Fecal transplants have been proven to successfully treat certain types of infection, but proponents of the treatment are still fighting what they say are unnecessarily strict regulations.
Mark Smith was a microbiology graduate student at the Massachusetts Institute of Technology when, in 2011, a family friend became infected with the notorious superbug clostridium difficile. C. diff can cause severe diarrhea, disability, and malnutrition and is responsible for roughly 14,000 deaths in the United States each year. In 2012, after taking seven rounds of the antibiotic vancomycin and failing to improve, Smith’s friend received a DIY fecal transplant from his roommate—in their apartment, using an over-the-counter enema kit. The friend recovered within days, but “the whole thing was absurd, not at all how it should be done,” Smith said.
Fecal transplantation—transferring the feces of a healthy person into the bowel of someone with an infection—appears in published case reports as early as 1958. But in the past few years, scientists have established with more rigor that it can resolve recurrent C. diff infections around 90 percent of the time. In 2013, a randomized controlled trial published in the New England Journal of Medicine showed that the procedure worked better for this condition than antibiotics—so much better that researchers stopped the study early, saying it was unethical to continue to deny the transplants to the control group.
Within two to three days of the transplant, most patients are “symptom free …They get their lives back,” said Michael Edmond, an infectious disease specialist at Virginia Commonwealth University. It’s about as close to a miracle cure as medicine offers.
“Their standards are incredibly high, and the testing they do is much better than what’s done in individual doctors’ offices,” said Edmond, who recently joined OpenBiome’s clinical advisory board. OpenBiome quarantines donors’ samples and retests them for pathogens after 60 days, since new infections, like HIV, can take time to show up on immunological tests. In addition, OpenBiome archives a portion of every sample, in case questions emerge down the road. “If I have a patient 10 years from now” with a virus that’s unknown today, “I can go back and see if it can be traced” to a stool transplant, Edmond said. “We couldn’t possibly have done that before.”
To date, OpenBiome has provided more than 930 samples to doctors and hospitals around the world. “There is nothing else like them in the country or anywhere else, as far as I know,” Rob Knight, a microbiome expert at the University of Colorado, Boulder told me. Not only are they making the procedure more accessible, they also have the potential to collect large-scale data on outcomes. And they can support research by providing standardized, well-characterized samples to scientists.
“That is an absolutely critical piece of the puzzle,” Knight said, since, for all the enthusiasm, researchers have yet to understand how, exactly, the treatment works. Like Jamil, most patients have undergone antibiotic therapy recently for another condition. Those antibiotics “start killing off good bacteria, then C. difftakes over and produces a toxin that causes the diarrhea,” Edmond said. Fecal transplantation reestablishes a healthier community of bugs that seems to drive out the C. diff or hold it in check. The approach is both holistic and rudimentary.
“It’s a crude tool we’re using to repair the damage done by another crude tool, which is antibiotics,” Alm said. Part of OpenBiome’s goal is to understand what usually enables fecal transplants to succeed—and what sometimes causes them to fail. In particular, the group is asking whether certain combinations of bugs, or certain genetic relationships between donor and recipient, are integral to the cure.
Research on the trillions of bacteria that live on and in our bodies is flourishing. Our skin, mouths, colons, lungs, and many other sites play host to these bugs, which in turn contribute to our health. These findings have supported a view of the body as an ecosystem, in which human and bacterial cells continually interact. Various diseases, from inflammatory bowel disease to type 2 diabetes, have been linked to reduced diversity in the ecosystem or other anomalies in the balance of bugs. There has been a wealth of association, a fascination with pattern-finding, and an exuberance toward new data not unusual for a fast-emerging field.
But as the science develops, and researchers hope to harness its insights in service of patients, it will be critical to establish which conditions are in fact caused by microbial disturbances and which are merely correlated with them. Fecal transplantation could play a valuable role in this regard, demonstrating whether altering the mix of bugs can also cure the disease. The nearly magical success of the treatment against recurrent C. diff does not necessarily mean, after all, that it will succeed for other conditions.
So far, researchers have published case reports or small studies testing fecal transplantation for inflammatory bowel disease, irritable bowel syndrome, chronic fatigue syndrome, and multiple sclerosis, among others. But few randomized controlled trials have yet been completed. In one study, published in 2012, Dutch researchers transplanted stool from lean donors to patients with metabolic syndrome, a condition that is characterized by insulin resistance and is often a precursor to diabetes. They found that the recipients’ insulin sensitivity improved, meaning that they were better able to process sugar. In another study, presented at a conference this summer, scientists from McMaster University in Canada studied fecal transplantation in patients with ulcerative colitis, a type of inflammatory bowel disease. They did not, however, find a statistically significant effect. “The result was disappointingly negative,” Richard Hunt, a gastroenterologist and emeritus professor at McMaster, said in an email. It may be that the dose of the stool, the duration of treatment, or the patients’ clinical characteristics will turn out to matter more for treating IBD than for C. diff. Even so, “there have been a number of trials now in IBD which have been negative and we probably need to think again before investing more time and money.”
