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Fecal microbiota transplantation moves into the mainstream

Published reports of fecal microbiota transplantation in modern history date as far back as the 1950s, but in just the past few years, it has rapidly moved from the fringe toward the mainstream as a highly effective therapy for recurrent Clostridium difficile infection. Mounting data have established fecal microbiota transplantation’s efficacy and apparent safety for this indication, and as the incidence of C. difficile infection continues to increase along with more recurrent, severe and antibiotic-resistant cases, fecal microbiota transplantation has become an increasingly accepted intervention by patients, physicians, researchers, industry and regulatory bodies.

While experts agree fecal microbiota transplantation (FMT) appears safe and is relatively simple to perform, a number of challenges continue to limit more widespread practice. These include evolving regulatory issues and the need for more prospective safety data, best practices and improved delivery methods. Furthermore, as FMT’s high cure rate for recurrent C. difficile infection is essentially a proof-of-concept for treating disease by altering the intestinal microbiome, a boom in research on FMT for other indications is currently ongoing, and refined therapeutic alternatives to whole stool transplantation are in development.

Infectious Disease News spoke with several experts about the safety and efficacy of FMT in the treatment of C. difficile, as well as the underlying mechanisms and broader implications of microbiome-based therapies.

Colleen R. Kelly, MD, from Brown University, said data supporting use of FMT for severe cases of C. difficile are promising.

Photo courtesy of Kelly CR

A mainstay for recurrent C. difficile, promising for severe C. difficile

In the past few years, multiple systematic reviews and meta-analyses have been published showing FMT has approximately 90% efficacy in treating recurrent C. difficile infection with minimal adverse events. A recent review by Drekonja and colleagues, which looked at two randomized controlled trials and 21 case series involving 516 patients who received FMT for recurrent C. difficile infection, demonstrated symptom resolution in 85% of patients across all studies.

“We have a large number of papers and great quality of data supporting great efficacy and safety of fecal transplant in the treatment of recurrent C. difficile,Monika Fischer, MD, MSc, from Indiana University Health, said during her presentation at Digestive Disease Week 2015 in Washington, D.C. In addition to the systematic reviews and meta-analyses, “now we have three [randomized controlled trials] evaluating this question,” the findings of which she summarized during her talk.

In the first study by van Nood and colleagues, published in 2013 in the New England Journal of Medicine, 43 patients were randomly assigned to receive FMT via nasoduodenal tube following an abbreviated vancomycin regimen and bowel lavage, a standard vancomycin regimen or a standard vancomycin regimen with bowel lavage. “This study ... was terminated early because of the interim analysis discovering superior results in the fecal transplant compared to the vancomycin group,” Fischer said.

The next, published by Youngster and colleagues in 2014 in Clinical Infectious Diseases, “evaluated the differences between colonoscopy and nasogastric tube delivery mode. They used frozen stool and they found slightly better outcomes in the colonoscopy delivery. ... Overall they showed a similarly high cure rate of 90% and notably, no adverse events were reported.”

The latest RCT by Cammarota and colleagues, recently published in Alimentary Pharmacology & Therapeutics, “randomized patients with recurrent C. difficile to either fecal transplants via colonoscopy after 3 days of pretreatment with vancomycin, or vancomycin for 10 days followed by a pulse regimen of vancomycin given every 2 to 3 days for at least 3 weeks. After the first FMT, the FMT group had a 65% success rate compared to only 26% in the vancomycin group. ... Again, the overall cure with repeat FMTs was great in the fecal transplant group: similarly 90% as we’ve seen in the previous RCTs.”

According to Fischer, this RCT also is the latest of several studies demonstrating promising results for FMT in patients with severe and severe/complicated C. difficile infection. Patients with pseudomembranous colitis in this study, who received a vigorous sequential FMT protocol wherein FMT was administered every 3 days until symptom resolution, “were eventually cured.” Similar phenomena, she said, were described in a case series by Alexander Khoruts, MD, from the University of Minnesota, who cured two patients after recognizing “reinitiation of vancomycin or an anti-C. difficile antibiotic might be necessary to achieve complete resolution, and also further FMTs might be needed.”

Prompted by these data and anecdotal experience, Fischer and colleagues developed a protocol at their institution “that contains sequential FMT plus selective use of vancomycin based upon the presence of pseudomembranes during index colonoscopy in patients with severe and severe complicated [C. difficile infection].” At the time of the presentation, 29 cases were included in their analysis and prospectively followed. “With this approach, we were able to cure 93% of patients who achieved complete resolution and were able to be discharged from the hospital at 1 month; 76% of patients survived at 3 months but all deaths after 3 months were unrelated to C. difficile.”

Similarly promising results were demonstrated in a multicenter retrospective series by Aroniadis and colleagues, Fischer added, with an overall cure rate of 94%.

While a 2010 expert consensus statement on indications for FMT does include even fulminant severe C. difficile infection that does not respond to standard therapy, data supporting its use for this indication are less robust, and thus, it should be used with caution in these high-risk patients, according to Colleen R. Kelly, MD, from Brown University. However, existing results appear promising, and there is interest among her colleagues in performing a larger controlled trial of FMT for severe disease, she said.

Monika Fischer

More recent recommendations of eligible patients from the 2013 American College of Gastroenterology C. difficile treatment guidelines include those with at least three recurrences, at least two severe episodes requiring hospitalization or recurrence despite vancomycin taper or pulse regimen. Physicians are currently able to follow these society recommendations due to the FDA’s current policy of “enforcement discretion” for FMT when used to treat C. difficile infection that does not respond to standard therapies. According to Kelly, while this policy has given many patients with recurrent C. difficile infection access to FMT, it is “probably only temporary,” and the FDA’s position will continue to evolve as it considers the issue further.

