section 8), the review team concluded that the data show substantial evidence of effectiveness for the licensed use.

Longer follow-up. The package insert also reports “sustained clinical response,” meaning success at 8 weeks and no further C. difficile episode through 6 months. That difference, 65.5% versus 56.5% (9.1 percentage points; 95% confidence interval −3.6 to 21.7), “was not statistically significant.”

Who was studied. The package insert notes that the two controlled trials excluded people with celiac disease, inflammatory bowel disease, irritable bowel syndrome and chronic diarrhea, and that people with food allergies were not excluded from any of the five studies. It states that the data are not sufficient to tell whether adults 65 and older respond differently from younger adults.

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7. Side Effects and Label Warnings

Common side effects. In the Phase 3 trial, the adverse reactions reported by at least 3% of recipients, and more often than with placebo, within 8 weeks were:

• abdominal pain: 8.9% (placebo 6.9%)
• diarrhea: 7.2% (placebo 3.4%)
• abdominal distension: 3.9% (placebo 2.3%)
• flatulence: 3.3% (placebo 0)
• nausea: 3.3% (placebo 1.1%)

The label states that most occurred in the first 2 weeks, that most were mild to moderate, and that no life-threatening adverse reaction was reported.

Serious events. In a pooled analysis of the five studies, 10.1% (60 of 595) of single-dose recipients and 7.2% (6 of 83) of placebo recipients reported a serious adverse event within 6 months; the label states that none was considered related to the product. The review describes imbalances in gastrointestinal events and in serious adverse events, including deaths (1.2% in the one-dose group versus 0% with placebo), and notes that rates rose with the number of doses received. It reports that the FDA, after reviewing the individual cases, did not identify a serious event or a death it considered caused by the product, and it gives reasons the comparison is hard to read: many doses were open-label, sicker placebo recipients crossed over to the product after a recurrence, and people given several doses were followed for longer.

Warnings and precautions in the label:

• Transmissible infectious agents. “Because [the product] is manufactured from human fecal matter it may carry a risk of transmitting infectious agents.”
• Acute allergic reactions. Appropriate medical treatment must be immediately available in case of an acute anaphylactic reaction. Severe allergic reaction to a product component is a contraindication.
• Food allergens. The product “may contain food allergens,” donors have no dietary restrictions with respect to potential food allergens, and “The potential for [the product] to cause adverse reactions due to food allergens is unknown.”

Other label statements. The product is not absorbed into the bloodstream after rectal use, and the label states that use in pregnancy is not expected to expose the fetus and breastfeeding is not expected to expose the child. Safety and effectiveness under 18 have not been established. The patient counseling section asks that patients be told the product may contain food allergens, that they tell their physician if persistent diarrhea returns, and that oral antibiotics are not to be taken for up to 8 weeks after the dose unless their physician directs it. Decisions about any treatment for recurrent C. difficile belong with a clinician.

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8. The Advisory Committee Meeting of September 22, 2022

The FDA’s Vaccines and Related Biological Products Advisory Committee, a panel of outside experts, met on September 22, 2022 to discuss the application. The review summarizes the discussion:

• Members noted that available therapies are not sufficient for patients with recurrent infection, “especially in patients who experience three or more recurrences.”
• They noted “the modest treatment effect” in each of the two placebo-controlled trials, but “acknowledged that even a modest treatment effect could be clinically meaningful” for patients who had not responded to other treatments.
• Some members were concerned about “the statistical robustness” of the Phase 3 result given the limited number of patients; others, citing the difficulty of recruiting while FMT was available under enforcement discretion, found the results sufficiently persuasive.
• Members said an FDA-approved product “would represent an improvement over unlicensed FMT products that are currently available under enforcement discretion.”
• Some were concerned about the imbalance in serious adverse events, while acknowledging the FDA had found no clear basis for a causal link.
• The committee was concerned about “the lack of diversity in participant enrollment because very few people of color were included in the trials,” and encouraged further studies in more diverse groups.
• There was “broad consensus” that, if the product were approved, postmarketing evaluation of safety and effectiveness “would be critical.”

