Category Archives: Fecal Microbiota Transplant (FMT)

FDA Publishes Additional Safety Protections For Use of Fecal Microbiota for Transplantation (FMT): Testing Donor Stool for Enteropathogenic Escherichia coli (EPEC) and Shigatoxin-producing Escherichia coli (STEC)

On April 6, 2020 the following publication was released by the US Food and Drug Administration (FDA):

 

 

Information Pertaining to Additional Safety Protections Regarding Use of Fecal Microbiota for Transplantation — Testing of Stool Donors for Enteropathogenic Escherichia coli and Shigatoxin-Producing Escherichia coli

On March 12, 2020, The Food and Drug Administration (FDA) informed health care providers and patients of the potential risk of serious or life-threatening infections with the use of fecal microbiota for transplantation (FMT).  Infections caused by enteropathogenic Escherichia coli (EPEC) and Shigatoxin-producing Escherichia coli (STEC) have occurred following investigational use of FMT for treatment of Clostridium difficile (also called Clostridioides difficile or C. difficile) infection not responsive to standard therapies. FDA suspects these infections are due to transmission of these pathogenic organisms from FMT product supplied by a stool bank company based in the United States.

After the release of FDA’s March 12, 2020, Safety Alert, the stool bank company publicly acknowledged FDA’s safety communication, so we are now identifying the stool bank as OpenBiome, a company based in Cambridge, Massachusetts.

Because of these serious adverse events that occurred with investigational FMT, FDA has determined that additional protections are needed for any investigational use of FMT, whether under an Investigational New Drug Application (IND) on file with the FDA or under FDA’s enforcement discretion policy.

FDA has already communicated with OpenBiome and individually with IND holders for investigational FMT to underscore the need for additional protections.

These additional protections include:

  1. Testing FMT donor stool by nucleic acid amplification tests (NAAT) for EPEC and STEC to exclude use of stool that tests positive for either EPEC or STEC.
    • Testing of stool from each donor before and after multiple stool donations, no more than 60 days apart; and, as applicable, quarantining FMT product lots manufactured from these donations until both pre- and post-donation EPEC and STEC tests are confirmed negative.
  2. Testing of all FMT products currently in storage for which the donor has not undergone stool testing for both EPEC and STEC using NAAT as described above.
    • Until this testing is able to be completed, placing those FMT products in quarantine until they have been tested using NAAT and found negative for EPEC and STEC.
    • In the case of FMT products manufactured using pooled donations from a single donor, performing stool testing on individual stool samples (not pooled) within the testing window described above for a given lot of FMT product.

Patients considering FMT to treat C. difficile infection should speak to their health care provider to understand the potential risks associated with the product’s use.

FDA encourages all health care providers who have administered FMT products to their patients to report suspected adverse events to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

Additional Resources:

Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Events Likely Due to Transmission of Pathogenic Organisms – March 12, 2020

Update to March 12, 2020 Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Events Likely Due to Transmission of Pathogenic Organisms – March 13, 2020

 

The Food and Drug Administration (FDA) Informs Health Care Providers and Patients of the Potential Risk of Transmission of SARS-CoV-2 Virus and COVID-19 By the Use of Fecal Microbiota for Transplantation (FMT)

The global public health community is responding to a rapidly evolving pandemic of respiratory disease caused by a novel coronavirus that was first detected in China.

 

The virus has been named “SARS-CoV-2” and the disease it causes has been named “COVID-19.”

The Food and Drug Administration (FDA) is informing health care providers and patients of the potential risk of transmission of SARS-CoV-2 virus by the use of fecal microbiota for transplantation (FMT) and that FDA has determined that additional safety protections are needed.

Summary of the Issue

Several recent studies have documented the presence of SARS-CoV-2 ribonucleic acid (RNA) and/or SARS-CoV-2 virus in stool of infected individuals.1,2,3 This information suggests that SARS-CoV-2 may be transmitted by FMT, although the risk of such transmission is unknown.4 At this time, testing nasopharyngeal specimens from stool donors for SARS-CoV-2 may not be widely available. Furthermore, there is limited information on the availability and sensitivity of direct testing of stool for SARS-CoV-2.

