Tag Archives: C. difficile and FMT

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

Fecal Microbiota Transplantation – Regulatory Harmonization Is Lacking

 

 

 

Abstract

During faecal microbiota transplantation, stool from a healthy donor is transplanted to treat a variety of dysbiosis-associated gut diseases.

Competent authorities are faced with the challenge to provide adequate regulation. Currently, regulatory harmonization is completely lacking and authorities apply non-existing to most stringent requirements.

A regulatory approach for faecal microbiota transplantation could be inserting faecal microbiota transplantation in the gene-, cell- and tissue regulations, including the hospital exemption system in the European Advanced Therapy Medicinal Products regulation, providing a pragmatic and efficacy-risk balanced approach and granting all patients as a matter of principle access to this therapy.

https://www.ncbi.nlm.nih.gov/pubmed/29179687?dopt=Abstract&utm_source=dlvr.it&utm_medium=twitter

Fecal Microbiota Transplantation From A Donor To Treat Recurrent C.difficle Infection

Fecal microbiota transplantation (FMT) from a donor (heterologous) to treat recurrent Clostridium difficile infection (CDI) is safe and more effective than self (autologous) transplantation, according to data from a randomized controlled, double-blind clinical trial.

However, the results, published online August 23 in the Annals of Internal Medicine, also show that the treatment success rate in the control group varied substantially between two study locations, which suggests there are subtleties not yet understood with the approach.

The efficacy of FMT using donor stool to treat recurrent CDI has made headlines, but so far it has largely been tested only in open-label clinical trials and case series.

 

To complement these studies, Colleen R. Kelly, MD, from the Women’s Medicine Collaborative, The Miriam Hospital, Providence, Rhode Island, and coworkers enrolled 46 patients who had had at least three recurrences of CDI and who were treated with vancomycin for the most recent infection and randomly assigned them to receive donor or self stool preparations by colonoscopy.

The researchers assessed adverse events for 6 months after FMT, defining efficacy as cessation of diarrhea without the need for further antibiotics during the 8 weeks after the intervention. All stool was subject to microbiota analysis before and after FMT.

Twenty of the 22 patients in the donor FMT group (90.9%; 95% confidence interval [CI],69.2% – 97.8%) were clinically cured compared with

15 of the 24 (62.5%; 95% CI, 41.6% – 79.6%) patients who received self FMT (P = .042).

The nine patients who developed CDI after self FMT were then given donor FMT and were cured.

Microbiome analysis revealed no improvement in gut microbial diversity after self FMT, but restoration of a normal microbiota with donor FMT, including increases in Bacteroidetes and Firmicutes and decreases in Proteobacteria and Verrucomicrobia populations.

An unexpected finding was that patients treated autologously at Montefiore Medical Center in the Bronx, New York had a much higher cure rate than those treated autologously at The Miriam Hospital in Providence. Specifically, for Rhode Island, cure rate with donor FMT was 90.0% (CI, 51.8% – 98.7%) vs 42.9% (CI, 20.1% – 69.0%) with self FMT. For New York, cure rate with donor FMT was 91.7% (CI, 57.2% – 98.9%) compared with 90.0% (CI, 51.8% – 98.7%) with self FMT.

The researchers list clinical differences among the patients at the two sites that could explain the different responses to self FMT:

  • NY patients were infected longer, had more recurrences, and had more courses of fidaxomicin than did Rhode Island patients.
  • NY patients waited longer to be treated and took antibiotics longer before entering the study, and may have been cured at that time.
  • Fecal microbiomes among NY patients had more Clostridia species, which may have occupied niches for C difficile.

Limitations of the study include lack of inclusion of baseline antibody titers and infection severity, small sample size attributed partly to unwillingness of participants to risk assignment to the autologous group, and nonuniform stool doses. In addition, the researchers mention that some patients may be infected according to polymerase chain reaction (PCR)-based identification of the pathogen, but be asymptomatic, and that some patients may have diarrhea resulting from undiagnosed irritable bowel syndrome but also be infected with C difficile, according to PCR testing.

In an accompanying editorial, Elizabeth L. Hohmann, MD, from Massachusetts General Hospital in Boston, points out another limitation, that “the population enrolled in this trial was younger (mean age, 50 years) and seemed healthier and more adventurous than most patients with recurrent CDI.” In contrast, about 60% of her patients with whom she discusses FMT are older than 60 years, and 30% are older than 75 years. However, the investigators had to recruit patients younger than 75 years to comply with FDA regulations to consider FMT as an investigational new drug.

No serious adverse events were reported. The researchers conclude, “FMT using fresh donor stool administered via colonoscopy after a course of vancomycin was effective at preventing further CDI episodes in patients with multiply recurrent infection.” They call for additional investigation to identify types of patients most likely to benefit from FMT using donor stool.

Dr Hohmann regards the differing response rates to autologous FMT at the two study sites as instructive, underscoring the value of conducting a rigorous controlled trial even when the tested technology has proven itself in other types of investigations. “Their results prompt us to ask again whether microbial manipulation has any as-yet unappreciated health benefits or risks and whether there are preferred microbiomes for specific human populations or locales,” she concludes.

To read this article in its entirety:

http://www.medscape.com/viewarticle/867727?nlid=108986_2981&src=wnl_dne_160823_mscpedit&uac=206986BK&impID=1183588&faf=1