In June, after a patient died and another was sickened from a fecal transplant that contained drug-resistant bacteria, the Food and Drug Administration stepped in and set new guidelines for the procedure.
The guidelines specified that both donors and their stool should be screened for the presence of “multidrug-resistant organisms.” They were included in an alert issued by the agency stating that the two patients who got sick had weakened immune systems, and that the donor stool they received had not been tested for the specific superbug that made them ill.
But no additional information on the cases was provided, such as how the stool was processed, how it was given to the patients or what it was being used to treat.
The announcement raised more questions than it answered. Chief among them: What happened, exactly, in the two cases? And, given the increasing threat posed by drug-resistant bacteria, why weren’t these guidelines already in place?
To the frustration of many doctors, the FDA has remained mum on the details of the cases. Beyond the short safety alert, the agency hasn’t provided additional information, presumably because the patients were part of a clinical trial, which meant the information was privileged.
As for the question of why there had been no guidelines, that requires a look back at the long history of the procedure.
Fecal transplants’ history
Until several years ago, fecal microbiota transplants, or FMTs, were completely unregulated. The procedures were considered to fall under the heading of “practice of medicine,” a rubric that allows doctors to use treatments that haven’t been approved and might not even have a very long track record.
But FMTs do, in fact, have a long track record. As far back as the 1950s, doctors in the United States started transplanting stool from healthy donors into patients with life-threatening diarrhea caused by infection with a nasty bacterium named C. difficile. The transplants worked, and the patients got better.
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The reason for the procedure’s success is what led the patients to get sick in the first place: All had a history of extensive antibiotic treatments.
“Doctors reasoned that the problem was that antibiotics had killed the normal microbes residing in the intestine and that somehow disrupted the normal ecosystem there, which allowed bad bacteria to flourish,” said Dr. Alexander Khoruts, a gastroenterologist and professor of medicine at the University of Minnesota. “They thought, maybe that could be reversed by adding [gut bacteria] from healthy people through enemas. It worked spectacularly well.”
Word of the treatment’s success started to spread and doctors around the country began to use the technique, even though there weren’t any clinical trials to prove its worth.
That changed in January 2013 when a study published in the New England Journal of Medicine showed that FMT was so effective for treating C. diff that the researchers had to stop enrolling new patients for their trial because it would be unethical to have a control group that didn’t receive the treatment.
In the meantime, specialists were starting to tweak how donated stool was processed. “Essentially the food, fiber and other material is all filtered out and all that’s left is the fluid with the bacteria,” said Dr. Daniel Uslan, clinical chief of infectious disease at UCLA Health.
These days, FMTs can also be given orally: Doctors refined the process so much that the bacteria can fit into a capsule that patients can swallow.
By 2012, a not-for-profit company named Open Biome began to collect and process stool from donors, selling their “product” to gastroenterologists who didn’t want to do it themselves.
However, the FDA still hadn’t established any guidelines about what doctors should look for in donors and their stool before carrying out transplants. To be sure, many providers did check for certain pathogens, but there was also an assumption that if the donor was healthy, their stool probably didn’t contain dangerous bacteria.
Following the publication of the New England Journal of Medicine article, the FDA stepped in.
In February 2013, a workshop was convened by the agency, which eventually concluded that the best way to proceed would be to designate FMT as an investigational drug, which could be used only in clinical trials. (Until a drug is approved by the FDA, it can be only used in clinical trials.)
The decision prompted a backlash from specialists who knew that many patients who needed the treatment would not be able to participate in those trials.
In response, the FDA relented slightly. The agency decided to permit, through what it calls “enforcement discretion,” the use of FMT outside of clinical trials for a specific group of patients: those with C. diff infections that didn’t go away with the standard antibiotic treatment. Doctors, for their part, had to be sure to explain the potential risks of the procedure.
At that time, nobody, including the FDA, knew exactly what those risks might be — indeed, that’s always a concern with an unstudied and unproven treatment — but according to Khoruts, the main worry from the FDA’s perspective was the risk of infection.
Despite the enforcement discretion, many specialists were unhappy to see the treatment designated as a drug, because it meant there was a possibility that in the future, companies would develop products marketed as microbiome replacements and then charge so much that some patients wouldn’t be able to afford it. (Still, the current treatment can be expensive: Open Biome, for example, charges between $1,595 and $1,950 for their processed stool.)
An alternative, Khoruts argued, would be to approach FMTs like organ transplants. That means doctors would continue to treat patients, some even doing their own studies, but without FDA regulation and with a lower likelihood that a drug company would enter the picture.
From the FDA’s perspective, however, the drug designation was only one way to keep tabs on the rapidly expanding field.
“We determined that it made the most sense to regulate it as a biologic drug,” Dr. Peter Marks, director of the Center for Biologics Evaluation and Research at the FDA, explained. “And in many ways, it does resemble a drug. Is it the perfect analogy? I’ll be the first to admit it’s not perfect.”
With the drug designation, the therapy was more likely to be tested in rigorous clinical trials, Marks said. In those trials, it would need to be evaluated for both its efficacy and safety, and scientists could study the best ways to administer the treatment.
“There are plenty of things in the history of medicine where the preliminary data looked good but when there were randomized controlled trials, they turned out not to be helping people and potentially harming them,” Marks told NBC News. “We want to protect public health while promoting people getting the treatments they need.”
There’s no question that FMT’s popularity has soared in recent years. On clinicaltrials.gov, there are more than 300 registered trials looking at FMT for a wide variety of conditions, many of which go far beyond the original intended use, including transplant rejection, obesity and cancer, as well as some of the more expected gastrointestinal disorders, such as irritable bowel syndrome and ulcerative colitis.
For Dr. Ari Grinspan, more monitoring is welcome, especially after a death involving FMT.
“My takeaway is that a lot of us in the field were a little cavalier with our use of it,” said Grinspan, an assistant professor of medicine in the division of gastroenterology at the Icahn School of Medicine at Mount Sinai. “This is a little like blood donation back in the ’80s when we didn’t know we should be screening for hepatitis B or HIV.”