Stronger Trials Needed to Understand FMT Risks, Benefits

April 24, 2020

Before undergoing fecal microbiota transplant, “patients deserve risk mitigation, which can be accomplished with thorough vetting and regulation,” the authors of a new paper wrote.

Patients could be better informed of potential benefits and risks of fecal microbiota transplant (FMT) through more high quality trials examining safety and efficacy, according to a paper published in Open Forum Infectious Diseases.

A multifaceted team of investigators conducted a meta-analysis in order to outline the current knowledge surrounding FMT. They asked and answered questions posed by the literature in their paper, including highlighting the gaps in clinical evidence and improvements needed for therapeutic options for patients to mitigate risk.

First, the authors discussed why antibiotics typically fail in Clostridium difficile (C diff) treatments. While exposure to broad-spectrum antibiotics is a risk factor for primary infection, recurrence is common in those with a history of more than 2 episodes. High rates of treatment failure—though not fully understood—can be linked to the way antibiotics cause change in the compositional and functional microbiome. Microbiome recovery is essential for clinical resolution and without effective antibiotics, this cannot take place.

FMT has emerged as a treatment for C diff but warrants further investigation. The Infectious Diseases Society of America/Society for Healthcare Epidemiology of America guidelines suggest FMT for recurrent C diff, but say there is only “moderate quality” evidence. The study authors went on to describe the limitations of this moderate quality evidence and how to remedy the situation: design quality studies of FMT, select diagnostic assays for C diff, using placebo arms when evaluating interventions, and the like.

Using a placebo arm provides information that cannot be obtained any other way. In one paper that the authors cited, rates of clinical resolution were 90% in both the intervention and placebo arms.

This raised concerns that patients may not have had true recurrent C diff at baseline, which the original authors acknowledged.

The authors also outlined the gaps in understanding the safety risks of FMT, though most experts believe it is safe based on uncontrolled trials that did not include placebo controls. In fact, one systematic review of adverse events following FMT noted potential underreporting because many studies did not report any adverse events, the investigators wrote.

In the largest FMT trial, the investigators found, 219 patients were randomized to receive fresh or frozen FMT via enema, though there were 6 deaths in the frozen arm and 11 in the fresh arm. However, the authors of that paper attributed none of the deaths to FMT.

Clinical trials can make connections between FMT and adverse events, the paper authors suggested. They recommend that future trials can be best understood by placebo-controlled trials that include a sufficient number of patients and adequate follow up periods.

The investigators wrote that the health care community could wind up with unintended consequences without adequate double blind, placebo-controlled trials. They warned that providers learned painful lessons regarding plasma-derived factors to treat hemophilia when that treatment unknowingly transmitted HIV.

“Patients deserve risk mitigation, which can be accomplished with thorough vetting and regulation,” the paper authors concluded.

“Mandatory screening guidelines for stool donors are urgently needed, although screening cannot prevent unanticipated emerging infections. Finally, the development of investigational microbiome therapeutics with defined microbial consortia will offer greater confidence in drug purity, identity and potency, in addition to risk mitigation for improved patient safety.”