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Fecal Microbiota Transplantation: Moving Mainstream, Regulatory Hurdles and Potential Future Indications

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 thus 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.

Healio Gastroenterology spoke to several experts who recently presented data on FMT at Digestive Disease Week 2015 in Washington, D.C., all of whom agreed that there is still much work to be done to refine FMT and better understand the underlying mechanisms and broader implications of microbiome-based therapies.

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. The most recent 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. diff,” Monika Fischer, MD, MSc, from Indiana University Health, said during her presentation at DDW. 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.

Monika Fischer, MD, MSc

Monika Fischer

In the first study by van Nood and colleagues, published in 2013 in the New England Journal of Medicine, a total of 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. diff 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 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 is also 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 University of Minnesota, who cured two patients after recognizing “reinitiation of vancomycin or an anti-C. diff antibiotic might be necessary to achieve complete resolution, and also further FMTs might be needed.”

Prompted by such 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. diff.”

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

Colleen R. Kelly, MD

Colleen R. Kelly

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.

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 they consider 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 Healio Gastroenterology. “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. 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, Mass., 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 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 our request for comment on the current status of this proposal, an FDA spokesperson said they are “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,” he told Healio Gastroenterology. “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,” he said.

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.

Carolyn A. Edelstein, MPA

Carolyn A. Edelstein

In an interview with Healio Gastroenterology, 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 co-exist in harmony. There is choice and this is something both patients and physicians seek.”

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 they approve 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.

In December 2014, Rebiotix Inc. 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-blinded, 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),” according to Mary Kay Sobcinski, RN, MHA, director of clinical operations at Rebiotix told Healio Gastroenterology. “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 to 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 heart 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.”

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 Studies of Other Indications

Early studies of FMT for an array of other indications are a major area of interest according to experts. These include irritable bowel syndrome, fatty liver disease, obesity, type 2 diabetes, metabolic syndrome, multidrug resistant organism eradication, hepatic encephalopathy, pediatric allergy disorders, autism, neuropsychiatric disorders, inflammatory arthritis and others. Among these, inflammatory bowel disease has the most available data, though it is still “too early for prime time,” Kassam said.

Zain Kassam, MD, MPH

Zain Kassam

In December 2014, Edward V. Loftus, MD, FACG, AGAF, from Mayo Clinic in Rochester, Minn., presented data at the Advances in IBD meeting showing FMT does not appear to have efficacy for IBD.

Early data was “encouraging,” Loftus said in his presentation, citing a 2012 systematic review and meta-analysis by Anderson and colleagues showing that, out of 24 patients, 63% had no evidence of active disease 3 to 36 months after FMT. However, he warned that, “now that we are seeing more rigorous studies, we are not seeing quite the same effect.” Another systematic review and meta-analysis by Colman and colleagues showed an overall response rate of 45% among 122 patients (22% UC, 61% Crohn’s disease), demonstrating safety but highly variable efficacy of FMT for IBD, he said. “So as more objectivity and reality is being infused into this area, the results are not nearly as glowing as they were initially described,” Loftus said.

Punctuating this point were results from an RCT conducted by Moayeddi and colleagues of 53 ulcerative colitis patients showing no difference in remission between FMT and placebo at week 6. “This study has been criticized by some because of the small sample size and short duration, but there’s not even a signal of a benefit in this study,” he said.

More recently, Kelly gave a presentation on FMT for IBD with updated data at DDW 2015, including two RCTs published in recent months by Rossen and colleagues, and another by Moayyedi and colleagues.

Both trials enrolled about half as many patients as they intended to, in part because they were both halted for futility at their interim analysis because neither were meeting their objectives, Kelly said. Rossen was a negative study, she said, but “what ended up happening is, Moayyedi had already enrolled about 22 people that hadn’t been treated by that point, and their board” decided to stop enrollment but complete treatment for those remaining participants, after which it was “all of a sudden a statistically significant, positive study … but barely so, in the sense that their control arm actually had a really low response rate.” This is unusual, she said, as controls in IBD studies tend to have about a 20% response rate, and theirs was 5%, which expanded the difference between the placebo and the FMT arms. Therefore, “some people have said really these were two negative studies,” Kelly said, though “there could be a signal of benefit in both of them. … There were some people who clearly responded and improved, and those who responded seemed to have more diversity of their microbiome after.”