The review states that a “substantial majority” of committee members gave a positive recommendation that the clinical data were adequate to support effectiveness. An advisory committee’s view is advice; the licensing decision is the FDA’s.

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9. Safety Monitoring After Licensure

The review and the approval letter describe what follows the license:

• Expedited reports. For 3 years after licensure, the manufacturer must report every serious adverse event to the FDA Adverse Event Reporting System as a 15-day expedited report, regardless of whether it was expected.
• Periodic reports. Quarterly periodic safety reports for 3 years, then annual reports, with aggregate analyses of serious events and of any adverse event in people treated while pregnant or breastfeeding, in people under 18 and in people with weakened immune systems.
• A planned surveillance study. The applicant plans a voluntary general safety surveillance study using a claims-based database to compare outcomes with comparator treatments.
• No REMS. The review states that the available data “do not suggest any safety signals that warrant a Risk Evaluation and Mitigation Strategy or safety-related postmarketing requirement study.” A REMS is a special FDA-required safety program for some higher-risk medicines.
• Manufacturing changes and deviations. Changes to manufacturing, testing, packaging or labeling need FDA review and written approval, and certain manufacturing deviations must be reported.

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10. What the Two Actions Do Not Do

• The license does not cover treating an active infection. The label’s limitation of use reads: “not indicated for treatment of CDI.” It is for preventing a recurrence after antibiotic treatment of recurrent infection.
• It does not cover children. The indication is for people 18 and older; safety and effectiveness under 18 have not been established.
• It does not cover a first episode. The indication is for people who have had recurrent infection.
• The enforcement policy does not approve fecal transplants. FMT used under the policy remains investigational, and the consent the policy describes says so.
• The policy does not reach other conditions. It concerns C. difficile infection not responding to standard therapies only.
• Neither action concerns probiotic supplements. The licensed product is a prescription biological product given rectally; the site’s Probiotics page covers foods and supplements.

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11. Dates and Legal Status as of October 18, 2026

• July 2013: the FDA’s earlier guidance on enforcement discretion for FMT to treat C. difficile.
• March 2016: draft guidance on the same subject.
• May 3 to November 30, 2021: the biologics license application is submitted in parts.
• January 28, 2022: the application is filed.
• September 22, 2022: the advisory committee meets.
• November 29, 2022: the final enforcement policy is announced (87 FR 73313; Docket No. FDA-2013-D-0811), finalizing the 2016 draft and superseding the 2013 guidance.
• November 30, 2022: the FDA licenses fecal microbiota, live-jslm (BLA STN 125739).

Status as of October 18, 2026: license in effect; final guidance in place. A check of the Federal Register for “fecal microbiota” from January 1, 2023 through October 18, 2026, made on October 18, 2026 during the research for this page, returned only patent-term notices (June 16 and July 2, 2025); no FDA document withdrawing or changing the license or the 2022 guidance was found. A guidance document describes how the FDA intends to apply the law; it does not itself create new legal requirements.

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12. How It Fits Other FDA Actions

The license is one of several FDA actions on products made of, or containing, live microbes. In 2023 the FDA warned that probiotics given to preterm infants can cause fatal infections. Like that warning, the label warnings for fecal microbiota, live-jslm center on what live organisms from outside the body can carry.

Among the other FDA actions of 2022, other drug and biologic decisions include the approval of tirzepatide for type 2 diabetes, the approval of an oral combination drug for ALS, which was later withdrawn, and the approval of teplizumab to delay type 1 diabetes.

The wider background on the gut’s microbes is on the site’s Gut Health page, and the full list of the year’s actions is on the FDA Actions of 2022 hub.

