FDA Proposes Tighter Rules for Fecal Transplants

March 16, 2016

The US Food and Drug Administration (FDA) already regulates Big Pharma.

Now the FDA wants to regulate Big Stool when it comes to curing stubborn Clostridium difficile infections with fecal microbiota for transplant (FMT). The agency's stated goal is to ensure that fecal transplants are safe as well as available to patients.

With growing reliance on FMT in the colon to treat C difficile, two nonprofit stool banks have sprung up to meet the need. They collect donated stools and convert them into transplantable products. Hospital laboratories do the same thing, but on a smaller, more customized scale.

These transplants, which can be administered via enemas, colonoscopy, capsules, or gastric intubation, have yet to receive FDA approval. Accordingly, they're deemed investigational new drugs (INDs), and clinicians must apply for FDA authorization to use them. However, under the guise of "enforcement discretion," the agency has dispensed with an IND application and has allowed the use of fecal transplants for patients who are not responding to standard therapies for C difficile infections. The only strings attached are that physicians must obtain adequate informed consent, which includes telling the patient that FMT is investigational, and discuss the risks.

These free and easy days appear to be ending, however. In draft guidance issued earlier this month, the FDA said that it would continue to exercise enforcement discretion for FMT regarding C difficile, but the agency added more conditions. Either the patient receiving the transplant or the treating clinician must know the donor. And the treating clinician must oversee the screening and testing of both the stool donor and the stool.

Furthermore, the FDA will no longer apply enforcement discretion regarding IND requirements to fecal transplants obtained from stool banks, because their clinician customers don't know the donors, nor do they oversee transplant testing and production. Centralized manufacturing in stool banks raises safety concerns "related to the use of FMT from a limited number of donors administered to multiple patients," the agency said in its proposed guidance. "These safety concerns include transmission of infectious agents and other unidentified risks related to changes in the microbiome."

Accordingly, stool banks must secure IND designation for their FMT, which entails identifying someone as the investigator. Physicians would be able to continue using fecal transplants from stool banks to cure C difficile infections as long as they are designated subinvestigators. Assuming that role might not be as onerous as expected, because an IND sponsor — such as a stool bank — may waive certain IND requirements for investigators and subinvestigators alike, the FDA noted.

Hospital laboratories that prepare FMT products for their patients are not considered stool banks in the FDA's proposed guidance.

Should IRB Approval Be Waived?

The United States has two stool banks — OpenBiome, in Medford, Massachusetts, and AdvancingBio, in Mather, California. Both are not-for-profit. Founded in 2012, OpenBiome is the older of the two, serving some 500 hospitals with ready-to-use fecal transplants. AdvancingBio, which opened in February 2015, has about 15 hospital customers.

In the for-profit sphere, a company called Rebiotix, in Roseville, Minnesota, seeks FDA approval of two FMT products for C difficile.

Officials at both OpenBiome and AdvancingBio told Medscape Medical News that they expect to weigh in on what IND requirements should be waived during the public comment period on the proposed guidance.

Carolyn Edelstein, director of policy and global partnerships at OpenBiome, said that the agency's final guidance should strike a balance between maintaining safety in stool banks and not placing undue burdens on physicians who want to use their products. One undue burden, Edelstein said, would be the requirement for IND subinvestigators to obtain approval from an institutional review board (IRB). Edelstein said OpenBiome operates under the auspices of an IRB, given that it has an IND application on file with the FDA for one clinical trial. However, OpenBiome currently doesn't ask clinicians who use their FMT to win the blessing of an IRB.

Edelstein added that her company does not entertain any immediate plans to seek FDA market clearance for its FMT. She said that if another company successfully commercializes fecal transplant products, OpenBiome may dedicate itself solely to clinical research as opposed to patient care.

Nicole Anderson, a senior vice president at AdvancingBio and BloodSource, its parent organization, told Medscape Medical News that her stool bank does not have any IND application on file with the FDA. However, AdvancingBio plans to voluntarily submit a so-called drug master file to the agency. This document describes how a company manufactures, processes, packages, and stores its products. Physicians who submit an IND application to the FDA on their use of FMT can refer to AdvancingBio's drug master file as a supporting document, according to Anderson.

OpenBiome already has submitted a drug master file to the FDA.

Like OpenBiome, AdvancingBio welcomes FDA oversight of its medical niche. "We're excited that that the FDA is continuing to go down the path to ensure a safe product that's accessible to patients," said Anderson.

"A Very Emerging Concept"

One OpenBiome user, gastroenterologist Colleen Kelly, MD, said that the IND requirements would not prevent her from using the company's FMT in her research.

Dr Kelly, an assistant professor of medicine at the Alpert Medical School of Brown University, in Providence, Rhode Island, told Medscape Medical News that she has conducted FMT studies under four different IND applications, and with IRB approval. Adjusting to IND requirements as a part of using OpenBiome FMT wouldn't be unduly burdensome, given the number of patients she treats, said Dr Kelly, who serves on the advisory board of Center for Gut Microbiome Research and Education at the American Gastroenterological Association.

"However, a doctor who might want to use the FMT material a couple of times a year might not want to go through the additional paperwork," she said. "It might dissuade you."

Dr Kelly said that stool banks ought to come under FDA oversight for safety's sake, including the requirement to report adverse events. OpenBiome is a poster child for good safety practices, she said, but future stool banks may not be as careful, especially when it comes to testing for infectious pathogens. OpenBiome claims to reject 97% of prospective donors for one reason or another.

Another impetus for FDA oversight of stool banks is the desire to steer more patients into FMT trials that assess safety and efficacy, said Dr Kelly. Right now, absent the need to follow IND rules, stool banks make it easy for physicians and patients to bypass such trials, which would force some patients seeking a C difficile cure to be in a control group. "Who wants to receive a placebo?" she said.

Therapeutic microbiota represents new territory for the FDA, and fecal transplants are only the beginning, said Dr Kelly. She envisions treatments based on vaginal and skin microbiota, for example.

Said Dr Kelly: "It's a very emerging concept."

As a further indication of this flux, the recently proposed FDA guidance on FMT is only interim in nature. The agency promises to develop a comprehensive approach to studying and using FMT products.

The FDA draft guidance, which includes instructions on how to submit comments, is available on the agency's website.

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