On April 6, 2020 the following publication was released by the US Food and Drug Administration (FDA):
Information Pertaining to Additional Safety Protections Regarding Use of Fecal Microbiota for Transplantation — Testing of Stool Donors for Enteropathogenic Escherichia coli and Shigatoxin-Producing Escherichia coli
On March 12, 2020, The Food and Drug Administration (FDA) informed health care providers and patients of the potential risk of serious or life-threatening infections with the use of fecal microbiota for transplantation (FMT). Infections caused by enteropathogenic Escherichia coli (EPEC) and Shigatoxin-producing Escherichia coli (STEC) have occurred following investigational use of FMT for treatment of Clostridium difficile (also called Clostridioides difficile or C. difficile) infection not responsive to standard therapies. FDA suspects these infections are due to transmission of these pathogenic organisms from FMT product supplied by a stool bank company based in the United States.
After the release of FDA’s March 12, 2020, Safety Alert, the stool bank company publicly acknowledged FDA’s safety communication, so we are now identifying the stool bank as OpenBiome, a company based in Cambridge, Massachusetts.
Because of these serious adverse events that occurred with investigational FMT, FDA has determined that additional protections are needed for any investigational use of FMT, whether under an Investigational New Drug Application (IND) on file with the FDA or under FDA’s enforcement discretion policy.
FDA has already communicated with OpenBiome and individually with IND holders for investigational FMT to underscore the need for additional protections.
These additional protections include:
Testing FMT donor stool by nucleic acid amplification tests (NAAT) for EPEC and STEC to exclude use of stool that tests positive for either EPEC or STEC.
Testing of stool from each donor before and after multiple stool donations, no more than 60 days apart; and, as applicable, quarantining FMT product lots manufactured from these donations until both pre- and post-donation EPEC and STEC tests are confirmed negative.
Testing of all FMT products currently in storage for which the donor has not undergone stool testing for both EPEC and STEC using NAAT as described above.
Until this testing is able to be completed, placing those FMT products in quarantine until they have been tested using NAAT and found negative for EPEC and STEC.
In the case of FMT products manufactured using pooled donations from a single donor, performing stool testing on individual stool samples (not pooled) within the testing window described above for a given lot of FMT product.
Patients considering FMT to treat C. difficile infection should speak to their health care provider to understand the potential risks associated with the product’s use.
FDA encourages all health care providers who have administered FMT products to their patients to report suspected adverse events to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.
The US Food and Drug Administration (FDA) yesterday issued a safety alert about the potential risk of serious, even life-threatening, infections linked to fecal microbiota transplantation (FMT) after six patients were infected with diarrhea-causing Escherichia coli following the procedure. March 13, 2020
According to the alert, two patients developed enteropathogenic E coli (EPEC) infections, and four developed Shiga toxin–producing E coli (STEC), after receiving FMT for Clostridoides difficile infection. Four of the six patients required hospitalization.
“FDA is informing patients and healthcare providers of the potential risk of transmission of pathogenic bacteria by FMT products and the resultant serious adverse reactions that may occur,” the agency said. “Patients considering FMT for the treatment of C. difficile infection should speak to their health care provider to understand the associated risks.”
STEC is a pathogenic form of E coli that causes abdominal pain, bloody diarrhea, vomiting, and mild fever. EPEC generally doesn’t cause any symptoms, but some strains can cause diarrhea.
Change in screening protocols
The stool used in the procedures all came from Boston-based OpenBiome, the country’s largest stool bank. The company said in a press release yesterday that the cases are the first reports of likely transmission of pathogens by FMT involving stool that came from OpenBiome, which has shipped more than 50,000 FMT treatments to physicians since 2013.
The patients who developed the infections received FMT product prepared from three OpenBiome donors. The two patients who developed EPEC infections were treated with stool from two donors, and the six STEC patients received stool from one donor. OpenBiome says all unused material from the donors has been destroyed.
The FDA says bacterial isolates from the patients’ stools are not yet available to determine if the STEC or EPEC organisms are genetically identical to the organisms from the stool donors—a finding that would confirm that the donor stool was the source of the infection.
In response to the safety alert, OpenBiome says it is immediately implementing changes to its screening program in collaboration with the FDA.
While the company has previously screened donor samples for STEC via enzyme immunoassay, and says the donor involved in the STEC cases tested negative at all screens, OpenBiome will add polymerase chain reaction (PCR) testing for STEC to its screening process. PCR tests on retained donor samples conducted after Openbiome was notified of the infections were found to be positive for STEC.
The retained stool samples from the donors linked to the EPEC infections were found to be positive for EPEC upon further testing from OpenBiome. The company says it has not previously screened donors for EPEC, a position based on international and national guidelines, but will immediately implement EPEC screening by PCR into its donor screening protocol.
“In addition to updating and implementing STEC and EPEC screening into our quality and safety protocols, OpenBiome is also working with FDA to implement retrospective screening of units to ensure that available material meets these new standards,” the company said.
After reporting the infections to the FDA, OpenBiome received information that two additional FMT recipients who received stool from the donor linked to the STEC infections had died. The company said in an update today that the treating clinician for one of the patients determined that the patient had died from underlying cardiac causes, and testing for STEC was not performed. In the second case, testing of donor material was negative for STEC.
“Therefore, it was determined that the death was unrelated to STEC,” the company said.
FMT safety issues
FMT has been found in several studies to be a highly effective treatment for recurrent C difficile infections that aren’t responding to antibiotics, and at least 10,000 FMT procedures for recurrent C difficile are performed each year. FMT is also being investigated for treating other conditions in more than 300 trials.
The idea behind the procedure is to introduce healthy bacteria from a donor into the gut microbiome of a sick recipient and restore the balance between good and bad bacteria.
But this is the second safety alert issued by the FDA regarding FMT. In June 2019, the agency warned of the potential for dangerous infections after two FMT patients developed drug-resistant bloodstream infections and one died, and the agency halted a number of FMT trials until additional screening measures could be put in place. A subsequent paper in the New England Journal of Medicine revealed that the two patients, both of whom were enrolled in clinical trials at Massachusetts General Hospital in Boston, had extended-spectrum beta-lacatamase (ESBL)-producing E coli in their blood.
The two patients had both received stool from Mass General that came from the same donor. While the hospital had screened the stool for C difficile and the presence of drug-resistant pathogens by the hospital, it had not screened it for ESBL-producing E coli. The authors of the paper could not conclusively attribute the infections to FMT, but suspected the patients likely acquired the pathogen from the procedure.
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, 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.
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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 CEO 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.
According to some scientists, medical professionals and industry partners, regulation for fecal transplants could be divided along the lines of who is providing the product and what the product is. “Stool-derived” products would be regulated more like biological drugs, with stool itself regulated more like a body tissue.
“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.