Rapidly evolving regulations

According to Kelly, the regulation of FMT is highly variable across the globe, but the FDA has determined it to be a drug and a biologic, which requires an investigational new drug (IND) application to administer due to its unapproved status.

“The FDA’s policy wasn’t initially enforcement discretion,” Kelly told Infectious Disease News. “When they initially announced their policy in May 2013, they basically said you need an IND to do FMT ... and everyone kind of flipped out.” Clinicians knew the IND process would be an enormous administrative burden, she said, and patient advocacy groups warned the policy would impede FMT’s availability and potentially lead to patients performing home treatments.

“The FDA reconsidered, and announced an ‘enforcement discretion’ policy in July 2013,” which still requires an IND except in cases of C. difficile infection not responding to standard therapy, “provided you give the patient informed consent, explain to them any potential risk and state that it is experimental,” Kelly said. “They left it like that for almost a year, and then the stool banks started.”

Stool banks

OpenBiome, for example, is a nonprofit stool bank established in 2012 in Medford, Massachusetts, with the goal of expanding safe access to FMT. “We are a nonprofit public stool bank dedicated to finding and rigorously screening universal donors,” Laura J. Burns, who recently presented data on OpenBiome’s rigorous universal donor screening methodology at DDW 2015, said. “We process their stool, bank it and then we can send it to physicians all over the country and all over the world.”

According to Kelly, who is a member of OpenBiome’s clinical advisory board, it was partially in response to stool banks operating without an IND that the FDA issued a March 2014 draft guidance that proposed a donor must be known by the recipient or physician, which “would obviously negate a stool bank” using volunteer donors. The FDA then “invited public comment on [the] draft guidance ... and there were a lot of comments from doctors, professional societies and industry,” Kelly said.

As a result, the draft guidance was never officially enacted, “so at this point it is still permissible to use stool from OpenBiome. ... They’re doing a fabulous job with their screening, and the FDA is fully aware of what they are doing,” Kelly said.

In response to a request for comment on the current status of this proposal, an FDA spokeswoman said in May that the administration is “currently reviewing and considering the comments received on the March draft guidance. Please note that the draft guidance has not yet been finalized, and the July 2013 guidance expresses the FDA’s current policy. It would be inappropriate for us to speculate at this time on when the draft guidance will be finalized.”

Currently, OpenBiome is FDA registered, is working closely with regulatory stakeholders and has, to date, shipped more than 4,200 doses across the country, according to Zain Kassam, MD, MPH, chief medical officer at OpenBiome and research affiliate at the MIT Center for Microbiome Informatics and Therapeutics.

“Our stool bank has a deep respect for the regulatory challenges the FDA is facing in this rapidly evolving space, and it’s important we recognize their thoughtful stance to allow enforcement discretion for the use of FMT in C. difficile not responsive to standard therapy,” Kassam told Infectious Disease News. “Crafting this policy has conservatively saved more than 4,000 patients from a terrible quality of life” and also saved the health care system millions of dollars.

“In my eyes, enforcement discretion highlights an understanding by the FDA that FMT is a square peg, and doesn’t nicely fit into the round hole like other treatments.”

Carolyn A. Edelstein

Also from OpenBiome, Carolyn A. Edelstein, MPA, a thought leader in FMT regulation, recently co-authored a paper appearing in the Journal of Law and Biosciences that examines the challenges in regulating FMT as a biologic drug and proposes a hybrid model similar to cord blood.

In an interview with Infectious Disease News, she said, “Fecal microbiota is an unusual substance to regulate, and one that doesn’t fit neatly under the drug paradigm. The complexity of the microbial community, which varies from person to person, and batch to batch, is not easy to break down into pure ‘active ingredients.’ Instead, the tissue model might make more sense: these regulations emphasize the methods for collecting, processing and storing the material, all of which we should worry about in the context of stool.”

“As a public health advocate, I think it’s possible to imagine creative policy and regulatory solutions,” Kassam said. “Drawing orthogonally from other spaces, we know that blood transfusions were the only treatment for anemia for many years. However, the emergence of erythropoietin, a conventional drug, hasn’t eliminated the need for blood transfusions. Both play important roles in the health care system. Both coexist in harmony. There is choice, and this is something both patients and physicians seek.”

Novel therapeutics

Stool banks like OpenBiome serve a purpose in the current regulatory landscape, but it is indeed possible that the FDA would cease the enforcement discretion policy once it approves a commercialized FMT preparation for recurrent C. difficile infection, a number of which are currently in development, Kelly said.

In September 2014, Seres Health announced a 97% cure rate achieved in a phase 1/2 study of SER-109, its oral microbiome therapeutic, which has received orphan drug designation for recurrent C. difficile infection by the FDA. The treatment is currently undergoing phase 3 study, according to investigator Colleen S. Kraft, MD, of Emory University School of Medicine, and if successful would be submitted to the FDA for approval.

In December 2014, Rebiotix announced the commencement of a placebo-controlled trial (PUNCH CD 2 study) for its microbiota-based drug RBX2660, which also has received orphan drug and fast track designations from the FDA. This followed positive results from a prospective, multicenter, randomized, double blind, placebo-controlled trial, in which “efficacy of RBX2660, defined as the absence of C. difficile infection at 8 weeks after the last treatment, was 87.1% (27/31),” Mary Kay Sobcinski, RN, MHA, director of clinical operations at Rebiotix, told Infectious Disease News. “RBX2660 demonstrated a satisfactory safety profile in the study targeted at recurrent C. difficile infection, which included very rigorous documentation of adverse events.”