The researchers also observed that donor and disease length appeared to affect outcomes. “FMT may be more efficacious in patients with a recent diagnosis of UC, and this is biologically plausible, as a perturbation in the microbiome might be more easily restored early in the course of the disease,” they wrote. “The efficacy of this approach may also be donor dependent and this may explain why some case series have shown promise and others have had disappointing results.”

According to Kassam, who co-authored the study, “although the current IBD trials have limitations, FMT is deeply promising for ulcerative colitis, but we have to understand a basic foundation of how to refine FMT protocols. It’s not going to be like C. difficile, where we were lucky. People are assuming the lessons learned in C. difficile apply directly to IBD, and I don’t think that’s the case.” FMT for IBD will likely have to be more personalized to the patient, Kassam said, and will likely require multiple treatments, an optimal donor and targeted delivery for the subpopulation that may be responsive.

Kelly agreed that larger, more adequately powered studies are needed to demonstrate efficacy of FMT for IBD. “These studies are probably going to need 300 people to show an effect,” Kelly said. She also agreed that FMT for IBD will have fundamental differences from C. difficile infection. “C. diff is easy; it’s pretty similar from patient to patient, while in IBD you’ve got UC, proctitis, pouchitis, ileal Crohn’s, colonic Crohn’s.” Additional questions include whether there is an ideal administration method for IBD patients, whether there is “a specific phenotype that will be responsive to FMT, or if FMT may make some of these IBD patients worse. I’ve seen true flares in IBD patients after their FMT.”

While there are at least 5 RCTs underway, Kelly said, including “one that’s actually pretty nicely sized being done in Australia,” whose results should be available within the next year, “I think we’re really far away from this in IBD.”

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 a lot 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%.”

“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    

References:
Anderson JL, et al. Aliment Pharmacol Ther. 2012;doi:10.1111/j.1365-2036.2012.05220.x.
Bakken JS, et al. Clin Gastroenterol Hepatol. 2011;doi:10.1016/j.cgh.2011.08.014.
Burns L, et al. Abstract 499. Presented at: Digestive Disease Week; May 16-19, 2015; Washington, D.C.
Cammarota G, et al. Aliment Pharmacol Ther. 2015;doi:10.1111/apt.13144.
Colman RJ, et al. J Crohns Colitis. 2014;doi:10.1016/j.crohns.2014.08.006.
Drekonja D, et al. Ann Intern Med. 2015;doi:10.7326/M14-2693.
Kelly CR, et al. Gastroenterology. 2015;doi:10.1053/j.gastro.2015.05.008.
Loftus EV. Presented at: 2014 Advances in Inflammatory Bowel Diseases, Dec. 4-6; Orlando, Fla.
Moayeddi P, et al. Gastroenterology. 2014;146:S-159.
Moayyedi P, et al. Gastroenterology. 2015;doi:10.1053/j.gastro.2015.04.001.
Rossen NG. et al. Gastroenterology. 2015;doi:10.1053/j.gastro.2015.03.045; in press.
Sachs RE, et al. J Law Biosci. 2015; in press.
Surawicz C. Sp788. Presented at: Digestive Disease Week; May 16-19, 2015; Washington, D.C.
Surawicz C, et al. Am J Gastroenterol. 2013;doi:10.1038/ajg.2013.4.
van Nood E, et al. New Engl J Med. 2013;doi:10.1056/NEJMoa1205037.
Youngster I, et al. Clin Infect Dis. 2014; doi:10.1093/cid/ciu135.
For more information:
Monika Fischer, MD, MSc, can be reached at mofische@iu.edu.
Zain Kassam, MD, MPH, can be reached at zain@openbiome.com.
Colleen R. Kelly, MD, can be reached at colleen_r_kelly@brown.edu.
Mary Kay Sobcinski, RN, MHA, can be reached at mksobcinski@rebiotix.com.
Disclosures: Fischer and Kassam report no relevant financial disclosures. Kelly reports she is a consultant for Seres Health and U.S. Endoscopy. Sobcinski is an employee of Rebiotix Inc.

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 thus 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.

