FDA NewsPerspective

FDA hears testimony on enforcement discretion of FMT for C. diff

The FDA held a public comment session on Monday in Washington, D.C., to hear testimony on the agency’s policy on enforcement discretion of fecal microbiota transplantation for patients with recurrent Clostridioides difficile infection, as well as what is needed to make a path forward toward approval.

Manufacturers, researchers, clinicians and patients were on hand to discuss how the policy has impacted everything from enrollment in clinical trials to the actual management of sick patients.

While FMT has not been approved for the treatment of any disease, over the last few years, the FDA has allowed clinicians to use FMT to treat patients with CDI as clinical development of therapy progressed through the approval process. This also included the use of stool banks. Draft guidance proposed in 2016 suggested that stool banks be excluded from this enforcement discretion.

Advocates said the inclusion of stool banks has provided better access to treatment for very sick patients, particularly those who do not live near trial sites or do not want to be enrolled in a clinical trial. However, some also believe that this policy has hindered development of an approved therapy and led to some safety concerns.

“The FDA policy has caused major obstacles to completing this work,” Lee Jones, president and CEO of Rebiotix, said in her testimony.

In a meta-analysis, Jones said of 55 studies, only eight were randomized controlled trials. Additionally, recruitment for clinical trials has fallen significantly at Rebiotix. Jones said there has been a fourfold decrease in enrollment from their first trial to their most recent.

Although the studies reported encouraging efficacy results, Jones said they provided only a low-level of rigorous clinical evidence.

“The studies reflect the pioneering characteristics of the work that’s been done and deserve recognition,” she said. “But collectively do not provide sufficient clinical evidence of safety and efficacy for commercialization of FMT for C. diff.”

Jones also testified that the FDA’s policy on enforcement has cost companies more time and money while they work toward getting therapies approved and potential safety risks for patients.

Conversely, some attendees of the hearing said the enforcement discretion is a critical part of ensuring patients get the care they need.

Amanda Kabage, donor program coordinator at the University of Minnesota Microbiota Therapeutics program, said it is important to consider if patients who are involved in RCTs are representative of the kinds of patients who would receive FMT after the FDA approves a product. Are data collected in these studies generalizable to all patients who currently receive FMT under discretion?

“In my experience as a researcher in this field, I think the answer is no,” Kabage said. “The recurrent C. difficile patients, by their very definition, are very sick individuals, which is why they require FMT in the first place. Many of these patients have comorbidities, and they are excluded from clinical trial participation.”

She said that the lack of data collection under discretion has limited development, but said large, observational studies are needed to better understand that patient population, as well as the safety and efficacy of FMT. To treat the entire patient population with C. diff, Kabage said RCTs and enforcement discretion need to find a way to coexist. by Alex Young

Reference:

FDA. Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies; Public Hearing; Request for Comments. November 4, 2019.

The FDA held a public comment session on Monday in Washington, D.C., to hear testimony on the agency’s policy on enforcement discretion of fecal microbiota transplantation for patients with recurrent Clostridioides difficile infection, as well as what is needed to make a path forward toward approval.

Manufacturers, researchers, clinicians and patients were on hand to discuss how the policy has impacted everything from enrollment in clinical trials to the actual management of sick patients.

While FMT has not been approved for the treatment of any disease, over the last few years, the FDA has allowed clinicians to use FMT to treat patients with CDI as clinical development of therapy progressed through the approval process. This also included the use of stool banks. Draft guidance proposed in 2016 suggested that stool banks be excluded from this enforcement discretion.

Advocates said the inclusion of stool banks has provided better access to treatment for very sick patients, particularly those who do not live near trial sites or do not want to be enrolled in a clinical trial. However, some also believe that this policy has hindered development of an approved therapy and led to some safety concerns.

“The FDA policy has caused major obstacles to completing this work,” Lee Jones, president and CEO of Rebiotix, said in her testimony.

