NEWS
The US Food and Drug Administration (FDA) took the unusual step of tightening its oversight for the increasingly popular fecal microbiota transplants (FMTs). The draft guidelines, announced in March, were a step back from an earlier draft guidance in which the agency exempted many doctors and companies from filing an investigational new drug (IND) application when using fecal transplants to treat Clostridium difficile infections not responsive to standard therapies. Demand for fecal transplants has surged from both physicians and patients. In the procedure, stool is given by enema, colonoscopy or through a nasal tube, thereby recolonizing or jiggering the balance of microbes in the gut. Its appeal hinges on some strong, if for the most part only loosely documented, evidence of success in treating recurrent C. difficile and a growing belief among biologists that repopulating a person’s gut microbiota might effectively treat a range of infectious diseases and immune-related conditions (Nat. Biotechnol. 31, 309, 2013, and Nat. Biotechnol. 31, 279, 2013). The media’s attraction to a story that’s easy to sensationalize has fueled its acceptability. For FDA, FMT is particularly worrisome given the ready availability of fecal material and the stories filling the Internet on ‘home brew’ FMT, using stool not adequately tested for viral contamination, among other risk factors. FMT was first described in the literature in 1958 and has been used more and more to treat antibiotic-resistant strains of C. difficile. The first randomized, controlled FMT trial, conducted in Amsterdam, was published in The
New England Journal of Medicine in January 2013 (NEJM 368, 407–415, 2013). The study was stopped early when C. difficile-associated diarrhea resolved in 13 of the 16 patients in the FMT-treated group, after a single infusion. Two of the three remaining patients were also cured after repeating the procedure. For the FDA, fecal transplant fits the definition of a biological agent and not transplanted tissue. In an April 2013 letter to the American Gastroenterological Association (AGA), it stated that fecal microbiota would require an IND submission (Nat. Biotechnol. 31, 358, 2013). The agency held a workshop on the subject a month later, and after hearing the pushback from AGA and others, modified its position. In July 2013, the agency said it would waive requirements for an IND for physicians wanting to use FMT to treat recurrent C. difficile by exercising enforcement discretion, on condition that they obtain informed consent. By waiving INDs, the agency was attempting to make FMT available for emergency cases, but expected that it would be a relatively infrequently used treatment. As it turned out, however, interest in stool-based therapies was growing at a faster pace than the agency had anticipated, propelled by a growing number of scientific publications on fecal transplants and a surge in microbiome research generally. And with the enforcement discretion in place, meaningful clinical data were not being collected. This precluded long-term FMT safety and efficacy assessments, which would normally be done for an experimental drug under IND.
Eye of Science/Science Source
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© 2014 Nature America, Inc. All rights reserved.
Fecal transplantation poses dilemma for FDA
A stool sample contains myriad bacteria, which, if transplanted, can re-colonize a person’s gut to treat disease.
NATURE BIOTECHNOLOGY VOLUME 32 NUMBER 5 MAY 2014
401
NEWS
npg
© 2014 Nature America, Inc. All rights reserved.
Box 1 Stool bank shut down In 2011, Eric Alm, an associate professor at MIT and an associate member of the Broad Institute in Cambridge, and Mark Smith, a PhD candidate in Alm’s laboratory, became interested in fecal transplant. At the time, the procedure was limited in scope. “We were trying to figure out where to get samples so we could sequence patients,” Smith says. As they delved into the area, they also became aware of the treatment risks individuals were taking with stool obtained without adequate quality checks. “[We feared] a black market of people doing this at home when there’s no access in a way that’s potentially dangerous,” Smith says. Banking stool, making it available in a standardized, quality-controlled manner to clinicians, seemed like “a good solution to make compliance a little easier and probably safer from the FDA’s perspective,” he says. But FDA thought otherwise. Its decision to allow FMT only when the stool source is known to either the physician or the patient was aimed at and has effectively shut down Open Biome’s efforts in the US. “We are the only organization that would be affected by [the ruling], and our conversation with FDA was consistent with that,” Smith says. Open Biome is working on an IND that investigators will be able to reference for their studies. “We will provide the Master Drug File [an essential part of an IND] as a material supplier,” Smith says, easing the IND process for clinicians. In the meantime, Open Biome is looking at supplying stool for researchers outside the US. “I’d like to create an international registry on FMT—a universal database for clinical and scientific studies.”
