Regulatory

A Clarification about Fecal Microbiota Transplantation

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We emphatically agree with Lee Jones' perspective in the essay “We’re Starting to Harness the Microbiome to Treat Disease” that regulated oversight of fecal microbiota transplantation (FMT) is vital for appropriate safety and stewardship of this investigational treatment.

However, the author failed to mention that FMT is now recommended by infectious disease and gastroenterology societies as the standard of care for recurrent C. difficile infection that has failed antibiotic therapy. Indeed, in their most recent guidelines, the British Society of Gastroenterology recommends that "where possible, FMT is best sourced from a centralized stool bank, from a healthy unrelated donor."

Read more here.

Faecal Quality Control

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Strict quality control and screening should be an essential part of the FMT procedure, as an increase in serious adverse events in the context of investigational FMT could lead to harder regulations and make access more difficult for patients, which would likely increase the demand for unregulated or ‘at-home’ FMT. However, obtaining safe stool for faecal transplantation is not trivial. In the US, a not-for-profit stool bank, OpenBiome (http://bit.ly/30nsE1B), was founded in 2012 and now supplies stool for most of the US investigational FTM procedures. Stool donors are selected through strict health screens and are closely monitored; additionally, samples are sequenced to screen for pathogens and to determine their composition, and then quarantined to ensure they were not obtained during the seroconversion period of an infectious disease. Aliquots of every stool preparation are kept for future reference in case of an adverse event.

The Death of a Patient and the Future of Fecal Transplants

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“Last month the Food and Drug Administration sent out an emergency alert: Two people who had undergone fecal transplants developed multi-drug-resistant infections from bacteria in the stool they were given, and one died.

The death and illness may be the first serious adverse events associated with the poopy procedure, out of tens of thou sands of times it's believed to have been performed in the US. If those numbers are accurate, that’s an awfully good safety record. But it’s hard to know for sure, because roughly a decade since the procedure became mainstream, it still occupies a legal gray area, and thus whatever data is being collected isn’t comprehensive or public. …

“The material in these cases did not come from OpenBiome,” says Majdi Osman, a physician and the clinical program director at the stool bank, which screens for health risks so thoroughly that it boasts of excluding more than 97 percent of potential donors.

It seems likely the first effect of the patient’s death will be new requirements for thorough donor screening at any place performing transplants. That isn’t yet universal because the relevant professional societies, which typically write such detailed standards, haven’t tackled fecal transplants so far. But in a follow-up to the announcement of the death, the FDA said it will require the places performing poop trans­plants not only to check donations for pathogens, but to question donors about their daily-life risks of exposure to bad bugs.”

Human Feces Can Cure Some Infections. Is The FDA About To Restrict It? (Audio)

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“The Boston area is the epicenter of a debate dividing the medical community.

The argument? How human feces should be regulated.

That's right — fecal transplanting is the process of transferring poop from a healthy donor to a sick patient. And it's proven effective for treating certain infections.

But some doctors and patient advocates are concerned that the Food and Drug Administration is about to clamp down on this radical therapy.”

listen more to the full segment here: https://www.wbur.org/radioboston/2019/04/12/human-feces-fda-restrict

Drug Companies and Doctors Battle Over the Future of Fecal Transplants

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“For now, most of the material used in fecal transplants comes from OpenBiome, the public stool bank in Cambridge that embraces its mission with both humor and gravitas. Giant poop emojis decorate its offices, conference rooms are named after sections of the intestinal tract and employee birthday cakes invariably come in one flavor: chocolate.

The organization produces 900 to 1,000 monthly treatments, most of them bottled liquids that are packed in dry ice and sent overnight to clinics across the country. Any unpleasant odors are confined to an airtight production facility, where employees in white hazmat suits gingerly handle clear plastic bags filled with a mud-colored slurry.

The material comes from donors who earn $40 a pop and must pass intensive screenings and regular medical checkups. “It’s harder to become a stool donor than it is to get into M.I.T.,” said Carolyn Edelstein, who runs the organization.

In 2012, Ms. Edelstein created OpenBiome with Dr. Smith, now her fiancé, after her cousin contracted recurrent C. diff and, facing a six-month wait for the procedure, did it at home with a roommate’s stool.

A few months later they started OpenBiome with seed money from a foundation and sent out six treatments that first year. “It’s been a wild ride,” Ms. Edelstein said as she showed off a room full of mammoth freezers that hold thousands of screened stool samples.

But OpenBiome and other stool banks are facing an uncertain future. Drug companies, which have been struggling to funnel patients into the clinical studies that are required for F.D.A. approval, would like federal officials to restrict the stool bank’s ability to distribute fecal matter in the hope that more patients will enroll in their trials.

The F.D.A. has ramped up oversight of OpenBiome’s production, leading to more rigorous testing and higher prices, which will double to $1,600 this month.

Patient advocates expect those prices to jump exponentially should the F.D.A. grant market exclusivity to one of the companies that are in the final stages of testing alternatives to raw stool transplants.”