“It’s going to be very difficult for any formulation ... to meet the FDA’s standardization requirement,” Kelly said, “but we’re headed in the direction of commercial formulations. I think we’re still 3 to 5 years away from seeing one out there for actual use.”

According to Kassam, these new biological drugs should be compared with conventional FMT instead of placebo in clinical trials, and long-term safety and efficacy data should be acquired before they are approved. “Speaking with patients, physicians and health care stakeholders, given the body of evidence for FMT in C. difficile, most believe newer agents must show a benefit over FMT to change their hearts and minds,” he said.

Edelstein added, “Also, if we license a drug manufacturer to provide FMT preparations, then physicians can provide the material off-label, which could undermine research efforts to explore the safety and efficacy of FMT for other indications.”

Despite the hurdle, standardized therapies such as these could remove many of the regulatory roadblocks currently plaguing recurring C. difficile treatment and are worth pursuing, Kraft said.

“The FDA does not like [FMT], so for a practitioner like myself, it’s a very hard place to be,” Kraft told Infectious Disease News. “I see the sort of excellent results we get and ... to withhold that from the patients [is] not a good thing. I don’t want to do something that’s always on the border.”

For now, the FDA’s enforcement discretion policy stands, which continues to serve a dual role Kassam describes as “nimble and thoughtful” and Kelly describes as “brilliant,” because it gives people access to FMT for C. difficile infection while at the same time blocking FMT for other indications for which safety and efficacy data are currently insufficient.

Early evidence of MDR organism recolonization

Early studies of FMT for an array of other indications are a major area of interest, including irritable bowel syndrome, fatty liver disease, obesity, type 2 diabetes, metabolic syndrome, hepatic encephalopathy, pediatric allergy disorders, autism, neuropsychiatric disorders, inflammatory arthritis and others. Although treatments for conditions outside C. difficile are still premature, Kraft said, FMT’s influence on the microbiome could reduce the impact of multidrug-resistant bacteria colonized in the gut.

“Instead of treating these patients with more and more antibiotics while their organisms become more and more resistant,” Kraft said, “if we change the colonization of their gut ... then we could eliminate the reservoir of some of these MDR organisms.”

A recent case study published in Open Forum Infectious Diseases by Joshua Stripling, MD, of the infectious disease division at the University of Alabama at Birmingham, and colleagues described a reduction of both C. difficile and vancomycin-resistant Enterococcus (VRE) following FMT. The patient, a female aged 33 years, received orthotopic cardiac and single cadaveric kidney transplants and later developed multiple episodes of bacteremia and urinary tract infections resulting from VRE and C. difficile fecal colonization. FMT was performed using donor fecal samples obtained from the patient’s spouse.

Analysis of 3-week and 7-month samples revealed that the patient’s gut microbiota, which was initially dominated by Enterococcus (84%), had increased overall diversity and reduced Enterococcus (24% and 0.2%). The procedure was well-tolerated by the patient, who has not demonstrated C. difficile or VRE episodes at 1 year follow-up and has not required hospitalization since FMT.

These data are the first in a human case demonstrating FMT’s ability to replace MDR bacteria in the gut, Stripling and colleagues wrote, and further study is still required to confirm its efficacy. Regardless, Kraft said the potential of these data represents “a very exciting realm for fecal transplant.”

“If you could create a normal microbiome so these things aren’t harbored, then we can decrease the number of bloodstream infections and pneumonia in individuals who are carrying these MDR organisms,” Kraft said. “They might still get infections, but they won’t be as drug-resistant.”

Refining the product

Further work on refining FMT is one of OpenBiome’s main priorities, Kassam said. For example, FMT is not currently prepared anaerobically at OpenBiome, so oxygen kills many of the bacteria, and thus “we’re really only doing FMT 10%. A lot of the microbial community is being killed by oxygen, which isn’t important for C. difficile, but it may matter a lot for other diseases where other bacteria sensitive to oxygen may produce very important small chain fatty acids and other products that are really a part of the transplant. We need to do 100% FMT, not just the 10%.”

Furthermore, not enough is known concerning the effect of FMT on a patient’s microbiome, Kassam said, and additional research is needed to fine tune the treatment of recurrent C. difficile.

“Right now, we’re killing a mosquito with an atomic bomb, in a way,” Kassam said. “We’re using a very broad, crude therapy to address what we think is, at this point, a relatively simple problem. But over time we may be able to discover the secret sauce. There are a number of key organisms that may be very important, but also, in the same breath, in finding the key organism, we must ensure that it’s safe, which is OpenBiome’s No. 1 priority. We don’t know yet, but an entire healthy ecosystem may be safer than a single set of organisms.” – by Adam Leitenberger and Dave Muoio

Editor’s note: This article originally appeared in IDN’s sister publication, Healio Gastroenterology.

Disclosures: Fischer and Kassam report no relevant financial disclosures. Kelly reports being a consultant for Seres Health and U.S. Endoscopy. Kraft is an investigator on a trial funded by Seres Health. Sobcinski is an employee of Rebiotix.

POINTCOUNTER

Is the FDA’s ‘enforcement discretion’ policy adequate for the regulation of FMT?

POINT

Yes.