Additional Protections for the Use of FMT

At this time, FDA is advising that clinical use of FMT has the potential to transmit SARS-CoV-2, whether used as part of a study under an Investigational New Drug Application (IND) on file with the FDA or under FDA’s enforcement discretion policy. To address the risk, stool used for FMT should have been donated before December 1, 2019. Due to the potential for serious adverse events to occur, FDA has determined that the following protections are needed for any use of FMT that is found to be necessary for clincal care if it involves stool donated after December 1, 2019:

  • Donor screening with questions directed at identifying donors who may be currently or recently infected with SARS-CoV-2;
  • Testing donors and/or donor stool for SARS-CoV-2, as feasible;
  • Development of criteria for exclusion of donors and donor stool based on screening and testing; and
  • Informed consent that includes information about the potential for transmission of SARS-CoV-2 via FMT, including FMT prepared from stool from donors who are asymptomatic for COVID-19.

Actions

FDA is in the process of notifying IND holders of the potential risk of transmission of SARS-CoV-2 via FMT and of FDA’s determination that additional safety protections that are needed.

FDA is communicating this information with this statement to all other stakeholders to ensure that everyone is fully informed.

As the scientific community learns more about SARS-CoV-2 and COVID-19, FDA will provide further information as warranted.

Information for Health Care Providers and Patients on Enforcement Discretion

In July 2013, FDA issued a guidance document stating that it intends to exercise enforcement discretion under limited conditions regarding the IND requirements for the use of FMT products to treat C. difficile infection in patients that have not responded to standard therapies. The guidance states that FDA intends to exercise enforcement discretion provided that the treating physician obtains adequate consent for the use of FMT from the patient or his or her legally authorized representative. The consent should include, at a minimum, a statement that the use of FMT to treat C. difficile is investigational and a discussion of its potential risks.

Reporting Adverse Events

FDA encourages all health care providers and patients to report any suspected adverse events or side effects related to the administration of FMT products to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

 


1 Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H, Evidence for gastrointestinal infection of SARS-CoV-2, Gastroenterology (2020), doi: https://doi.org/10.1053/j.gastro.2020.02.055External Link Disclaimer
2 Tang A, Tong Z-d, Wang H-l, Dai Y-x, Li K-f, Liu J-n, et al. Detection of novel coronavirus by RT-PCR in stool specimen from asymptomatic child, China. Emerg Infect Dis. (2020), https://doi.org/10.3201/eid2606.200301External Link Disclaimer from https://wwwnc.cdc.gov/eid/article/26/6/20-0301_article
3 Wang, W, Xu, Y, Gao, R, et al., Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA (2020), https://doi.org/10.1001/jama.2020.3786External Link Disclaimer
4 Gu J, Han B, Wang J, COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission, Gastroenterology (2020), doi: https://doi.org/10.1053/j.gastro.2020.02.054

US Food and Drug Administration (FDA) Issued a Safety Alert About Potential Risks of Serious, Even Life-Threatening Infections Linked To Fecal Microbiota Transplantation (FMT)

The US Food and Drug Administration (FDA) yesterday issued a safety alert about the potential risk of serious, even life-threatening, infections linked to fecal microbiota transplantation (FMT) after six patients were infected with diarrhea-causing Escherichia coli following the procedure.  March 13, 2020

According to the alert, two patients developed enteropathogenic E coli (EPEC) infections, and four developed Shiga toxin–producing E coli (STEC), after receiving FMT for Clostridoides difficile infection. Four of the six patients required hospitalization.

“FDA is informing patients and healthcare providers of the potential risk of transmission of pathogenic bacteria by FMT products and the resultant serious adverse reactions that may occur,” the agency said. “Patients considering FMT for the treatment of C. difficile infection should speak to their health care provider to understand the associated risks.”

STEC is a pathogenic form of E coli that causes abdominal pain, bloody diarrhea, vomiting, and mild fever. EPEC generally doesn’t cause any symptoms, but some strains can cause diarrhea.