Healio Gastroenterology spoke to several experts who recently presented data on FMT at Digestive Disease Week 2015 in Washington, D.C., all of whom agreed that there is still much work to be done to refine FMT and better understand the underlying mechanisms and broader implications of microbiome-based therapies.

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. The most recent 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. diff,” Monika Fischer, MD, MSc, from Indiana University Health, said during her presentation at DDW. 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.

Monika Fischer, MD, MSc

Monika Fischer

In the first study by van Nood and colleagues, published in 2013 in the New England Journal of Medicine, a total of 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.”

PAGE BREAK

The latest RCT by Cammarota and colleagues, recently published in Alimentary Pharmacology & Therapeutics, “randomized patients with recurrent C. diff 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 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 is also 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 University of Minnesota, who cured two patients after recognizing “reinitiation of vancomycin or an anti-C. diff antibiotic might be necessary to achieve complete resolution, and also further FMTs might be needed.”

Prompted by such 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. diff.”

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

Colleen R. Kelly, MD

Colleen R. Kelly

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.

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 they consider 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.

PAGE BREAK

“The FDA’s policy wasn’t initially enforcement discretion,” Kelly told Healio Gastroenterology. “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. 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, Mass., 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 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 our request for comment on the current status of this proposal, an FDA spokesperson said they are “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,” he told Healio Gastroenterology. “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,” he said.

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.

Carolyn A. Edelstein, MPA

Carolyn A. Edelstein

In an interview with Healio Gastroenterology, 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 co-exist in harmony. There is choice and this is something both patients and physicians seek.”

PAGE BREAK

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 they approve 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.

In December 2014, Rebiotix Inc. 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-blinded, 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),” according to Mary Kay Sobcinski, RN, MHA, director of clinical operations at Rebiotix told Healio Gastroenterology. “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 to 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 heart 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.”

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 Studies of Other Indications

Early studies of FMT for an array of other indications are a major area of interest according to experts. These include irritable bowel syndrome, fatty liver disease, obesity, type 2 diabetes, metabolic syndrome, multidrug resistant organism eradication, hepatic encephalopathy, pediatric allergy disorders, autism, neuropsychiatric disorders, inflammatory arthritis and others. Among these, inflammatory bowel disease has the most available data, though it is still “too early for prime time,” Kassam said.

Zain Kassam, MD, MPH

Zain Kassam

In December 2014, Edward V. Loftus, MD, FACG, AGAF, from Mayo Clinic in Rochester, Minn., presented data at the Advances in IBD meeting showing FMT does not appear to have efficacy for IBD.

Early data was “encouraging,” Loftus said in his presentation, citing a 2012 systematic review and meta-analysis by Anderson and colleagues showing that, out of 24 patients, 63% had no evidence of active disease 3 to 36 months after FMT. However, he warned that, “now that we are seeing more rigorous studies, we are not seeing quite the same effect.” Another systematic review and meta-analysis by Colman and colleagues showed an overall response rate of 45% among 122 patients (22% UC, 61% Crohn’s disease), demonstrating safety but highly variable efficacy of FMT for IBD, he said. “So as more objectivity and reality is being infused into this area, the results are not nearly as glowing as they were initially described,” Loftus said.

Punctuating this point were results from an RCT conducted by Moayeddi and colleagues of 53 ulcerative colitis patients showing no difference in remission between FMT and placebo at week 6. “This study has been criticized by some because of the small sample size and short duration, but there’s not even a signal of a benefit in this study,” he said.

More recently, Kelly gave a presentation on FMT for IBD with updated data at DDW 2015, including two RCTs published in recent months by Rossen and colleagues, and another by Moayyedi and colleagues.

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Both trials enrolled about half as many patients as they intended to, in part because they were both halted for futility at their interim analysis because neither were meeting their objectives, Kelly said. Rossen was a negative study, she said, but “what ended up happening is, Moayyedi had already enrolled about 22 people that hadn’t been treated by that point, and their board” decided to stop enrollment but complete treatment for those remaining participants, after which it was “all of a sudden a statistically significant, positive study … but barely so, in the sense that their control arm actually had a really low response rate.” This is unusual, she said, as controls in IBD studies tend to have about a 20% response rate, and theirs was 5%, which expanded the difference between the placebo and the FMT arms. Therefore, “some people have said really these were two negative studies,” Kelly said, though “there could be a signal of benefit in both of them. … There were some people who clearly responded and improved, and those who responded seemed to have more diversity of their microbiome after.”