The FDA has taken an appropriate position for treatment of Clostridium difficile infection. It is to the agency’s credit that it has assessed the clinical landscape and responded to this fast-moving field. It would not be a valuable use of anyone’s time to be submitting and reviewing clinical uses of stool for single patients, and sadly there are simply too many patients with recurrent C. difficile infection seeking this highly effective therapy to set up even modest hurdles, in my opinion. There are standard recommendations for screening of donors that can be fairly easily undertaken, though I suspect that for close family members, or an intimate partner of a patient, a standard stool culture for enteric pathogens may be all that is done sometimes. The “full Monty” of donor screening tests can cost upward of $1,200 and much more if a patient were to be charged the full freight at a laboratory, putting individualized therapy out of range of many who do not have good insurance coverage. Ironically, some family donors have stool tests done and charged to their own insurance, with the diagnosis of “diarrhea!” Beware of engaging your compliance and billing people on that one. This field is challenging enough; patients and doctors should not be asked to run a regulatory gauntlet as well. Despite the fact that most patients getting FMT for recurrent C. difficile infection are older and have numerous medical comorbidities, to my knowledge there are no convincing reports of infections transmitted by FMT. This does not mean it will not happen, but I think it means the incidence is very low in the hands of responsible GI and ID practitioners (A Google map for FMT providers in the United States can be found here: www.google.com/maps/d/viewer?mid=z2AxJq2nTqAg.k5dy1hmJP39E&hl=en_US).

For the older active person confined to their home because of recurrent and unpredictable diarrhea, the benefit/risk ratio of FMT seems entirely reasonable. I recently consulted on just such a patient who lived alone and had fallen and fractured a rib while running to the bathroom because of relapsed C. difficile infection, necessitating hospitalization. I envisioned pneumonia, more antibiotics, more C. difficile ... the beat goes on! An interesting issue to consider is how the regulatory landscape will change when the FDA approves microbiome-based treatments. The two products furthest along are SER-109 (Seres Therapeutics) and Rebiotix’s RBX2660, both on a fast-track pathway at the FDA (another good, if obvious, decision). These human stool-derived products will undoubtedly come with a fairly hefty price tag. Also, both of these products as currently designed are frozen, and they are not something that will be stored and available at every pharmacy. Of course, the ultimate goal is a defined mixture of cultured, freeze-dried beneficial microbes. One wonders whether “regular” FMT will still be done, perhaps as a “cheap” alternative, as these milestones are reached and how FMT will in the future be viewed from a regulatory perspective. It is worth a mention that as an “FMT provider,” I receive calls at least weekly from patients seeking FMT for all manner of non-C. difficile infection indications. That is, and should be, under careful review and investigation by regulators, clinicians and scientists.

Elizabeth L. Hohmann MD, is an associate professor of medicine and infectious diseases and the chair and director of Partners Human Research Committees at Brigham and Women’s Hospital and Massachusetts General Hospital. Disclosure: Hohmann is an investigator in a clinical study of SER-109.

COUNTER

Yes, but ...

FMT and its clinical efficacy represent a challenge to regulatory agencies, health care payors, clinicians and patients. Unlike most pharmaceutical agents, FMT defies standardization. The striking consistency of the reported cure rate of 90% for recurrent C. difficile infection in numerous studies contrasts with the microbial diversity and unpredictable standardization from donor to donor and sample to curative sample.

The FDA and general medical community have three priorities to fulfill in regards to FMT for recurrent C. difficile infection: 1) to assure safety and minimize the risk for transmission of infectious agents; 2) to promote the most effective treatments for recurrent C. difficile infection — a miserable, dangerous and contagious disorder recognized as an “urgent health threat” by the CDC; and 3) to explore the compelling implications for human health that are implied by FMT’s restoration of the gut microbiome.

Clinicians who provide FMT cope with the requirements of identifying and screening suitable donors, processing fecal material and administering FMT, and providing ongoing care for patients. The FDA’s current policy (issued July 2013) of exercising “enforcement discretion” is permissive of this effort. The policy mandates an informed consent process in which FMT is described as investigational and that the risks of the procedure be reviewed. Published guidelines set clinical standards of safety (Bakken JS, et al. Clin Gastroenterol Hepatol. 2011;doi:10.1016/j.cgh.2011.08.014). The scientific community has embraced the microbiome as a focus of investigation.

The persisting characterization of FMT as “experimental” is obsolete. With three randomized clinical trials, multiple case series and clinical acceptance, FMT is emerging as a standard of care for recurrent C. difficile infection. FMT relieves suffering, provides value to our patients and enhances the safety of the community. Health care payors’ response has been slow and inadequate. Typical reimbursement rates for FMT approximates half of the cost of a course of oral vancomycin and less than one-tenth of the cost of Dificid (fidaxomicin, Cubist Pharmaceuticals). The requirements of effort and time limit the availability of this high-value, though unconventional, treatment. Low availability of this effective therapeutic risks “do-it-yourself” patient efforts with increased potential of spread of infectious agents.

The FDA’s permissive policy and ongoing review makes FMT possible. Health care payors, including CMS, need to honor its value. Clinicians should access resources and refer appropriately to make FMT available to patients. We all need to learn about microbiota-based therapeutics to promote health.

Bruce E. Hirsch MD, FACP, AAHIVS, is an attending physician in the division of infectious diseases at North Shore University Hospital. Disclosure: Hirsch is president for clinical affairs at Symbiotic Health, a start-up dedicated to developing bacteria-based therapeutics, now focused on oral capsules for recurrent C. difficile infection.

