Neill Stollman has been called the Tupac of poop transplants. The Oakland-based, board-certified gastroenterologist didn’t invent the treatment. But he did bring it to the west coast. His first patient was a woman in her 80s with a horrible case of Clostridium difficile, a gut infection that can strike patients after a course of antibiotics clears out their existing bacterial community. It’s also one of the deadliest antibiotic-resistant threats in the US, costing the healthcare system an estimated $5 billion each year. Drugs had stopped working for the woman, and without some kind of treatment, she was going to die.
So Stollman took a stool sample provided by the patient’s nurse’s husband, made a poop shake, and performed California’s first fecal microbiota transplant—a so-called FMT. The new bacteria repopulated her gut and she made a full recovery. Since then, Stollman has successfully performed the procedure hundreds of times, though he no longer has to ask his staff to break out the blender. Now he gets a few frozen poopsicles a week, which he can thaw out on a patient-by-patient basis. “I used to be the only guy doing this for 500 miles,” he says. “I had to beg my staff to do it.” Today, 98 percent of the US population lives within two hours of a fecal transplant provider.
Since the nation’s first stool bank opened in 2012, it's sent out nearly 30,000 frozen FMT doses. But nobody, least of all the US Food and Drug Administration, sees stool banks as a long-term solution. Most doctors expect the FDA will shut them down the moment a less-messy treatment gains approval—there are a handful of contenders currently in the pipeline, including microbiome-based drugs from Seres, Rebiotix, and Vedanta Biosciences. For now though, no poop pills have crossed the finish line, and stool banks remain unregulated. Fecal transplants are caught in a legal limbo even as they grow in popularity.
Which is why some scientists and legal experts are suggesting that poop be treated not like a drug, but like a tissue—requiring stool banks to report to a registry that tracks patient outcomes and safety data. Writing today in Science, a group of doctors, researchers, and lawyers from the University of Maryland recommend a major regulatory overhaul that will keep access to the life-saving treatment available to patients, while hitting the pause button on anything not backed by serious science.
Over the past four years, the FDA has struggled with how to regulate FMTs, changing and unchanging its mind several times. In May 2013, the agency declared it would treat the transplants like drugs, meaning the only way patients could get them was by enrolling in a clinical trial. Two months later, after much patient and physician outcry, the agency made an exception for doctors using transplants to treat recurrent C diff. But they were still prohibited from using it to treat anything else. In 2016, that stance got even more restrictive, as the agency proposed an effective ban on doctors buying samples from stool banks for anything but approved clinical trials. That draft guidance is still awaiting finalization.
“The way the regulations are written now, everything is being done under enforcement discretion,” says Diane Hoffman, a professor of health law at the University of Maryland, and first author on the Science paper. The FDA is just choosing to bend the rules for C. diff. patients. But the agency could just as easily unbend them, whenever it wants. Which is why Hoffman and her colleagues are suggesting transplants used for C. diff be regulated as a “practice of medicine” rather than a drug, when the stool comes from someone the patient or physician knows, i.e. not a stool bank. Then it would only be subject to state, rather than federal regulation. More patients could then access the treatment—which has cure rates above 80 percent—regardless of market winds or agency whims. All other uses of FMT would still be subject to formal clinical trials overseen by the FDA.
That’s what Hoffman calls Track 1 of their proposed regulatory scheme. Track 2 would be to actually regulate stool banks, the same way the government regulates blood banks. Banks would have to submit safety data to the FDA and outcome information to a national registry. OpenBiome, the first and largest stool bank in the US, already does all that, voluntarily. Physicians at the non-profit’s 968 partner providers track every transplant from product arrival through an eight-week follow-up, before faxing over the data to OpenBiome, where it’s entered in a master database. They publish those results bi-annually and report adverse events to the FDA (though so far, no side effects have been definitively linked to the treatment).
“OpenBiome has always supported a regulatory framework for stool banking,” says Carolyn Edelstein, the organization’s director of outreach and public affairs. Although, she admits they always saw their position as temporary; that stool banks would eventually only serve clinical trials. “From day one we’ve been preparing for that outcome,” she says.
Which is why at the beginning of this year, OpenBiome spun out a company called Finch Therapeutics, which is leveraging the stool bank’s manufacturing quality system to develop its own poop pill for treating entrenched C. diff. In October, the startup merged with fellow microbiome manipulator, Crestovo, and are currently enrolling patients in a phase two trial. (The same spot where Seres struck out last year).
And players like Seres and Rebiotix don’t just have to worry about competition coming from within the stool banks. They’ve also got to worry about Crispr. North Carolina-based Locus Biosciences is planning to send phages—viruses that only attack bacteria—weaponized with Crispr to C. diff trials later next year. In November, the biotech startup secured $19 million in funding to move its Crispr-equipped antimicrobial drugs to the clinic.
Hoffman’s proposals would allow and encourage stool banking to exist side-by-side with any such future products, which would surely cost more than FMT’s $300 price tag. (There's also a Track 3 that describes the traditional, i.e. costly, drug-approval process for any “modified stool-based products.”) And while that coexistence could interfere with companies’ abilities to recruit trial participants, Stollman says that’s a small price to pay to keep the treatment attainable for patients. “If you ask 99 percent of physicians who do this, they will tell you anything that came along to limit access to stool banks would be catastrophic,” he says. Plus, there’s no guarantee the microbiome even can be successfully be pulled apart and put back together in pill form. “People have spent 50 years trying to come up with synthetic blood and we still have a blood bank," says Stollman. "Who’s to say stool will be any different?”