What FDA had also not foreseen was that the move prompted organizations to start shipping stool across the country, citing the enforcement discretion policy. Stool banks such as Open Biome, launched by researchers at the Massachusetts Institute of Technology in Cambridge, Massachusetts, were operating without oversight. So in March 2014, FDA changed the guidelines under which it would exercise discretion, adding the caveats that the donor must be known to the physician or the provider and that the donor sample be screened under the direction of the provider. Effectively, it shut down Open Biome (Box 1). “I am disappointed by the new rules,” says Rob Knight of the University of Colorado at Boulder. “I would have thought having banked stool would have a number of advantages,” both in ease of use and the ability to generate overall data. Gerard Honig of Symbiotic Health in New York, which is developing a stool-derived pill now in a clinical trial, agrees. “It’s hard to understand why the specific identity of the donor and the recipient is fundamental to the safety and efficacy of the procedure,” he says. Ironically, in a couple of cases, even as clinicians were bogged down in paperwork in order to comply with FDA, companies were given a pass on the IND requirement. Seres Health of Cambridge, Massachusetts, had filed an application to begin a study of a pill that delivers a small number of organisms originally sourced from stool and specifically selected for the treatment of C. difficile, only to be told later by FDA to withdraw it once the enforcement discretion was in place. (The company, which started a trial of its compound, SER-109, in late 402
2013, reported interim data in January showing an absence of recurrent C. difficile in nine of ten patients treated. It declined to comment on the regulatory process for SER-109.) “I feel like FDA is lurching back and forth,” says Elizabeth Hohmann of the Massachusetts General Hospital in Boston, who is an investigator in the Seres study and separately has two academic trials of FMT ongoing. Her latest study uses frozen encapsulated stool from healthy volunteers she screens. “We were teeing it up for submission to FDA and then they specifically told me I didn’t have to,” she says. The mixed signals are understandable. “The thing that’s a little bit peculiar about [doing studies with FMT] is there’s such strong evidence of clinical efficacy in a number of different formulations,” says infectious disease specialist Bruce Hirsch of North Shore University Hospital in Manhasset, New York, who was similarly contacted by FDA after submitting an IND for an FMT product in collaboration with Symbiotic Health. “It’s a little bit backward because we are starting with high efficacy rates. I feel like I’m in the midst of a phase 4 [post-marketing] trial.” “I think the treatment is [effective] for C. difficile, but for all these other indications, it’s a can of worms,” adds Colleen Kelly of the Alpert Medical School at Brown University in Providence, Rhode Island. Kelly recently wrote a paper guiding investigators on how to prepare an IND for FMT. “Most people who email me want FMT for something else,” she says. “That’s where the FDA doesn’t want to get overly excited.” FMT and related products, be they distilled or purified forms of gut microbiota, are being thought of as potential treat-
ments for decolonization of organisms like vancomycin-resistant enterococcus; infection control surveillance; other antibiotic-induced disruption of gastrointestinal function including from cancer chemotherapy; ulcerative colitis; irritable bowel syndrome; associations with immune activation in HIV; in metabolic syndrome; and to induce weight loss by influencing microbiome shift. “We have no long-term safety data and no efficacy data except for C. difficile,” Kelly says. “FDA has to get a handle on it.” At the same time, she wouldn’t want the regulations to be overly burdensome such that a doctor couldn’t look up the protocol, find a good donor and give FMT to a patient with recurrent C. difficile. Evidence from C. difficile treatments has meant FMT has had “an outsized influence in the whole field of the microbiome,” says Bernat Olle of Vedanta Biosciences in Boston, a startup developing a cocktail of microbiota for treating C. difficile infection. Limited reimbursement is available for FMT in recurrent C. difficile in the US. And FMT is widely accepted as the standard of care for the infection in Europe: the UK National Institute for Health and Care Excellence stated in March that FMT is safe and effective for treating the condition. “All the substantial clinical evidence for the promise of the [microbiome] field has come from fecal transplants,” says Olle. “We don’t want anyone to poison the well and screw up fecal transplant work and the progress or the safety of the field.” That said, FMT is a first step in microbiomial drug development. “It’s a crude wholesale rewrite of the microbiome,” says David Berry of Seres Health. “Part of the challenge when dealing with wholesale material is there’s a lot more in there than just a set of bacteria.” It’s also costly. Hohmann estimates her laboratory would at minimum have to spend $800–900 to do the appropriate medical screening and stool screening of the donors for FMT. Despite the constraints, fecal transplants will remain competitive, says Symbiotic Health’s Honig. But he also expects that a targeted therapy could compete in terms of the cost of production. “I see this as the beginning of a progression of [improvements],” says Lee Jones of Rebiotix in Roseville, Minnesota, the only company to run an FMT trial under an IND thus far. It has completed enrollment of a phase 2 study using a suspension of fecal material formulated for enema delivery, a preparation that can be inventoried, stored and shipped. “I’d bet that in five years we will go back and laugh that we started out this way,” Jones says. Mark Ratner Boca Raton, Florida