Published reports of fecal microbiota transplantation in modern history date as far back as the 1950s, but in just the past few years, it has rapidly moved from the fringe toward the mainstream as a highly effective therapy for recurrent Clostridium difficile infection. Mounting data have established fecal microbiota transplantation’s efficacy and apparent safety for this indication, and as the incidence of C. difficile infection continues to increase along with more recurrent, severe and antibiotic-resistant cases, fecal microbiota transplantation has become an increasingly accepted intervention by patients, physicians, researchers, industry and regulatory bodies.

While experts agree fecal microbiota transplantation (FMT) appears safe and is relatively simple to perform, a number of challenges continue to limit more widespread practice. These include evolving regulatory issues and the need for more prospective safety data, best practices and improved delivery methods. Furthermore, as FMT’s high cure rate for recurrent C. difficile infection is essentially a proof-of-concept for treating disease by altering the intestinal microbiome, a boom in research on FMT for other indications is currently ongoing, and refined therapeutic alternatives to whole stool transplantation are in development.

Infectious Disease News spoke with several experts about the safety and efficacy of FMT in the treatment of C. difficile, as well as the underlying mechanisms and broader implications of microbiome-based therapies.

Colleen R. Kelly, MD, from Brown University, said data supporting use of FMT for severe cases of C. difficile are promising.

Photo courtesy of Kelly CR

A mainstay for recurrent C. difficile, promising for severe C. difficile

In the past few years, multiple systematic reviews and meta-analyses have been published showing FMT has approximately 90% efficacy in treating recurrent C. difficile infection with minimal adverse events. A recent review by Drekonja and colleagues, which looked at two randomized controlled trials and 21 case series involving 516 patients who received FMT for recurrent C. difficile infection, demonstrated symptom resolution in 85% of patients across all studies.

“We have a large number of papers and great quality of data supporting great efficacy and safety of fecal transplant in the treatment of recurrent C. difficile,Monika Fischer, MD, MSc, from Indiana University Health, said during her presentation at Digestive Disease Week 2015 in Washington, D.C. In addition to the systematic reviews and meta-analyses, “now we have three [randomized controlled trials] evaluating this question,” the findings of which she summarized during her talk.

In the first study by van Nood and colleagues, published in 2013 in the New England Journal of Medicine, 43 patients were randomly assigned to receive FMT via nasoduodenal tube following an abbreviated vancomycin regimen and bowel lavage, a standard vancomycin regimen or a standard vancomycin regimen with bowel lavage. “This study ... was terminated early because of the interim analysis discovering superior results in the fecal transplant compared to the vancomycin group,” Fischer said.

The next, published by Youngster and colleagues in 2014 in Clinical Infectious Diseases, “evaluated the differences between colonoscopy and nasogastric tube delivery mode. They used frozen stool and they found slightly better outcomes in the colonoscopy delivery. ... Overall they showed a similarly high cure rate of 90% and notably, no adverse events were reported.”

The latest RCT by Cammarota and colleagues, recently published in Alimentary Pharmacology & Therapeutics, “randomized patients with recurrent C. difficile to either fecal transplants via colonoscopy after 3 days of pretreatment with vancomycin, or vancomycin for 10 days followed by a pulse regimen of vancomycin given every 2 to 3 days for at least 3 weeks. After the first FMT, the FMT group had a 65% success rate compared to only 26% in the vancomycin group. ... Again, the overall cure with repeat FMTs was great in the fecal transplant group: similarly 90% as we’ve seen in the previous RCTs.”

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According to Fischer, this RCT also is the latest of several studies demonstrating promising results for FMT in patients with severe and severe/complicated C. difficile infection. Patients with pseudomembranous colitis in this study, who received a vigorous sequential FMT protocol wherein FMT was administered every 3 days until symptom resolution, “were eventually cured.” Similar phenomena, she said, were described in a case series by Alexander Khoruts, MD, from the University of Minnesota, who cured two patients after recognizing “reinitiation of vancomycin or an anti-C. difficile antibiotic might be necessary to achieve complete resolution, and also further FMTs might be needed.”

Prompted by these data and anecdotal experience, Fischer and colleagues developed a protocol at their institution “that contains sequential FMT plus selective use of vancomycin based upon the presence of pseudomembranes during index colonoscopy in patients with severe and severe complicated [C. difficile infection].” At the time of the presentation, 29 cases were included in their analysis and prospectively followed. “With this approach, we were able to cure 93% of patients who achieved complete resolution and were able to be discharged from the hospital at 1 month; 76% of patients survived at 3 months but all deaths after 3 months were unrelated to C. difficile.”

Similarly promising results were demonstrated in a multicenter retrospective series by Aroniadis and colleagues, Fischer added, with an overall cure rate of 94%.

While a 2010 expert consensus statement on indications for FMT does include even fulminant severe C. difficile infection that does not respond to standard therapy, data supporting its use for this indication are less robust, and thus, it should be used with caution in these high-risk patients, according to Colleen R. Kelly, MD, from Brown University. However, existing results appear promising, and there is interest among her colleagues in performing a larger controlled trial of FMT for severe disease, she said.

Monika Fischer

More recent recommendations of eligible patients from the 2013 American College of Gastroenterology C. difficile treatment guidelines include those with at least three recurrences, at least two severe episodes requiring hospitalization or recurrence despite vancomycin taper or pulse regimen. Physicians are currently able to follow these society recommendations due to the FDA’s current policy of “enforcement discretion” for FMT when used to treat C. difficile infection that does not respond to standard therapies. According to Kelly, while this policy has given many patients with recurrent C. difficile infection access to FMT, it is “probably only temporary,” and the FDA’s position will continue to evolve as it considers the issue further.