Change in screening protocols

The stool used in the procedures all came from Boston-based OpenBiome, the country’s largest stool bank. The company said in a press release yesterday that the cases are the first reports of likely transmission of pathogens by FMT involving stool that came from OpenBiome, which has shipped more than 50,000 FMT treatments to physicians since 2013.

The patients who developed the infections received FMT product prepared from three OpenBiome donors. The two patients who developed EPEC infections were treated with stool from two donors, and the six STEC patients received stool from one donor. OpenBiome says all unused material from the donors has been destroyed.

The FDA says bacterial isolates from the patients’ stools are not yet available to determine if the STEC or EPEC organisms are genetically identical to the organisms from the stool donors—a finding that would confirm that the donor stool was the source of the infection.

In response to the safety alert, OpenBiome says it is immediately implementing changes to its screening program in collaboration with the FDA.

While the company has previously screened donor samples for STEC via enzyme immunoassay, and says the donor involved in the STEC cases tested negative at all screens, OpenBiome will add polymerase chain reaction (PCR) testing for STEC to its screening process. PCR tests on retained donor samples conducted after Openbiome was notified of the infections were found to be positive for STEC.

The retained stool samples from the donors linked to the EPEC infections were found to be positive for EPEC upon further testing from OpenBiome. The company says it has not previously screened donors for EPEC, a position based on international and national guidelines, but will immediately implement EPEC screening by PCR into its donor screening protocol.

“In addition to updating and implementing STEC and EPEC screening into our quality and safety protocols, OpenBiome is also working with FDA to implement retrospective screening of units to ensure that available material meets these new standards,” the company said.

After reporting the infections to the FDA, OpenBiome received information that two additional FMT recipients who received stool from the donor linked to the STEC infections had died. The company said in an update today that the treating clinician for one of the patients determined that the patient had died from underlying cardiac causes, and testing for STEC was not performed. In the second case, testing of donor material was negative for STEC.

“Therefore, it was determined that the death was unrelated to STEC,” the company said.

FMT safety issues

FMT has been found in several studies to be a highly effective treatment for recurrent C difficile infections that aren’t responding to antibiotics, and at least 10,000 FMT procedures for recurrent C difficile are performed each year. FMT is also being investigated for treating other conditions in more than 300 trials.

The idea behind the procedure is to introduce healthy bacteria from a donor into the gut microbiome of a sick recipient and restore the balance between good and bad bacteria.

But this is the second safety alert issued by the FDA regarding FMT. In June 2019, the agency warned of the potential for dangerous infections after two FMT patients developed drug-resistant bloodstream infections and one died, and the agency halted a number of FMT trials until additional screening measures could be put in place. A subsequent paper in the New England Journal of Medicine revealed that the two patients, both of whom were enrolled in clinical trials at Massachusetts General Hospital in Boston, had extended-spectrum beta-lacatamase (ESBL)-producing E coli in their blood.

The two patients had both received stool from Mass General that came from the same donor. While the hospital had screened the stool for C difficile and the presence of drug-resistant pathogens by the hospital, it had not screened it for ESBL-producing E coli. The authors of the paper could not conclusively attribute the infections to FMT, but suspected the patients likely acquired the pathogen from the procedure.

RESOURCE:  http://www.cidrap.umn.edu/news-perspective/2020/03/fda-warns-about-infections-linked-fecal-microbiota-transplants?utm_source=dlvr.it&utm_medium

 

 

On June 13th the U.S. Food and Drug Administration Warned of Infections From Fecal Microbiota Transplantation (FMT) Linked to a Patient’s Death

Dr. Peter Marks, director the Center for Biologics Evaluation and Research at the U.S. Food and Drug Administration stated, “While we support this area of scientific discovery, it’s important to note that fecal microbiota for transplantation does not come without risk,”

Two patients contracted severe infections, and one of them died, from fecal transplants that contained drug-resistant bacteria.