The researchers also observed that donor and disease length appeared to affect outcomes. “FMT may be more efficacious in patients with a recent diagnosis of UC, and this is biologically plausible, as a perturbation in the microbiome might be more easily restored early in the course of the disease,” they wrote. “The efficacy of this approach may also be donor dependent and this may explain why some case series have shown promise and others have had disappointing results.”

According to Kassam, who co-authored the study, “although the current IBD trials have limitations, FMT is deeply promising for ulcerative colitis, but we have to understand a basic foundation of how to refine FMT protocols. It’s not going to be like C. difficile, where we were lucky. People are assuming the lessons learned in C. difficile apply directly to IBD, and I don’t think that’s the case.” FMT for IBD will likely have to be more personalized to the patient, Kassam said, and will likely require multiple treatments, an optimal donor and targeted delivery for the subpopulation that may be responsive.

Kelly agreed that larger, more adequately powered studies are needed to demonstrate efficacy of FMT for IBD. “These studies are probably going to need 300 people to show an effect,” Kelly said. She also agreed that FMT for IBD will have fundamental differences from C. difficile infection. “C. diff is easy; it’s pretty similar from patient to patient, while in IBD you’ve got UC, proctitis, pouchitis, ileal Crohn’s, colonic Crohn’s.” Additional questions include whether there is an ideal administration method for IBD patients, whether there is “a specific phenotype that will be responsive to FMT, or if FMT may make some of these IBD patients worse. I’ve seen true flares in IBD patients after their FMT.”

While there are at least 5 RCTs underway, Kelly said, including “one that’s actually pretty nicely sized being done in Australia,” whose results should be available within the next year, “I think we’re really far away from this in IBD.”

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 a lot 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%.”

“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    

References:
Anderson JL, et al. Aliment Pharmacol Ther. 2012;doi:10.1111/j.1365-2036.2012.05220.x.
Bakken JS, et al. Clin Gastroenterol Hepatol. 2011;doi:10.1016/j.cgh.2011.08.014.
Burns L, et al. Abstract 499. Presented at: Digestive Disease Week; May 16-19, 2015; Washington, D.C.
Cammarota G, et al. Aliment Pharmacol Ther. 2015;doi:10.1111/apt.13144.
Colman RJ, et al. J Crohns Colitis. 2014;doi:10.1016/j.crohns.2014.08.006.
Drekonja D, et al. Ann Intern Med. 2015;doi:10.7326/M14-2693.
Kelly CR, et al. Gastroenterology. 2015;doi:10.1053/j.gastro.2015.05.008.
Loftus EV. Presented at: 2014 Advances in Inflammatory Bowel Diseases, Dec. 4-6; Orlando, Fla.
Moayeddi P, et al. Gastroenterology. 2014;146:S-159.
Moayyedi P, et al. Gastroenterology. 2015;doi:10.1053/j.gastro.2015.04.001.
Rossen NG. et al. Gastroenterology. 2015;doi:10.1053/j.gastro.2015.03.045; in press.
Sachs RE, et al. J Law Biosci. 2015; in press.
Surawicz C. Sp788. Presented at: Digestive Disease Week; May 16-19, 2015; Washington, D.C.
Surawicz C, et al. Am J Gastroenterol. 2013;doi:10.1038/ajg.2013.4.
van Nood E, et al. New Engl J Med. 2013;doi:10.1056/NEJMoa1205037.
Youngster I, et al. Clin Infect Dis. 2014; doi:10.1093/cid/ciu135.
For more information:
Monika Fischer, MD, MSc, can be reached at mofische@iu.edu.
Zain Kassam, MD, MPH, can be reached at zain@openbiome.com.
Colleen R. Kelly, MD, can be reached at colleen_r_kelly@brown.edu.
Mary Kay Sobcinski, RN, MHA, can be reached at mksobcinski@rebiotix.com.
Disclosures: Fischer and Kassam report no relevant financial disclosures. Kelly reports she is a consultant for Seres Health and U.S. Endoscopy. Sobcinski is an employee of Rebiotix Inc.