For C. diff, adverse events associated with fecal transplantation are rare: Some patients report mild bloating, abdominal pain, or constipation. (If the stool is administered by colonoscopy, the risks of that procedure also apply.) But it’s possible that negative outcomes may be underreported, since no national registry of patients yet exists. (No one even knows how many fecal transplants are performed in the U.S. each year, Smith said.) As the largest single provider of fecal matter, OpenBiome might therefore help to verify its safety—or reveal any longer-term risks, like obesity or diabetes. “It’s important for patients to be able to make informed decisions,” Smith said, even if desperation may drive them to get the treatment anyway. Edmond, too, is sensitive to the importance of further research, but as he puts it: “If you’re 80 years old and can’t leave the house because you’re having 20 bowel movements a day, do you really care if you might be at higher risk for a chronic disease 10 years from now?”
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The Food and Drug Administration, however, is clearly concerned about potential risks. In 2013, the agency indicated that it regarded stool for the procedure as an investigational new drug. That meant that hospitals or physicians could only offer it to patients if they submitted an investigational new drug, or IND, application, with all of the attendant scientific and bureaucratic requirements. The backlash was swift. Doctors and patients worried that red tape would limit access to a lifesaving therapy and drive more people to perform the procedure on their own, with fewer safeguards. “I have at least three more patients in the process of preparing for self-administered fecal transplant at home,” Edmond wrote in May 2013. “These patients are highly motivated, know the data on effectiveness and won’t be told no!”
In June 2013, the FDA relented. It announced that it would not enforce its rule, temporarily at least, as it studied the matter further. Doctors could offer fecal transplants for recurrent C. diff, as long as patients gave their informed consent. The issue remained unresolved, however, and in February 2014, the FDA offered an updated draft guidelinethat once again set advocates on edge: The agency proposed that its previous enforcement discretion would be contingent, in part, on either the doctor or the patient knowing the donor personally. So “if I test a donor once for infections and that donor is known to the patient, I don’t need an IND,” Edmond wrote at the time. “But if I obtain the stool from a stool bank that has a small number of highly selected donors that are tested serially every 60 days … I need an IND?” Such a requirement, if implemented, would undermine large-scale stool banking like that done by OpenBiome, its founders said.
Ironically, this requirement might also increase the risks associated with fecal transplants. The risk of blood transfusions is known to be higher when recipients choose donors, rather than when they receive blood anonymously—perhaps because friends or family members feel pressured to donate even if they have engaged in risky behavior. “There is no reason to think it would be different here,” Edmond has written. (The FDA said that it is considering this point, among others, and that “the draft guidance document has not been finalized or issued for implementation.”)
The agency’s regulation of potentially infectious material is fraught with legal and historical peculiarities. For instance, the FDA does not regulate donated breast milk, although it warns on its website that milk can transmit infectious diseases, like HIV, and should be screened. Nor does it require manufacturers of dietary supplements, which can include probiotics containing live bacteria, to seek the agency’s approval. (The FDA’s Center for Biologics Evaluation and Research does have jurisdiction, however, over probiotics that are intended to prevent, treat, or cure disease.)
In theory, fecal matter could be regulated as a human tissue, like lungs or livers used for transplantation. Smith, Alm, and a gastroenterologist named Colleen Kelly made the case for this approach in February in an article in Nature, noting that the “human gut microbiome has been described as a ‘virtual organ.’” And several experts agreed: “Of all the categories the FDA has for regulation, tissue is the one that makes the most sense,” said Rob Knight of the University of Colorado, Boulder. “Someone’s body made that liver,” he added, and the same could be said of stool for transplant. Formally, though, the category of “human cells, tissues, or cellular or tissue-based products,” as the FDA defines it, excludes “secreted or extracted human products.” (This means that milk is excluded, though for some reason semen is not.) It’s possible that a senior official within the executive branch could redefine stool as a tissue, but “we’re really uncertain how these decisions are made,” James Burgess of OpenBiome said. The FDA said it “cannot make predictions regarding the future regulation” of therapies using fecal transplantation.
Someday, a commercial product may replace stool, making some of these issues less fraught. “Initially our whole plan was that this would be a bridge,” Burgess said. “We thought it was crazy [that] people weren’t getting treated.” Work conducted with material from OpenBiome might also aid efforts to figure out the “active ingredients” for treating C. diff, thus guiding efforts to create a synthetic substitute. That is a “huge research priority for us,” Alm said. If such a product became available, it’s even possible that OpenBiome would alter its mission to focus more heavily on research.
In the meantime, though, the group is making nice with the FDA. It is working to broker a compromise regarding the agency’s investigational new drug requirements. OpenBiome has agreed to help four of its providers perform fecal transplants as part of an IND study. This multicenter, phase-two trial will track up to 200 patients with recurrent C. diff for a year after they receive the procedure. Regulators are “rightly concerned” about unregulated transplants, Smith said, but “they see we can help drive rigorous data collection … They will get more good data working with us than they would have otherwise.”