Rapidly evolving regulations

According to Kelly, the regulation of FMT is highly variable across the globe, but the FDA has determined it to be a drug and a biologic, which requires an investigational new drug (IND) application to administer due to its unapproved status.

“The FDA’s policy wasn’t initially enforcement discretion,” Kelly told Infectious Disease News. “When they initially announced their policy in May 2013, they basically said you need an IND to do FMT ... and everyone kind of flipped out.” Clinicians knew the IND process would be an enormous administrative burden, she said, and patient advocacy groups warned the policy would impede FMT’s availability and potentially lead to patients performing home treatments.

“The FDA reconsidered, and announced an ‘enforcement discretion’ policy in July 2013,” which still requires an IND except in cases of C. difficile infection not responding to standard therapy, “provided you give the patient informed consent, explain to them any potential risk and state that it is experimental,” Kelly said. “They left it like that for almost a year, and then the stool banks started.”

Stool banks

OpenBiome, for example, is a nonprofit stool bank established in 2012 in Medford, Massachusetts, with the goal of expanding safe access to FMT. “We are a nonprofit public stool bank dedicated to finding and rigorously screening universal donors,” Laura J. Burns, who recently presented data on OpenBiome’s rigorous universal donor screening methodology at DDW 2015, said. “We process their stool, bank it and then we can send it to physicians all over the country and all over the world.”

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According to Kelly, who is a member of OpenBiome’s clinical advisory board, it was partially in response to stool banks operating without an IND that the FDA issued a March 2014 draft guidance that proposed a donor must be known by the recipient or physician, which “would obviously negate a stool bank” using volunteer donors. The FDA then “invited public comment on [the] draft guidance ... and there were a lot of comments from doctors, professional societies and industry,” Kelly said.

As a result, the draft guidance was never officially enacted, “so at this point it is still permissible to use stool from OpenBiome. ... They’re doing a fabulous job with their screening, and the FDA is fully aware of what they are doing,” Kelly said.

In response to a request for comment on the current status of this proposal, an FDA spokeswoman said in May that the administration is “currently reviewing and considering the comments received on the March draft guidance. Please note that the draft guidance has not yet been finalized, and the July 2013 guidance expresses the FDA’s current policy. It would be inappropriate for us to speculate at this time on when the draft guidance will be finalized.”

Currently, OpenBiome is FDA registered, is working closely with regulatory stakeholders and has, to date, shipped more than 4,200 doses across the country, according to Zain Kassam, MD, MPH, chief medical officer at OpenBiome and research affiliate at the MIT Center for Microbiome Informatics and Therapeutics.

“Our stool bank has a deep respect for the regulatory challenges the FDA is facing in this rapidly evolving space, and it’s important we recognize their thoughtful stance to allow enforcement discretion for the use of FMT in C. difficile not responsive to standard therapy,” Kassam told Infectious Disease News. “Crafting this policy has conservatively saved more than 4,000 patients from a terrible quality of life” and also saved the health care system millions of dollars.

“In my eyes, enforcement discretion highlights an understanding by the FDA that FMT is a square peg, and doesn’t nicely fit into the round hole like other treatments.”

Carolyn A. Edelstein

Also from OpenBiome, Carolyn A. Edelstein, MPA, a thought leader in FMT regulation, recently co-authored a paper appearing in the Journal of Law and Biosciences that examines the challenges in regulating FMT as a biologic drug and proposes a hybrid model similar to cord blood.

In an interview with Infectious Disease News, she said, “Fecal microbiota is an unusual substance to regulate, and one that doesn’t fit neatly under the drug paradigm. The complexity of the microbial community, which varies from person to person, and batch to batch, is not easy to break down into pure ‘active ingredients.’ Instead, the tissue model might make more sense: these regulations emphasize the methods for collecting, processing and storing the material, all of which we should worry about in the context of stool.”

“As a public health advocate, I think it’s possible to imagine creative policy and regulatory solutions,” Kassam said. “Drawing orthogonally from other spaces, we know that blood transfusions were the only treatment for anemia for many years. However, the emergence of erythropoietin, a conventional drug, hasn’t eliminated the need for blood transfusions. Both play important roles in the health care system. Both coexist in harmony. There is choice, and this is something both patients and physicians seek.”

Novel therapeutics

Stool banks like OpenBiome serve a purpose in the current regulatory landscape, but it is indeed possible that the FDA would cease the enforcement discretion policy once it approves a commercialized FMT preparation for recurrent C. difficile infection, a number of which are currently in development, Kelly said.

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In September 2014, Seres Health announced a 97% cure rate achieved in a phase 1/2 study of SER-109, its oral microbiome therapeutic, which has received orphan drug designation for recurrent C. difficile infection by the FDA. The treatment is currently undergoing phase 3 study, according to investigator Colleen S. Kraft, MD, of Emory University School of Medicine, and if successful would be submitted to the FDA for approval.

In December 2014, Rebiotix announced the commencement of a placebo-controlled trial (PUNCH CD 2 study) for its microbiota-based drug RBX2660, which also has received orphan drug and fast track designations from the FDA. This followed positive results from a prospective, multicenter, randomized, double blind, placebo-controlled trial, in which “efficacy of RBX2660, defined as the absence of C. difficile infection at 8 weeks after the last treatment, was 87.1% (27/31),” Mary Kay Sobcinski, RN, MHA, director of clinical operations at Rebiotix, told Infectious Disease News. “RBX2660 demonstrated a satisfactory safety profile in the study targeted at recurrent C. difficile infection, which included very rigorous documentation of adverse events.”