In a meta-analysis, Jones said of 55 studies, only eight were randomized controlled trials. Additionally, recruitment for clinical trials has fallen significantly at Rebiotix. Jones said there has been a fourfold decrease in enrollment from their first trial to their most recent.

Although the studies reported encouraging efficacy results, Jones said they provided only a low-level of rigorous clinical evidence.

“The studies reflect the pioneering characteristics of the work that’s been done and deserve recognition,” she said. “But collectively do not provide sufficient clinical evidence of safety and efficacy for commercialization of FMT for C. diff.”

Jones also testified that the FDA’s policy on enforcement has cost companies more time and money while they work toward getting therapies approved and potential safety risks for patients.

Conversely, some attendees of the hearing said the enforcement discretion is a critical part of ensuring patients get the care they need.

Amanda Kabage, donor program coordinator at the University of Minnesota Microbiota Therapeutics program, said it is important to consider if patients who are involved in RCTs are representative of the kinds of patients who would receive FMT after the FDA approves a product. Are data collected in these studies generalizable to all patients who currently receive FMT under discretion?

“In my experience as a researcher in this field, I think the answer is no,” Kabage said. “The recurrent C. difficile patients, by their very definition, are very sick individuals, which is why they require FMT in the first place. Many of these patients have comorbidities, and they are excluded from clinical trial participation.”

She said that the lack of data collection under discretion has limited development, but said large, observational studies are needed to better understand that patient population, as well as the safety and efficacy of FMT. To treat the entire patient population with C. diff, Kabage said RCTs and enforcement discretion need to find a way to coexist. by Alex Young

Reference:

FDA. Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies; Public Hearing; Request for Comments. November 4, 2019.

    Perspective
    Sandra G. Gompf

    Sandra G. Gompf

    The recent bacteremias and one death caused by an extended spectrum beta-lactamase E. coli transmitted via FMT is sobering. These unique cases involved immunocompromised patients and clinical trials that did not include screening for resistant Gram-negative bacilli in an era of antimicrobial resistance. My experience is in sharp contrast.

    In 2012, I performed our hospital’s first FMT for recurrent Clostridioides difficile, at the desperate behest of a miserable patient. We carefully chose and screened a related donor, following then-available tissue transplantation guidelines and using tests available from our hospital laboratory. A dedicated pharmacist prepared the product. Our patient was cured and has remained so — and ever grateful. We continued cautiously, in compliance with FDA’s 2013 policy for permitting this treatment without investigational new drug application, fully informing each patient of the unknowns and investigational nature of FMT. We then discovered OpenBiome.org, a nonprofit that has evolved ever more rigorous donor screening that excludes 97% of donors. OpenBiome screens for MRSA, vancomycin-resistant Enterococci, ESBL and carbapenem-resistant Enterobacteriaceae organisms, along with a host of other pathogens. Its products have not been affected by multi-drug resistant organisms.

    There will always be unknowns in putting a biological product from one person into another. This is why careful screening of recipients and standardized screening of the donor product remains essential. Despite requests for other conditions, we continue to restrict FMT to immunocompetent patients with recurrent or refractory C. diff infection who have failed other options. We have treated at least 20 patients who had no other recourse, some who specifically sought us out for FMT, without serious adverse events and at least 85% success.

    I believe FDA's allowance of FMT has healed misery and saved lives, and I hope we can continue to offer it. Strictly regulating FMT now without similarly effective options is perilous. We are just beginning to understand the ecology of MDROs outside the health care environment and in the food supply. If a healthy donor without known risk factors shared a resistant Gram negative bacilli with several patients (some who are now colonized) in a clinical trial setting, imagine an uncontrolled scenario involving desperate patients using readily-Googled DIY procedures (stool being a free, “natural,” and renewable resource). I shudder to think of it.

    • Sandra G. Gompf, MD
    • Associate Professor of Medicine
      Division of Infectious Diseases and International Medicine
      University of South Florida Morsani College of Medicine

    Disclosures: Gompf reports no relevant financial disclosures.

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