The Efficacy and Safety of Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection: Current Understanding and Gap Analysis
Mark H. Wilcox,1,2 Barbara H. McGovern,3, and Gail A. Hecht4,5
1 Department of Microbiology, Old Medical School, Leeds Teaching Hospitals NHS Trust, Leeds, UK, 2 University of Leeds, Leeds, UK, 3 Seres Therapeutics, Medical Affairs, Cambridge, Massachusetts, USA, 4 Department of Medicine, Division of Gastroenterology, Loyola University Chicago, Chicago, Illinois, USA, and 5 Department of Microbiology and Immunology, Loyola University Chicago, Chicago, Illinois, USA The leading risk factor for Clostridioides
Abstract: The leading risk factor for Clostridioides (Clostridium) difficile infection (CDI) is broad-spectrum antibiotics, which lead to low microbial diversity, or dysbiosis. Current therapeutic strategies for CDI are insufficient, as they do not address the key role of the microbiome in preventing C. difficile spore germination into toxin-producing vegetative bacteria, which leads to symptomatic disease. Fecal microbiota transplant (FMT) appears to reduce the risk of recurrent CDI through microbiome restoration. However, a wide range of efficacy rates have been reported, and few placebo-controlled trials have been conducted, limiting our understanding of FMT efficacy and safety. We discuss the current knowledge gaps driven by questions around the quality and consistency of clinical trial results, patient selection, diagnostic methodologies, use of suppressive antibiotic therapy, and methods for adverse event reporting. We provide specific recommendations for future trial designs of FMT to provide improved quality of the clinical evidence to better inform treatment guidelines.
To review this publication in its entirety please click on the link below to be redirected.
We are pleased to welcome Dr. Sahil Khanna
as a Member of the C Diff Foundation and Medical Advisory Board.
Dr. Sahil Khanna is an Associate Professor of Medicine in the Division of Gastroenterology and Hepatology at Mayo Clinic, Rochester, MN. He is directing the Comprehensive Gastroenterology Interest group, C. difficile Clinic, Fecal Microbiota Transplantation program and C. difficile related Clinical Trials at Mayo Clinic, Rochester, MN.
He completed Medical School at the All India Institute of Medical Sciences, New Delhi; followed by Post Doctoral Research at University of California San Diego, CA; residency in Internal Medicine and Fellowship in Gastroenterology and Hepatology at Mayo Clinic, Rochester, MN before joining the Faculty. He also completed Masters in Clinical and Translational Sciences during his fellowship. His research and clinical interests include Epidemiology, Outcomes and Emerging Therapeutics for Clostridium difficile infection, an arena in which he has had numerous publications and presentations.
Dr. Khanna has over 100 peer-reviewed publications and serves as reviewer and on the editorial board of several journals. He has won numerous awards including the Miles and Shirley Fiterman Award, Mayo Brothers Distinguished Fellowship Award, Donald C. Balfour Mayo Clinic Alumni Association Research Award, Hartz Foundation Young Investigators’ Scholarship and the Most Distinguished Resident Physician Award from the American Association of Physicians of Indian Origin.
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.
To read the article in its entirety – please click on the following link:
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.
During faecal microbiota transplantation, stool from a healthy donor is transplanted to treat a variety of dysbiosis-associated gut diseases.
Competent authorities are faced with the challenge to provide adequate regulation. Currently, regulatory harmonization is completely lacking and authorities apply non-existing to most stringent requirements.
A regulatory approach for faecal microbiota transplantation could be inserting faecal microbiota transplantation in the gene-, cell- and tissue regulations, including the hospital exemption system in the European Advanced Therapy Medicinal Products regulation, providing a pragmatic and efficacy-risk balanced approach and granting all patients as a matter of principle access to this therapy.
Pick a disease or disorder, and somebody, somewhere, has said that a probiotic supplement—an over-the-counter, unregulated pill usually filled with a single strain of friendly gut bacteria—might cure it, whether it’s cancer, obsessive-compulsive disorder, or a yeast infection.
But there’s very little evidence that probiotic supplements do any good. “There’s a lot of promise here but not a lot of proof yet,” said Cliff McDonald, associate director for science at the Centers for Disease Control and Prevention’s Division of Healthcare Quality Promotion.
Half a million people a year are infected with C. diff in the U.S., the CDC estimates, with 29,000 annual deaths related to the diarrheic bacterium. More than 65 percent of C. diff infections involve exposure in a health-care facility, according to a 2015 study, creating more than $4.8 billion in excess health-care costs at acute-care facilities alone.
C. diff. Treatments On The Horizon:
To Learn More About ALL C. diff. Clinical Trials In Progress Click On The Following Link:
Seres Therapeutics, a microbiome-based biopharmaceutical company in Cambridge, Mass., is developing a pill, subject to a rigorous approval process under the Food and Drug Administration, to tackle recurrent Clostridium difficile. (The digestive system’s microbiome is the community of healthy gut bacteria that normally reside in the body.)