“It’s going to be very difficult for any formulation ... to meet the FDA’s standardization requirement,” Kelly said, “but we’re headed in the direction of commercial formulations. I think we’re still 3 to 5 years away from seeing one out there for actual use.”

According to Kassam, these new biological drugs should be compared with conventional FMT instead of placebo in clinical trials, and long-term safety and efficacy data should be acquired before they are approved. “Speaking with patients, physicians and health care stakeholders, given the body of evidence for FMT in C. difficile, most believe newer agents must show a benefit over FMT to change their hearts and minds,” he said.

Edelstein added, “Also, if we license a drug manufacturer to provide FMT preparations, then physicians can provide the material off-label, which could undermine research efforts to explore the safety and efficacy of FMT for other indications.”

Despite the hurdle, standardized therapies such as these could remove many of the regulatory roadblocks currently plaguing recurring C. difficile treatment and are worth pursuing, Kraft said.

“The FDA does not like [FMT], so for a practitioner like myself, it’s a very hard place to be,” Kraft told Infectious Disease News. “I see the sort of excellent results we get and ... to withhold that from the patients [is] not a good thing. I don’t want to do something that’s always on the border.”

For now, the FDA’s enforcement discretion policy stands, which continues to serve a dual role Kassam describes as “nimble and thoughtful” and Kelly describes as “brilliant,” because it gives people access to FMT for C. difficile infection while at the same time blocking FMT for other indications for which safety and efficacy data are currently insufficient.

Early evidence of MDR organism recolonization

Early studies of FMT for an array of other indications are a major area of interest, including irritable bowel syndrome, fatty liver disease, obesity, type 2 diabetes, metabolic syndrome, hepatic encephalopathy, pediatric allergy disorders, autism, neuropsychiatric disorders, inflammatory arthritis and others. Although treatments for conditions outside C. difficile are still premature, Kraft said, FMT’s influence on the microbiome could reduce the impact of multidrug-resistant bacteria colonized in the gut.

“Instead of treating these patients with more and more antibiotics while their organisms become more and more resistant,” Kraft said, “if we change the colonization of their gut ... then we could eliminate the reservoir of some of these MDR organisms.”

A recent case study published in Open Forum Infectious Diseases by Joshua Stripling, MD, of the infectious disease division at the University of Alabama at Birmingham, and colleagues described a reduction of both C. difficile and vancomycin-resistant Enterococcus (VRE) following FMT. The patient, a female aged 33 years, received orthotopic cardiac and single cadaveric kidney transplants and later developed multiple episodes of bacteremia and urinary tract infections resulting from VRE and C. difficile fecal colonization. FMT was performed using donor fecal samples obtained from the patient’s spouse.

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Analysis of 3-week and 7-month samples revealed that the patient’s gut microbiota, which was initially dominated by Enterococcus (84%), had increased overall diversity and reduced Enterococcus (24% and 0.2%). The procedure was well-tolerated by the patient, who has not demonstrated C. difficile or VRE episodes at 1 year follow-up and has not required hospitalization since FMT.

These data are the first in a human case demonstrating FMT’s ability to replace MDR bacteria in the gut, Stripling and colleagues wrote, and further study is still required to confirm its efficacy. Regardless, Kraft said the potential of these data represents “a very exciting realm for fecal transplant.”

“If you could create a normal microbiome so these things aren’t harbored, then we can decrease the number of bloodstream infections and pneumonia in individuals who are carrying these MDR organisms,” Kraft said. “They might still get infections, but they won’t be as drug-resistant.”

Refining the product

Further work on refining FMT is one of OpenBiome’s main priorities, Kassam said. For example, FMT is not currently prepared anaerobically at OpenBiome, so oxygen kills many of the bacteria, and thus “we’re really only doing FMT 10%. A lot of the microbial community is being killed by oxygen, which isn’t important for C. difficile, but it may matter a lot for other diseases where other bacteria sensitive to oxygen may produce very important small chain fatty acids and other products that are really a part of the transplant. We need to do 100% FMT, not just the 10%.”

Furthermore, not enough is known concerning the effect of FMT on a patient’s microbiome, Kassam said, and additional research is needed to fine tune the treatment of recurrent C. difficile.

“Right now, we’re killing a mosquito with an atomic bomb, in a way,” Kassam said. “We’re using a very broad, crude therapy to address what we think is, at this point, a relatively simple problem. But over time we may be able to discover the secret sauce. There are a number of key organisms that may be very important, but also, in the same breath, in finding the key organism, we must ensure that it’s safe, which is OpenBiome’s No. 1 priority. We don’t know yet, but an entire healthy ecosystem may be safer than a single set of organisms.” – by Adam Leitenberger and Dave Muoio

Editor’s note: This article originally appeared in IDN’s sister publication, Healio Gastroenterology.

Disclosures: Fischer and Kassam report no relevant financial disclosures. Kelly reports being a consultant for Seres Health and U.S. Endoscopy. Kraft is an investigator on a trial funded by Seres Health. Sobcinski is an employee of Rebiotix.

POINTCOUNTER

Is the FDA’s ‘enforcement discretion’ policy adequate for the regulation of FMT?

POINT

Yes.