A Delicate Matter

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“Screening donors on an individual basis is not only expensive—it is also not for the squeamish. Carolyn Edelstein is the executive director of OpenBiome, the first stool bank, which operates in the Boston area and provides physicians and researchers with prescreened fecal matter. Before stool banks existed, Edelstein says, physicians had “shelves and shelves of blenders” in which, if they got as far as finding and screening a donor and acquiring a sample, they would need to puree the donation so it could be siphoned through a colonoscopy tube. The blenders had to be thrown away afterward, as they could not be properly sterilized. It was not a sideline most doctors found alluring.

The 2014 FDA guidelines provided no role for—or regulation of—such organizations. “Limiting donations to people the patient or physician knows would eliminate the possibility of using a stool bank,” says Hoffmann. The guidance was updated in 2016, allowing physicians to use a hospital stool bank, but even then the stool sample had to be obtained under the direction of the treating physician.”

Experts call for new approach to regulating fecal transplants

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"A paper today in Science calls for a better way to regulate an increasingly popular method of treating recurrent Clostridium difficile infection (CDI).

The method, known as fecal microbiota transplantation (FMT), involves the transfer of stool from a healthy donor—via colonoscopy, nasogastric tube, or enema—into the colon of a patient who has recurrent CDI to re-introduce healthy bacteria into the gut. While still an investigational treatment, FMT has produced strong results in several small clinical trials in recent years, with cure rates as high as 90%.

A growing number of physicians are turning to it as an alternative to antibiotics—which can contribute to re-infection by wiping out the beneficial gut bacteria that keep C difficile bacteria in check—and several medical societies have said it should be a standard of care for patients with multiply recurrent CDI.

But proponents of FMT are concerned that the unsettled regulatory landscape may be preventing the procedure from being more widely accessible."

Patients Want Poop Transplants. Here's How to Make Them Safe

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“'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."

Read more.

These companies want to transform our gut bugs into drugs. How close are they to market?

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“If you had wanted to be a feces donor for a certain major hospital system before February 2016, you would have had to buy yourself a blender.

On the morning of the transplant, you would have woken up, produced a bit of fresh dung, and blended it with salt water until it had what the hospital described as “a milk-shake-like consistency.” You would have put the slurry in a Ziploc, carried it to the hospital, and — after some futzing — it would have been deposited into the gastrointestinal tract of a family member or friend.

In some ways, the field has come a long way since those DIY days of freezer bags and blenders.”

(Subscription required)

It's Time for FDA-Approved Poo

In an op-ed in the Huffington Post, Catherine Duff, founding president of the Fecal Transplant Foundation and Carolyn Edelstein, director of outreach and public affairs at OpenBiome, reflect on OpenBiome's announcement of its collaboration with Finch Therapeutics and on how an FDA-approved microbiota treatment for recurrent C. difficile infection would transform patient care. 

View the op-ed here. 

Banking on stool despite an uncertain future

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Tina Amirtha from Science discusses the regulatory future of fecal transplants, and how universal stool banks like OpenBiome could continue to make an impact. Here's an excerpt from the article:

"Whatever the commercial future of FMTs, the stool banks say they’ll have other work to do. OpenBiome may focus more on research, Edelstein says. Besides stool, OpenBiome provides guidance on experimental designs, safety protocols, and IND applications. The Leiden bank seeks to advance science as well. It just started a research collaboration with Vedanta Biosciences, and it plans to study whether fecal transplants should be given to C. difficile patients at an earlier stage. “Now, patients receive [an] FMT when they have tried all the other options,” Kuijper says. “But more can easily benefit.” 

Click here for the full article. 

Stool Transplants Save Lives. Why Don't We Use Them Early For Deadly C. Diff?

There is better efficacy data for FMT treatment than for many things that we do to our patients. Isn’t it time that we got over our juvenile squeamishness and offered our patients life-saving stool transplants initially, without cumbersome barriers? This treatment appears more efficacious and is almost certainly cost-effective as well. It’s time for widespread adaptation of this technique, including in those who are acutely ill.

Click here for the full article.

 

OpenBiome remains open to serve the medical community

Members of OpenBiome's leadership authored a Letter to the Editor of Nature Biotechnology in the September 2014 edition, correcting an article that gave the impression that FDA regulations had changed and OpenBiome was no longer in operation.  Here is an excerpt: 

"The article contained a box titled “Stool bank shut down,” indicating that OpenBiome would no longer be able to supply processed stool from rigorously screened anonymous donors for FMT. We would like to clarify that this is not the case. Current FDA guidance allows clinicians to provide FMT for patients with recurrent Clostridium difficile infection (CDI) using material either from patient-identified donors or from stool banks, such as OpenBiome. Indeed, as of July 10, OpenBiome has provided material for >600 treatments to 65 hospitals and clinics in 27 states."

The full letter, which is behind a paywall, may be available to some readers here

FDA grapples with oversight of fecal transplants

"With so few providers available, proponents of stool transplantation have come up with innovative solutions. One big hurdle is the high cost of screening a stool sample, which can run up to $1,500 per sample. Insurance typically doesn't cover testing the stool sample because donors are usually healthy without signs of sickness.

