Clinicians Ask FDA for Continued 'Discretion' to Do Fecal Transplants

Alicia Ault

November 05, 2019

Attendees at a public meeting on Monday gave the US Food and Drug Administration (FDA) conflicting views on whether the agency should continue to allow a relatively loose regulatory environment for fecal microbiota transplants (FMT) — debating the limits of "enforcement discretion" the FDA now has in place.

The question is especially relevant as use of the procedure is growing, while safety data is not being rigorously collected in all cases. The death of an immunocompromised FMT patient earlier in 2018 from an invasive bacterial infection caused by drug-resistant Escherichia coli, as reported by Medscape Medical News, is seen by some as an example of the consequences of a loose policy.

Still, the American Gastroenterological Association (AGA) presented new, unpublished follow-up data at the meeting that showed that the majority of FMT patients in a national registry had no adverse events.

Some companies developing FMT-based products argued at the meeting that the agency should impose stricter requirements, while stool banks and clinicians offering the therapy outside of clinical trials said that the current policy — in place since 2013 — in which the FDA has exercised "enforcement discretion," should be allowed to continue.

"Enforcement discretion has been successful in enabling and overcoming key barriers to access to treatment," said Majdi Osman, MD, MPH, clinical program director at OpenBiome, a nonprofit stool bank based in Cambridge, Massachusetts. Osman said that 98% of the US population now lives within a 2-hour drive of an FMT provider.

Amanda Kabage, a researcher and donor program coordinator for the Microbiota Therapeutics program at the University of Minnesota in Minneapolis, and herself a former recipient of FMT, said she was in favor of continuing the FDA policy.

"If enforcement discretion were to go away, patients far sicker than I was will not have access. They'll get sicker and they will die," Kabage said.

But, she added, the FDA had missed an opportunity by not insisting on collecting outcomes and safety data. Minnesota has established a patient registry to do just that, and physicians cannot administer FMT unless they agree to participate, she said. In response, FDA panelists noted that the agency cannot mandate data collection under an enforcement policy.

Lee Jones, founder and chief executive officer of Rebiotix/Ferring, a biotech company focused on the development of microbiome-based therapeutics, argued for tighter restrictions, however, claiming that increased access — and the FDA policy — had led to a fourfold decrease in enrolment since the company began study of its lead FMT product, RBX2660, in 2013.

"We're dealing with an orphan indication and the patients were hard to come by to begin with," she said, at the meeting. "Enforcement discretion has slowed our clinical development and delayed patient access to FDA-approved therapies by over two years."

An investigator at the University of Texas Health Science Center at Houston, Herbert DuPont, MD, who has administered FMT and is conducting a trial for Rebiotix, said his center wanted the FDA policy to continue "allowing multiple groups to perform FMT for recurrent [Clostridium difficile], because of the incredible public health need."

But, he added, "We're very concerned about industry and ability to do clinical trials."

Those trials are important, DuPont said. "I think we have to address very actively how industry can move these products through," he said, "because all of us want to remove the F from FMT," by isolating the necessary elements of the process while not having the risk sometimes associated with human stool.

Policy Slow to Evolve

"I'm frustrated that it's taken over 6 years and three draft guidances to get us this far," said Christian John Lillis, executive director of the Peggy Lillis Foundation — a group dedicated to creating awareness about the dangers of C difficile — at the meeting.

Lillis said that probably several thousand deaths had been prevented through increased FMT access, but that it was time to create a concrete policy that advanced the therapy.

The FDA guidance issued in 2013 allowed physicians to provide FMT for recurrent or refractory C difficile infection without filing an investigational new drug (IND) application.

Clinicians must obtain informed consent that includes a discussion of the risks, and a statement that FMT is investigational. In March 2016, the agency issued a revised draft guidance that it was aiming to require stool banks to apply for INDs, as reported by Medscape Medical News.

OpenBiome has flourished under the current policy. It has provided more than 50,000 treatments to 1200 hospitals and clinics, and has provided FMT for 49 clinical trials and for 16 single patients who received INDs, Osman said.

But requiring INDs for all centers is a bad idea, he said. "IND requirements are insurmountable for most health centers," Osman said, noting that most of the FMT material OpenBiome produces is sent to community-based physicians.

"These requirements would likely mean restrictions in access for stool-bank-provided FMT and potentially pushing patients to physician-directed FMT or discouraging physicians from using FMT at all," he said.

Stacy Kahn, MD, FMT director at Boston Children's Hospital in Massachusetts, said that having ready access from a stool bank was crucial.

"Universal donor FMT is much easier, much faster and much more cost effective than what we can do as clinicians," she said.

New Safety and Efficacy Data

One unpublished study showed that 75% of patients treated since 2011 had a sustained cure, noted Colleen Kelly, MD, a Brown University professor of medicine and principal investigator for the National Institutes of Health-funded national FMT registry (although the data in this study were not from the national FMT registry).

The study, which was a collaboration between the Alpert Medical School of Brown University, Brigham and Women’s Hospital and Indiana University School of Medicine, attempted follow-up on 533 patients; 208 were successfully contacted, and an additional 55 had died, none due to FMT.

Kelly also presented data from the FMT National Registry showing that at 1 month posttransplant, two (1%) of 253 patients had an infection possibly related to FMT; one with Bacteroides fragilis and one with enteropathogenic E coli. Seven hospitalizations were deemed related or possibly related to FMT, including two recurrences of C difficile.

At 6 months posttransplant, eight (5%) of 152 patients had a serious infection, and 23 patients reported a diagnosis of a new condition, primarily diarrhea-predominant irritable bowel syndrome, which is common post-FMT, said Kelly, who presented the data on behalf of AGA, which administers the registry.

The AGA supports a continuation of the enforcement discretion as a means to maintain patient access where the evidence supports the use of FMT, but the group does not back use of FMT outside medical supervision, Kelly said.

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