Seres aims to put the science behind a proven treatment of recurrent C. diff, fecal transplants, in a pill, which wouldn’t require a colonoscopy. Like probiotic supplements, it’s a gut bacteria product. Unlike the supplements, by the time it’s available it will have gone through the FDA wringer. It will contain about 50 strains of bacteria proven effective in treating C. diff and will require a doctor’s prescription.
Recurrent C. diff is an obvious entry point for Seres, said Chief Executive Officer Roger Pomerantz. “We asked, what is the lowest-hanging fruit?” But it’s hardly the end. The company has built a microbiome library of 14,000 strains of human bacteria it hopes will help it treat a range of diseases, eventually without needing feces at all. Seres has embarked on the research with some pretty lofty goals, including finding treatments for obesity, liver disease, and cancer. It has partnerships with Massachusetts General Hospital, the Mayo Clinic, Memorial Sloan Kettering Cancer Center, and other respected medical institutions. “We will figure out exactly what’s wrong with the microbiome, design a drug, and then pull the organisms out with our library, never touching a human donation,” Pomerantz said. Seres’s lead product candidate, SER-109, will treat recurrent C. diff with four capsules taken orally instead of with transplants. While fecal matter is the raw material for the pills, the final product consists only of the spores necessary to treat the infection, which will have been extracted and purified. SER-109 is expected to become the first oral microbiome therapy approved by the FDA, though Seres declined to predict exactly when it will arrive. Results from the latest trials are due by midyear, and Phase 3 trials are scheduled to follow later in the year. Seres hopes to follow up quickly with SER-287, a drug to treat ulcerative colitis, which could be the first microbiome drug to treat a chronic disease, and SER-262, to treat primary C. diff before it turns into the recurrent kind.
Other companies are racing to collect enough data for FDA approval, but right now Seres, which is publicly traded, looks to be the one to beat. “Seres is probably going to be the first one that’s going to knock at the FDA’s door,” said Mohan Iyer, chief business officer at Second Genome, a microbiome company studying how to treat disease with the compounds produced by gut bacteria instead of the gut bacteria themselves.
“SER-109 is poised to be first-in-class among fecal microbiota transplant-derived drugs,” Joseph Schwartz, an analyst at Leerink Partners, wrote in a May report. The report says the latest trial results “wowed the Street” but warns that the company could still be held back by “disappointing clinical data” and obstacles in the regulatory process.
Another top contender is Rebiotix. Its RBX2660 is also designed to treat recurrent C. diff but, unlike SER-109, is administered with an enema; an oral version is in development. The treatment also differs significantly from Seres’s in formulation, including thousands of kinds of microbes from the donor’s stool, compared with SER-109’s 50 or so, as many as could be preserved and some of which haven’t even been identified.
“We make sure we have a minimum concentration of certain kinds that we know the patients lack,” CEO Lee Jones said. “But we don’t identify all of them. There’s no way to do that.” A recent study estimated that 1014 bacteria are in the human gut, most of which have never been isolated. Jones said the drug could hit the market by 2018.
The medications have been shown to be similarly effective—with no C. diff-associated diarrhea for 29 of 30 of Seres’s patients and 27 of 31 of Rebiotix’s, in the companies’ latest results—and equally safe. Adverse reactions for both are limited to such problems as moderate diarrhea and abdominal cramping, which could be from the C. diff itself. Both have been designated as “breakthrough therapies” by the FDA, allowing for an expedited approval process, and both are likely soon to provide an at-home alternative to fecal transplants.
Point Of View:
“I don’t know who is going to make it across the line first,” said Gail Hecht, director of gastroenterology and nutrition at Loyola University Medical Center and chairwoman of the American Gastroenterological Association for Gut Microbiome Research & Education. Hecht has attended a Seres advisory board meeting but doesn’t have a financial interest in the company. “It is indeed a race,” she said.
Seres does have at least one distinct market advantage. “Patients have different preferences,” Hecht observes, but “in general, people don’t particularly like enemas.”
Human Fecal Transplants:
For nearly two thousand years, doctors have looked to this unlikeliest of places for medicine. One of the earliest documented applications is from the fourth-century Chinese medical doctor Ge Hong, whose “yellow soup” recipe to treat diarrhea included a healthy person’s dried or fermented feces. Sixteen hundred years later, in 1958, patients infected with C. diff received the first known human fecal transplants.
Stool Bank Information:
Today the effectiveness of fecal transplants (formally known as fecal microbiota transplants) to treat recurrent C. diff is supported by a long list of studies, with researchers attributing the results to the restoration of the microbiome. OpenBiome, a nonprofit stool bank, shipped 1,828 treatments in 2014, a number that ballooned to 7,140 treatments in 2015 and looks to be eclipsed this year, with 4,323 treatments shipped to its clinical partners through May 31. And these numbers don’t take into account the transplants performed through directed fecal donations.