The FDA has taken an appropriate position for treatment of Clostridium difficile infection. It is to the agency’s credit that it has assessed the clinical landscape and responded to this fast-moving field. It would not be a valuable use of anyone’s time to be submitting and reviewing clinical uses of stool for single patients, and sadly there are simply too many patients with recurrent C. difficile infection seeking this highly effective therapy to set up even modest hurdles, in my opinion. There are standard recommendations for screening of donors that can be fairly easily undertaken, though I suspect that for close family members, or an intimate partner of a patient, a standard stool culture for enteric pathogens may be all that is done sometimes. The “full Monty” of donor screening tests can cost upward of $1,200 and much more if a patient were to be charged the full freight at a laboratory, putting individualized therapy out of range of many who do not have good insurance coverage. Ironically, some family donors have stool tests done and charged to their own insurance, with the diagnosis of “diarrhea!” Beware of engaging your compliance and billing people on that one. This field is challenging enough; patients and doctors should not be asked to run a regulatory gauntlet as well. Despite the fact that most patients getting FMT for recurrent C. difficile infection are older and have numerous medical comorbidities, to my knowledge there are no convincing reports of infections transmitted by FMT. This does not mean it will not happen, but I think it means the incidence is very low in the hands of responsible GI and ID practitioners (A Google map for FMT providers in the United States can be found here: www.google.com/maps/d/viewer?mid=z2AxJq2nTqAg.k5dy1hmJP39E&hl=en_US).

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For the older active person confined to their home because of recurrent and unpredictable diarrhea, the benefit/risk ratio of FMT seems entirely reasonable. I recently consulted on just such a patient who lived alone and had fallen and fractured a rib while running to the bathroom because of relapsed C. difficile infection, necessitating hospitalization. I envisioned pneumonia, more antibiotics, more C. difficile ... the beat goes on! An interesting issue to consider is how the regulatory landscape will change when the FDA approves microbiome-based treatments. The two products furthest along are SER-109 (Seres Therapeutics) and Rebiotix’s RBX2660, both on a fast-track pathway at the FDA (another good, if obvious, decision). These human stool-derived products will undoubtedly come with a fairly hefty price tag. Also, both of these products as currently designed are frozen, and they are not something that will be stored and available at every pharmacy. Of course, the ultimate goal is a defined mixture of cultured, freeze-dried beneficial microbes. One wonders whether “regular” FMT will still be done, perhaps as a “cheap” alternative, as these milestones are reached and how FMT will in the future be viewed from a regulatory perspective. It is worth a mention that as an “FMT provider,” I receive calls at least weekly from patients seeking FMT for all manner of non-C. difficile infection indications. That is, and should be, under careful review and investigation by regulators, clinicians and scientists.

Elizabeth L. Hohmann MD, is an associate professor of medicine and infectious diseases and the chair and director of Partners Human Research Committees at Brigham and Women’s Hospital and Massachusetts General Hospital. Disclosure: Hohmann is an investigator in a clinical study of SER-109.

COUNTER

Yes, but ...

FMT and its clinical efficacy represent a challenge to regulatory agencies, health care payors, clinicians and patients. Unlike most pharmaceutical agents, FMT defies standardization. The striking consistency of the reported cure rate of 90% for recurrent C. difficile infection in numerous studies contrasts with the microbial diversity and unpredictable standardization from donor to donor and sample to curative sample.

The FDA and general medical community have three priorities to fulfill in regards to FMT for recurrent C. difficile infection: 1) to assure safety and minimize the risk for transmission of infectious agents; 2) to promote the most effective treatments for recurrent C. difficile infection — a miserable, dangerous and contagious disorder recognized as an “urgent health threat” by the CDC; and 3) to explore the compelling implications for human health that are implied by FMT’s restoration of the gut microbiome.

Clinicians who provide FMT cope with the requirements of identifying and screening suitable donors, processing fecal material and administering FMT, and providing ongoing care for patients. The FDA’s current policy (issued July 2013) of exercising “enforcement discretion” is permissive of this effort. The policy mandates an informed consent process in which FMT is described as investigational and that the risks of the procedure be reviewed. Published guidelines set clinical standards of safety (Bakken JS, et al. Clin Gastroenterol Hepatol. 2011;doi:10.1016/j.cgh.2011.08.014). The scientific community has embraced the microbiome as a focus of investigation.

The persisting characterization of FMT as “experimental” is obsolete. With three randomized clinical trials, multiple case series and clinical acceptance, FMT is emerging as a standard of care for recurrent C. difficile infection. FMT relieves suffering, provides value to our patients and enhances the safety of the community. Health care payors’ response has been slow and inadequate. Typical reimbursement rates for FMT approximates half of the cost of a course of oral vancomycin and less than one-tenth of the cost of Dificid (fidaxomicin, Cubist Pharmaceuticals). The requirements of effort and time limit the availability of this high-value, though unconventional, treatment. Low availability of this effective therapeutic risks “do-it-yourself” patient efforts with increased potential of spread of infectious agents.

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The FDA’s permissive policy and ongoing review makes FMT possible. Health care payors, including CMS, need to honor its value. Clinicians should access resources and refer appropriately to make FMT available to patients. We all need to learn about microbiota-based therapeutics to promote health.

Bruce E. Hirsch MD, FACP, AAHIVS, is an attending physician in the division of infectious diseases at North Shore University Hospital. Disclosure: Hirsch is president for clinical affairs at Symbiotic Health, a start-up dedicated to developing bacteria-based therapeutics, now focused on oral capsules for recurrent C. difficile infection.