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13. Primary Documents

1. Food and Drug Administration, HHS (2022). Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation To Treat Clostridioides difficile Infection Not Responsive to Standard Therapies; Guidance for Industry; Availability. Notice of availability. Federal Register 87 FR 73313, November 29, 2022. Docket No. FDA-2013-D-0811 — FR Doc. 2022-26000
2. U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. Approval letter, BLA STN 125739/0, fecal microbiota, live-jslm. November 30, 2022 — fda.gov approval letter (PDF)
3. U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. Summary Basis for Regulatory Action, BLA STN 125739/0. November 30, 2022 — fda.gov Summary Basis for Regulatory Action (PDF)
4. U.S. Food and Drug Administration. Prescribing information (package insert), fecal microbiota, live-jslm, suspension for rectal use — fda.gov package insert (PDF)
5. U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. Product page for fecal microbiota, live-jslm (STN 125739), on fda.gov under Vaccines, Blood & Biologics. Its web address carries the brand name, so it is not linked here.
6. Public docket FDA-2013-D-0811 — regulations.gov FDA-2013-D-0811

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Key Research Papers

1. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ (2013). Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368(5):407-415 — PubMed PMID: 23323867
2. Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, Weese JS, Collins S, Moayyedi P, Crowther M, Ropeleski MJ, Jayaratne P, Higgins D, Li Y, Rau NV, Kim PT (2016). Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA 2016;315(2):142-149 — PubMed PMID: 26757463
3. Kelly CR, Khoruts A, Staley C, Sadowsky MJ, Abd M, Alani M, Bakow B, Curran P, McKenney J, Tisch A, Reinert SE, Machan JT, Brandt LJ (2016). Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med 2016;165(9):609-616 — PubMed PMID: 27547925
4. Hota SS, Sales V, Tomlinson G, Salpeter MJ, McGeer A, Coburn B, Guttman DS, Low DE, Poutanen SM (2017). Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial. Clin Infect Dis 2017;64(3):265-271 — PubMed PMID: 28011612
5. Hvas CL, Dahl Jørgensen SM, Jørgensen SP, Storgaard M, Lemming L, Hansen MM, Erikstrup C, Dahlerup JF (2019). Fecal Microbiota Transplantation Is Superior to Fidaxomicin for Treatment of Recurrent Clostridium difficile Infection. Gastroenterology 2019;156(5):1324-1332.e3 — PubMed PMID: 30610862
6. Guh AY, Mu Y, Winston LG, Johnston H, Olson D, Farley MM, Wilson LE, Holzbauer SM, Phipps EC, Dumyati GK, Beldavs ZG, Kainer MA, Karlsson M, Gerding DN, McDonald LC; Emerging Infections Program Clostridioides difficile Infection Working Group (2020). Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes. N Engl J Med 2020;382(14):1320-1330 — PubMed PMID: 32242357
7. Kelly CR, Fischer M, Allegretti JR, LaPlante K, Stewart DB, Limketkai BN, Stollman NH (2021). ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Am J Gastroenterol 2021;116(6):1124-1147 — PubMed PMID: 34003176
8. Johnson S, Lavergne V, Skinner AM, Gonzales-Luna AJ, Garey KW, Kelly CP, Wilcox MH (2021). 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. Clin Infect Dis 2021;73(5):e1029-e1044 — PubMed PMID: 34164674

All eight papers are cited in the FDA’s Summary Basis for Regulatory Action for the licensed product. The first five are randomized trials of fecal microbiota transplantation for recurrent C. difficile infection; the review cites them as trials of other FMT products whose success rates were similar to the one seen in the Phase 3 trial. The sixth is the U.S. surveillance study the review cites for trends in the infection’s burden, and the last two are the U.S. practice guidelines it cites for treatment options.

PubMed Topic Searches

1. PubMed: fecal microbiota transplantation for recurrent C. difficile
2. PubMed: live biotherapeutics to prevent C. difficile recurrence
3. PubMed: FMT donor screening and safety

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Connections

• FDA Actions of 2022
• FDA and Regulation
• Clostridioides difficile Infection
• Clostridium difficile (C. diff)
• Bacterial Illnesses
• Gut Health
• Gastroenterology
• Probiotics
• Probiotics in Preterm Infants Warning (2023)
• Tirzepatide for Type 2 Diabetes (2022)
• ALS Drug Approval, Later Withdrawn (2022)
• Teplizumab to Delay Type 1 Diabetes (2022)

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