VOLUME 32 NUMBER 5 MAY 2014 NATURE BIOTECHNOLOGY
The US Food and Drug Administration (FDA) took the unusual step of tightening its oversight for the increasingly popular fecal microbiota transplants (FMTs). The draft guidelines, announced in March, were a step back from an earlier draft guidance in which the agency exempted many doctors and companies from filing an investigational new drug (IND) application when using fecal transplants to treat Clostridium difficile infections not responsive to standard therapies. Demand for fecal transplants has surged from both physicians and patients. In the procedure, stool is given by enema, colonoscopy or through a nasal tube, thereby recolonizing or jiggering the balance of microbes in the gut. Its appeal hinges on some strong, if for the most part only loosely documented, evidence of success in treating recurrent C. difficile and a growing belief among biologists that repopulating a person’s gut microbiota might effectively treat a range of infectious diseases and immune-related conditions (Nat. Biotechnol. 31, 309, 2013, and Nat. Biotechnol. 31, 279, 2013). The media’s attraction to a story that’s easy to sensationalize has fueled its acceptability. For FDA, FMT is particularly worrisome given the ready availability of fecal material and the stories filling the Internet on ‘home brew’ FMT, using stool not adequately tested for viral contamination, among other risk factors. FMT was first described in the literature in 1958 and has been used more and more to treat antibiotic-resistant strains of C. difficile. The first randomized, controlled FMT trial, conducted in Amsterdam, was published in The
New England Journal of Medicine in January 2013 (NEJM 368, 407–415, 2013). The study was stopped early when C. difficile-associated diarrhea resolved in 13 of the 16 patients in the FMT-treated group, after a single infusion. Two of the three remaining patients were also cured after repeating the procedure. For the FDA, fecal transplant fits the definition of a biological agent and not transplanted tissue. In an April 2013 letter to the American Gastroenterological Association (AGA), it stated that fecal microbiota would require an IND submission (Nat. Biotechnol. 31, 358, 2013). The agency held a workshop on the subject a month later, and after hearing the pushback from AGA and others, modified its position. In July 2013, the agency said it would waive requirements for an IND for physicians wanting to use FMT to treat recurrent C. difficile by exercising enforcement discretion, on condition that they obtain informed consent. By waiving INDs, the agency was attempting to make FMT available for emergency cases, but expected that it would be a relatively infrequently used treatment. As it turned out, however, interest in stool-based therapies was growing at a faster pace than the agency had anticipated, propelled by a growing number of scientific publications on fecal transplants and a surge in microbiome research generally. And with the enforcement discretion in place, meaningful clinical data were not being collected. This precluded long-term FMT safety and efficacy assessments, which would normally be done for an experimental drug under IND.
Eye of Science/Science Source
npg
© 2014 Nature America, Inc. All rights reserved.
Fecal transplantation poses dilemma for FDA
A stool sample contains myriad bacteria, which, if transplanted, can re-colonize a person’s gut to treat disease.
NATURE BIOTECHNOLOGY VOLUME 32 NUMBER 5 MAY 2014
401
NEWS
npg
© 2014 Nature America, Inc. All rights reserved.
Box 1 Stool bank shut down In 2011, Eric Alm, an associate professor at MIT and an associate member of the Broad Institute in Cambridge, and Mark Smith, a PhD candidate in Alm’s laboratory, became interested in fecal transplant. At the time, the procedure was limited in scope. “We were trying to figure out where to get samples so we could sequence patients,” Smith says. As they delved into the area, they also became aware of the treatment risks individuals were taking with stool obtained without adequate quality checks. “[We feared] a black market of people doing this at home when there’s no access in a way that’s potentially dangerous,” Smith says. Banking stool, making it available in a standardized, quality-controlled manner to clinicians, seemed like “a good solution to make compliance a little easier and probably safer from the FDA’s perspective,” he says. But FDA thought otherwise. Its decision to allow FMT only when the stool source is known to either the physician or the patient was aimed at and has effectively shut down Open Biome’s efforts in the US. “We are the only organization that would be affected by [the ruling], and our conversation with FDA was consistent with that,” Smith says. Open Biome is working on an IND that investigators will be able to reference for their studies. “We will provide the Master Drug File [an essential part of an IND] as a material supplier,” Smith says, easing the IND process for clinicians. In the meantime, Open Biome is looking at supplying stool for researchers outside the US. “I’d like to create an international registry on FMT—a universal database for clinical and scientific studies.”