The agency said two patients received donated stool that had not been screened for drug-resistant germs, leading it to halt clinical trials until researchers prove proper testing procedures are in place.

After reports of serious, antibiotic-resistant infections linked to the procedures, the FDA wants “to alert all health care professionals who administer FMT [fecal microbiota transplant] about this potential serious risk so they can inform their patients.” said Dr. Peter Marks, director the Center for Biologics Evaluation and Research at the U.S. Food and Drug Administration.

Other samples from the same donor were tested after the patients got sick. The samples were found to harbor the same dangerous germs found in the patients, known as multi-drug-resistant organisms (MDRO). They were E. coli bacteria that produced an enzyme called extended-spectrum beta-lactamase, which makes them resistant to multiple antibiotics. The stool had not been tested for the germs before being given to the patients.

The F.D.A. on Thursday issued a warning to researchers that stool from donors in studies of fecal transplantation should be screened for drug-resistant microbes, and not used if those were present. It is also warning patients that the procedure can be risky, is not approved by the agency and should be used only as a last resort when C. difficile does not respond to standard treatments.

Dr. Marks said the agency was trying to strike a balance between giving patients who need the treatment access to it while also establishing safeguards to protect them from infection. In a statement, he said, “While we support this area of scientific discovery, it’s important to note that fecal microbiota for transplantation does not come without risk.”

Researchers are also looking into the use of fecal transplants to treat chronic gastrointestinal illnesses such as ulcerative colitis or irritable bowel syndrome.

The patients received treatment as part of a clinical trial, and the researchers conducting the trial reported the cases as adverse events to the F.D.A., which they are required to do. But the rules governing this kind of experiment prohibit the F.D.A. from revealing details about the treatment or who provided it.

 

SOURCE:  https://www.nytimes.com/2019/06/13/health/fecal-transplant-fda.html

FDA Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Reactions d/t Multi-drug Resistant Organisms

Important Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms

The Food and Drug Administration (FDA) is informing health care providers and patients of the potential risk of serious or life-threatening infections with the use of fecal microbiota for transplantation (FMT).  The agency is now aware of bacterial infections caused by multi-drug resistant organisms (MDROs) that have occurred due to transmission of a MDRO from use of investigational FMT.

Summary of the Issue

  • Two immunocompromised adults who received investigational FMT developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E.coli). One of the individuals died.
  • FMT used in these two individuals were prepared from stool obtained from the same donor.
  • The donor stool and resulting FMT used in these two individuals were not tested for ESBL-producing gram-negative organisms prior to use. After these adverse events occurred, stored preparations of FMT from this stool donor were tested and found to be positive for ESBL-producing E. coli identical to the organisms isolated from the two patients.

Information for Health Care Providers and Patients

In July 2013, FDA issued guidance stating that it intends to exercise enforcement discretion under limited conditions regarding the IND requirements for the use of FMT to treat Clostridium difficile (C. difficile) infection in patients who have not responded to standard therapies. The guidance states that FDA intends to exercise enforcement discretion provided that the treating physician obtains adequate consent for the use of FMT from the patient or his or her legally authorized representative. The consent should include, at a minimum, a statement that the use of FMT to treat C. difficile is investigational and a discussion of its potential risks. FDA is informing members of the medical and scientific communities and other interested persons of the potential risk of transmission of MDROs by FMT and the resultant serious adverse reactions that may occur.

Patients considering FMT to treat C. difficile infection should speak to their health care provider to understand the potential risks associated with the product’s use.

Additional Protections for Investigational Use of FMT

  • Because of these serious adverse reactions that occurred with investigational FMT, FDA has determined that the following protections are needed for any investigational use of FMT:
    • Donor screening with questions that specifically address risk factors for colonization with MDROs, and exclusion of individuals at higher risk of colonization with MDROs.
    • MDRO testing of donor stool and exclusion of stool that tests positive for MDRO. FDA scientists have determined the specific MDRO testing and frequency that should be implemented.

Reporting Adverse Event

FDA encourages all health care providers administering FMT products to report suspected adverse events to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

June 13, 2019