Since October 2013, a Boston-based "stool bank" has managed to bring costs down to about $250 per treatment by screening samples in bulk. To date, OpenBiome has shipped over 300 stool samples in ready-to-use frozen preparations to 39 hospitals.

But in March, the FDA released an updated proposal for regulating fecal transplants, saying doctors should only use stool from a donor who is "known" to either the patient or their physician. Some doctors and patients worried the proposal, if finalized, would shutter OpenBiome and a handful of other stool banks, which use anonymous donors and ship to providers hundreds of miles away.

But OpenBiome founder, Mark Smith, says his group continues operating after having several productive discussions with the FDA. Smith says regulators have encouraged him to set up a formal study in which hospitals that work with OpenBiome will contribute data on the safety and effectiveness of fecal transplants."

Read the full story here on Fox or here on Businessweek. 

MIT Lab Hosts Nation's First Stool Bank, But Will It Survive?

"You walk through a labyrinth of MIT buildings and into what looks like a typical laboratory: white walls and clean counters, the constant buzz of machines, the clutter of pipettes. In the corner, you open the door to a hulking freezer. When the puff of frosty air clears, you see stacks of plastic bottles filled with what looks a little like smoothies — in tawny, rusty colors Odwalla would never market. That’s your first hint of this lab’s unique purpose. Then there’s the giveaway: on the sterile countertop, you see a trophy of a squatting muscleman, labeled “Most Generous Donation.” Welcome to the first national stool bank. It’s like a blood bank, but for fecal matter. And that brown smoothie is actually very healthy stool, parasite-free and loaded with happy bacteria."

Here's the full piece. 

Cambridge stool bank helps meet growing need for fecal transplants

A new post by Carolyn Johnson in the Science in Mind section of Boston.com describes the proposal put forth by OpenBiome co-founder Mark Smith, Dr. Colleen Kelly, and Professor Eric J. Alm in Nature that stool for fecal transplants should be regulated not as a drug but similarly to tissue or blood.  Here is an excerpt:

"A group of researchers from the Massachusetts Institute of Technology and the Alpert Medical School of Brown University proposed Wednesday that fecal transplants be regulated similarly to tissue or blood.

In fecal transplants, a slurry of feces containing the gut bacteria from a healthy donor are implanted into the intestine, either through a nasal tube or a procedure similar to a colonoscopy. Official guidelines about how to screen donors and ensure samples are safe will help bring clarity and uniformity to a field that has become something of a Wild West. Researchers are concerned because YouTube videos now offer guidance on DIY fecal transplants for at-home use, and misinformation is abundant. The team that wrote the study has received questions from people suffering from gastrointestinal infections who wonder whether their pets could be used as donors. (They cannot.)"

The full text is here

Policy: How to regulate faecal transplants

Today in Nature,  a new comment by Mark B. Smith, Colleen Kelly, and Eric J. Alm makes the case that stool used in medical practice should be regulated like tissue or blood, and not like a drug, as current regulations dictate.  The piece highlights the role for stool banks like OpenBiome in facilitating safe access to material, to avoid circumstances in which patients, with no other alternatives, try to perform fecal transplants themselves.  Here's an excerpt: 

"[The first randomized controlled trial investigating the medical use of human feces] was stopped ahead of schedule because the faecal slurry was more than twice as effective in resolving symptoms as antibiotics alone1. Non-randomized studies, with outcomes collected from hundreds of people suffering from recurrent C. difficile infections and treated with similar procedures, have had typical success rates of around 90% (ref. 2).

First described3 in the scientific literature in 1958, faecal microbiota transplantation (FMT), delivers processed stool from a healthy individual to the gut of a sick person through enema, colonoscopy or other means. The goal is to displace pathogenic microbes from the intestine by re-establishing a healthy microbial community. Interest has surged in the past five years (see 'Stool treatment'). At the same time, new regulatory barriers have made FMT more difficult to study or practice."

Mark is a co-founder of OpenBiome and PhD candidate in microbiology at MIT, Dr. Colleen Kelly is a gastroenterologist and clinical assistant professor of medicine at the Alpert Medical School at Brown University, and Dr. Eric Alm is an associate professor of biological engineering at MIT and OpenBiome team member. 

Read the full piece here

Dr. Mike Edmond: "Great news for patients with C. Difficile"

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Dr. Edmond is the Richard P. Wenzel Professor of Internal Medicine in the Division of Infectious Diseases at Virginia Commonwealth University. He also holds a faculty appointment in the Department of Epidemiology and Community Health and serves as the Hospital Epidemiologist for the VCU Health System. He posted about OpenBiome on the blog, Controversies in Hospital Prevention. Here is an excerpt:  

Yesterday I stumbled on OpenBiome's website and as I explored it I was nearly euphoric. [...] The company provides processed, frozen human stool from donors that have been carefully selected and screened for multiple infectious diseases at least twice, at a cost that's 1/6 the price of me testing one donor, and 5 to 14-fold cheaper than the drugs that these patients have taken without success. 

Read the full post here.