To regulate fecal transplants, FDA has to first answer a serious question: What is poop?

When severe, chronic diarrhea strikes, sometimes the only cure is … more feces. It might seem bizarre, but a transplant of healthy human stool and its bacterial ecosystem can mean freedom from a painful, life-threatening illness.  

The transplants — called fecal microbiota transplants, or FMTs — are becoming more and more popular. So popular that the stool bank OpenBiome has supplied more than 30,000 stool samples to clinicians and scientists since 2012. Right now, though, the government isn’t quite sure how to regulate fecal transplants. That uncertainty comes from what seems like a simple question: What is poop? Is it a drug? Is it a bodily tissue? Is it a little of both? Then, is the transplant itself a procedure? That’s a whole other regulatory category.

Out of concern that regulations would cut out desperate patients or send companies running to more profitable enterprises, some FMTs aren’t actually regulated at all. That leads to the potential for unscreened and potentially dangerous fecal samples to flood the market. A group of doctors and scientists from the University of Maryland School of Medicine in Baltimore have tried to cut through the confusion with a three-track policy plan that would help keep poop transplants clean (as clean as fecal matter gets, anyway), while still allowing patients to get transplants when they need them. The scientists also hope to encourage companies to develop potentially lucrative products for future FMTs — including options that are almost feces-free.

A fecal transplant involves taking a mixture of a donor’s poop and saline (sometimes mixed with the help of a kitchen blender) and inserting it into a patient’s large intestine or far down the gut with a nasogastric tube. Companies are working on alternatives to that procedure, such as pills that deliver the same benefits with less of an “ick” factor.

Currently, FMTs have the most potential for treating Clostridium difficile infections. C. diff is a bacterium normally found in our guts and feces. But unchecked, it can take over the large intestine. The result is inflammation and chronic severe diarrhea that can last weeks or months. There are more than 450,000 estimated cases in the United States each year, and more than 29,000 deaths. Doctors can prescribe antibiotics to kick the bugs out, but in 20 percent of patients, the infection comes back again. And again.

For those patients, FMTs can be a miracle. They resolve symptoms in 85 percent of patients with recurrent C. diff infections, compared with the roughly 20 to 30 percent success rates of antibiotics.

Unfortunately, FMTs also come with a dose of danger. Feces is a mixture of our undigested waste, the beneficial microbes needed to keep our guts healthy and whatever bacteria, fungi and viruses we’ve picked up in our busy lives. So donors need to be screened for pathogens that might make a sick recipient sicker. And the poop needs to be handled carefully to avoid contamination or infection in the people who handle and receive it. 

Gastroenterologist Erik von Rosenvinge of the University of Maryland School of Medicine in Baltimore has performed more than 40 FMTs. “When I first started doing these in 2013, I was having the patients identify a friend or family member, and they would bring in the stool and I would process it myself,” he says. After the first few donations, von Rosenvinge switched to using stool from the OpenBiome stool bank. It saves money and time.

For each donation, the stool bank or hospital will test the feces for pathogens. But who sets the standard to ensure that people getting treated for C. diff are receiving “clean” stool, either from their friends or from a stool bank?

Well, right now, no one.

Poop: Drug or tissue?

The first problem is to figure out what an FMT actually is, at least, in terms of how the government should regulate one. Feces is like a drug, in that the microbes in it can change how the body functions. But because of those very microbes, feces is also a living thing that differs from person to person. In fact, in some ways, poop is like biological tissue, in that it comes from the human body.

But then, the FMT itself is something like a procedure — there’s a method involved in getting one. But that procedure is also delivering a drug. Or is it transplanting a tissue? Here we go again.

“The FDA has been reticent to create a new regulatory product category,” says Jacques Ravel, who studies the microbiome and women’s health at the University of Maryland School of Medicine.  “They’ve been trying to fit the stool into one of the regulated product categories, and there’s limitations every time you do, there’s pros and cons.”

In 2013, the FDA declared that FMTs counted as a drug (technically a “live biotherapeutic product”) in terms of how they would be regulated, which, von Rosenvinge notes, “means all of us are pharmaceutical factories,” pooping out “drugs” once a day on average.

But FMTs don’t have FDA approval yet, so as a drug, an FMT is considered “investigational.” Giving one to a patient would require an investigational new drug application, or IND. Those are associated with clinical trials, meaning someone who needed an FMT would probably have to get into a clinical trial to get treatment.  “At that point [in 2013], I’d only done a handful, and I had to stop because I didn’t have an IND,” von Rosenvinge recalls.

The FDA’s goal was to make sure that FMTs were safe for people. But the requirements meant that most doctors could not give FMTs. At a public workshop about FMTs in 2013, scientists and physicians spoke out against the requirements. In response, the FDA noted that it would practice “enforcement discretion.” That’s government-speak for politely looking the other way while doctors treated C. diff patients outside of clinical trials.

Unfortunately, looking the other way means that FMTs — whether prepared from a donor by a doctor or purchased from a stool bank — are still completely unregulated. As FMTs gain popularity for C. diff, von Rosenvinge notes, that could lead to problems. “You don’t want someone grabbing poop out of the local [port-a-potty] and selling it. That would be horrible,” he says. “If someone’s going to be using stool to put into a human, you want to have assurances that it was properly handled, that the donor was properly screened, that we’re doing everything within reason to minimize risk of causing problems.”

