In 2008, Rhode Island gastroenterologist Colleen Kelly diagnosed a patient with a Clostridium difficile bacterial infection. The infection alters the composition of the community of microbes in the gut, leading to mild to severe diarrhea. It can be life-threatening but is often treatable with antibiotics.
This particular infection wasn’t responsive. “We went through all the standard antibiotic therapies, and it kept coming back,” says Kelly. Consultants in Boston recommended a fecal microbiota transplantation (FMT), a transfer of the microbial community from a healthy donor, acquired from a stool sample.
The patient was on board, but Kelly had never administered an FMT, and the experts in Boston weren’t equipped to perform the procedure, either. So Kelly developed a protocol with her nurses and successfully treated the infection. She began receiving referrals from Boston. That led to her participation in the early medical research of FMT, a stool transplant that seems to work when nothing else will.
Kelly, of the Women’s Medicine Collaborative and Brown University, is now one of the leaders of the largest FMT study to date, the Fecal Microbiota Transplantation National Registry. The registry is a project of the American Gastroenterological Association and recently began enrollment to collect data from 4,000 patients with follow-ups for at least five years after their procedures. It could help establish the safety and efficacy of FMT and may even reveal other diseases that are treatable with FMT, though the regulatory future of the procedure remains uncertain.
Once the “very ambitious” study is completed, Kelly says, “We’ll be able to answer, when patients ask, ‘What are the odds of infection or developing a condition after FMT?’ We’ll be able to better counsel patients about the risks of getting an FMT.”
Until now, safety and efficacy data have been limited to small studies and anecdotal evidence. Although miraculous last-ditch C. diff. recoveries are well-documented, there may be a tendency to underreport unsuccessful or negative results. And FMT has grown in popularity over the past decade. Physicians and patients are not only considering it an urgent, much-needed treatment for C. diff. infections but also for treating other gut diseases, microbiome-associated conditions, and even melanoma immunotherapy. Kelly estimates that around 10,000 FMTs were completed in the U.S. in the last year alone.
Currently, FMTs must be performed under provisional oversight from the FDA. Because treatments vary so much, regulations haven’t settled either. “[The FDA] has gone back and forth in how they want to treat FMT and whether it requires clinical trials or not,” says Diane Hoffmann, professor of healthcare law at the University of Maryland.
Last year, Hoffmann convened a working group of experts, including Kelly, to propose a regulatory definition for FMT. They published their recommendation in early 2017, although the FDA is under no obligation to consider it.
For now, the FDA has classified FMT as an “investigational new drug.” Its use is limited to research, though exceptions are made for recurrent C. diff. infections. That status may not change until randomized controlled trials have been conducted.
The new FMT registry could help definitively establish the procedure’s efficacy for treating various diseases. This includes C. diff. infections, as well as conditions such as inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and irritable bowel syndrome. “I think C. diff. was the low hanging fruit,” Kelly says. “Other conditions are much more complicated. It may not be as easy as, ‘Hey, drop some good poo in there, and we’ll solve things.’”
Some rare short- and long-term effects of FMT might include increased risk for other conditions, such as obesity and diabetes. That’s why the registry asks doctors to follow up with patients at 1, 6, 12, and 24 months after FMT and to seek annual patient reports for five to ten years afterwards.
The registry has received funding support from the National Institutes of Health and the National Institute of Allergy and Infectious Disease. Healthy stool samples for transplantation will be provided by the nonprofit stool bank OpenBiome. The registry will also collect stool samples from patients before and after their FMT. Materials from 75 different sites across the country will be genetically analyzed and frozen at a biobank at the University of California, San Diego. Mining that data could help doctors screen and select the best donor samples for individual patients and avoid ineffective or even harmful combinations.
There are a variety of ways a stool sample could be processed before being transplanted into a patient. Stool samples could come from an individual donor, for example, and contain a great deal of natural variation. Other FMT products could be more drug-like, highly-controlled, bacterial cultures. Each of these products may also have its own unique delivery method. For example, FMT can be delivered via enema or a swallowed capsule.
If the development of standardized, drug-like products is successful, it could mean the FDA will divide FMT into more than one class with different regulations governing each.
“There’s a lot of uncertainty,” says Hoffmann. “It’s a unique situation.”