What FDA had also not foreseen was that the move prompted organizations to start shipping stool across the country, citing the enforcement discretion policy. Stool banks such as Open Biome, launched by researchers at the Massachusetts Institute of Technology in Cambridge, Massachusetts, were operating without oversight. So in March 2014, FDA changed the guidelines under which it would exercise discretion, adding the caveats that the donor must be known to the physician or the provider and that the donor sample be screened under the direction of the provider. Effectively, it shut down Open Biome (Box 1). “I am disappointed by the new rules,” says Rob Knight of the University of Colorado at Boulder. “I would have thought having banked stool would have a number of advantages,” both in ease of use and the ability to generate overall data. Gerard Honig of Symbiotic Health in New York, which is developing a stool-derived pill now in a clinical trial, agrees. “It’s hard to understand why the specific identity of the donor and the recipient is fundamental to the safety and efficacy of the procedure,” he says. Ironically, in a couple of cases, even as clinicians were bogged down in paperwork in order to comply with FDA, companies were given a pass on the IND requirement. Seres Health of Cambridge, Massachusetts, had filed an application to begin a study of a pill that delivers a small number of organisms originally sourced from stool and specifically selected for the treatment of C. difficile, only to be told later by FDA to withdraw it once the enforcement discretion was in place. (The company, which started a trial of its compound, SER-109, in late 402
2013, reported interim data in January showing an absence of recurrent C. difficile in nine of ten patients treated. It declined to comment on the regulatory process for SER-109.) “I feel like FDA is lurching back and forth,” says Elizabeth Hohmann of the Massachusetts General Hospital in Boston, who is an investigator in the Seres study and separately has two academic trials of FMT ongoing. Her latest study uses frozen encapsulated stool from healthy volunteers she screens. “We were teeing it up for submission to FDA and then they specifically told me I didn’t have to,” she says. The mixed signals are understandable. “The thing that’s a little bit peculiar about [doing studies with FMT] is there’s such strong evidence of clinical efficacy in a number of different formulations,” says infectious disease specialist Bruce Hirsch of North Shore University Hospital in Manhasset, New York, who was similarly contacted by FDA after submitting an IND for an FMT product in collaboration with Symbiotic Health. “It’s a little bit backward because we are starting with high efficacy rates. I feel like I’m in the midst of a phase 4 [post-marketing] trial.” “I think the treatment is [effective] for C. difficile, but for all these other indications, it’s a can of worms,” adds Colleen Kelly of the Alpert Medical School at Brown University in Providence, Rhode Island. Kelly recently wrote a paper guiding investigators on how to prepare an IND for FMT. “Most people who email me want FMT for something else,” she says. “That’s where the FDA doesn’t want to get overly excited.” FMT and related products, be they distilled or purified forms of gut microbiota, are being thought of as potential treat-
ments for decolonization of organisms like vancomycin-resistant enterococcus; infection control surveillance; other antibiotic-induced disruption of gastrointestinal function including from cancer chemotherapy; ulcerative colitis; irritable bowel syndrome; associations with immune activation in HIV; in metabolic syndrome; and to induce weight loss by influencing microbiome shift. “We have no long-term safety data and no efficacy data except for C. difficile,” Kelly says. “FDA has to get a handle on it.” At the same time, she wouldn’t want the regulations to be overly burdensome such that a doctor couldn’t look up the protocol, find a good donor and give FMT to a patient with recurrent C. difficile. Evidence from C. difficile treatments has meant FMT has had “an outsized influence in the whole field of the microbiome,” says Bernat Olle of Vedanta Biosciences in Boston, a startup developing a cocktail of microbiota for treating C. difficile infection. Limited reimbursement is available for FMT in recurrent C. difficile in the US. And FMT is widely accepted as the standard of care for the infection in Europe: the UK National Institute for Health and Care Excellence stated in March that FMT is safe and effective for treating the condition. “All the substantial clinical evidence for the promise of the [microbiome] field has come from fecal transplants,” says Olle. “We don’t want anyone to poison the well and screw up fecal transplant work and the progress or the safety of the field.” That said, FMT is a first step in microbiomial drug development. “It’s a crude wholesale rewrite of the microbiome,” says David Berry of Seres Health. “Part of the challenge when dealing with wholesale material is there’s a lot more in there than just a set of bacteria.” It’s also costly. Hohmann estimates her laboratory would at minimum have to spend $800–900 to do the appropriate medical screening and stool screening of the donors for FMT. Despite the constraints, fecal transplants will remain competitive, says Symbiotic Health’s Honig. But he also expects that a targeted therapy could compete in terms of the cost of production. “I see this as the beginning of a progression of [improvements],” says Lee Jones of Rebiotix in Roseville, Minnesota, the only company to run an FMT trial under an IND thus far. It has completed enrollment of a phase 2 study using a suspension of fecal material formulated for enema delivery, a preparation that can be inventoried, stored and shipped. “I’d bet that in five years we will go back and laugh that we started out this way,” Jones says. Mark Ratner Boca Raton, Florida
VOLUME 32 NUMBER 5 MAY 2014 NATURE BIOTECHNOLOGY