The stool banks themselves aren’t pleased with the arrangement, either. “We’re all operating on a bit of uncertainty,” says Carolyn Edelstein, the executive director of OpenBiome. Right now, OpenBiome screens all of their samples by their own standards, because the government hasn’t given them any. Everyone knows that “looking the other way” could end at any time, a move that the FDA proposed in March 2016. Then, INDs would be required again, and patients could be out of luck.

Balancing regulation and access

To patients, access — cheap access — is paramount. “The big challenge at the end of the day is access to treatment, and the fact that FMT is really cheap as its performed right now,” says Ravel. “Right now there’s no true alternative, even those coming down the pipe may be able to cure [C. diff], but they’re not going to be cheap.”

But to doctors, scientists and government, access needs to be balanced with safety. “People are doing this at home, and I think that raises issues about the safety of donations,” notes Diane Hoffman, who studies health law at the University of Maryland. “Do [patients] understand the potential for contamination and disease transmission?”

The right balance might also help promote the development of new drugs for treating C. diff — ones that extract the most useful bacteria, for example, and don’t involve an enema.  

To this end, Hoffman, von Rosenvinge, Ravel and colleagues worked with a large working group of scientists, lawyers, industry partners and patient advocates to come up with recommendations for regulating FMTs, which they outlined in December in Science. The result is a slim, three-track system.

Individual FMTs for C. diff done by doctors with donors who are friends or family of the patients would be classified under “practice of medicine.”  This is an exception that allows doctors to use their expertise and judgment when treating patients, as long as the treatments they’re using are legally available. No FDA approval or IND required. “We’re trusting the doctor to do what’s in the best interests of the patient,” Hoffman explains.

Stool banks, on the other hand, would be regulated like tissue banks. They’d have to comply with good manufacturing and safety practices and screen and test their donors. The banks would also have to track the patients who receive donations, and submit their long-term data to a national registry. The banks would be free to sell FMT samples, but only to treat C. diff. Any other use that the FMT hasn’t been approved for would still require a clinical trial.

The third track would be for “stool-based products.” These would be pills or delivery systems that offer, say, combinations of microbes, rather than the current practice of basically “polishing a turd,” notes von Rosenvinge. These would be regulated as biological products or drugs.

In practice, this would mean stool banks and stool transplants would be regulated more like cell and tissue banks and transplants. “Stool-based products” on the other hand, would be regulated more like drugs. No matter what, patients would have to be informed of all the risks associated with an FMT.

“I think the stand-out, excellent point of this proposed regulatory scheme is that stool banks need to be regulated, and there need to be rigorous data collection of outcomes,” says Kelly Hills, a bioethicist with Rogue Bioethics. “Track everything. The whole enchilada. We have historical precedents [such as in vitro fertilization] where we didn’t track outcomes, and 20 or 40 years down the line we’ve been kicking ourselves. It’d be nice to learn from our mistakes!”

This is especially important because while FMTs have very clear benefits for C. diff in the short term, no one really knows what the long-term effects will be. “We don’t have a lot of [long-term data] right now,” Hills notes. “We know that when you change someone’s gut microbiome you actually change a lot in their life. We have the anecdotal stories of people losing lots of weight, for example, or people’s dietary desires changing.” But the plural of anecdote isn’t data. A registry might help scientists keep track of exactly what transplants people received and their long-term effects.

But “practice of medicine” might give too much leeway to doctors to try FMT for things that they probably shouldn’t, worries Leigh Turner, a bioethicist at the University of Minnesota in Minneapolis. “‘Practice of medicine’ isn’t a curb on advertising or promotional claims,” he notes.

The group behind the policy proposal was careful not to stand in the way of further drug development. That third track was designed with the hope of promoting stool-based products, so that companies might be encouraged to pursue more of them. But if FMTs aren’t broken, why would companies — let alone patients — want to take the risks to fix them? With FMTs freely available, it might be hard to recruit patients to potential clinical trials for new drugs. “If you have a cheap solution that works and you have a patient with C. diff, that patient will not want to enter a trial with a placebo arm,” notes Ravel. After all, what if they got the placebo? They want a cure, not a game of roulette.

The policy brief isn’t policy, and the FDA hasn’t made a final call. But looking the other way isn’t going to cut it in the long term. FMTs are only used for recurrent C. diff infections right now. But scientists are interested in them for many other things. “You can get into weird science fiction areas. Would athletes start doing FMTs to try and improve their Tour de France time? Could you lose weight?” notes Hills. Some of these could be lucrative options for companies. And because FMTs are so easy to perform, people are already making headlines with the do-it-yourself route.

No matter what, a lack of regulation isn’t a long-term strategy. People are going to find other uses for feces, and the FDA will need to be prepared when they do.

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Editor’s note: This story was updated on May 21, 2018 to correct Carolyn Edelstein’s title. She is the executive director, not CEO, of OpenBiome. On May 23, we clarified the first sentence of the third paragraph to note that only some, not all, FMTs are not subject to regulation. Enforcement discretion applies only for FMTs for treating recurrent C. diff.