Tag Archives: Stool Bank

Fecal Transplants (FMT) Treating Clostridium difficile Infections; U.S. Food and Drug Administration (FDA) Seeks Comment on What Investigational New Drug (IND) Requirements To Waive

Fecal Transplants to Treat C. difficile: FDA Seeks Comment on What IND Requirements to Waive

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The US Food and Drug Administration (FDA) on Monday February 29, 2016,announced new draft guidance that aims to further assure that patients infected with the bacterium Clostridium difficile and not responding to standard therapies can access poop transplants, also known as fecal microbiota for transplantation (FMT).

FDA considers FMT an investigational new drug (IND), which requires physicians and scientists to file an IND application if they intend to use the treatment for clinical practice or research.

However, FDA has issued guidance stating that FMT may be used to treat 

C. difficile infection not responsive to standard therapies outside of a clinical trial. 

New Guidance

The latest draft guidance offers new notice that FDA intends to exercise enforcement discretion regarding the IND requirements for the use of FMT to treat C. difficile infection.

As far as what FDA wants to discuss on this new draft guidance, the agency says it’s requesting comments on which IND requirements are appropriate to waive.

In particular, FDA is requesting comments on the requirement for institutional review board review of the use of FMT to treat patients with C. difficile infection not responding to standard therapies when the FMT is provided by a stool bank,” FDA says.

Background

The draft guidance comes as over the past few years, FMT, which basically involves the transfer of a healthy donor stool to the bowel of a patient infected with C. difficile, has emerged as an effective means to treat recurrent forms of the bacterial infections, according to a study in the Journal of Law and Biosciences.

Rachel Sachs, an academic fellow at Harvard University’s Petrie-Flom Center for Health Law Policy, Biotechnology and Bioethics, and an author of that study, explained to Focus that previously FDA said it would regulate FMT like a biologic, but that the decentralized, hospital-based model of FMT envisioned in this new draft guidance more closely resembles the agency’s models for regulating tissue or cord blood products.

Two companies – Rebiotix and Seres Therapeutics – have been granted orphan drug designations for their INDs as FMT treatments for recurrent C. difficile infections, which affect between 85,000 and 110,000 people in the US annually.

And Sachs said she’s under the assumption that once a company gets FDA approval for their FMT product, FDA will revoke its enforcement discretion included in this new guidance.

Guidance Details

FDA said Monday it intends to use this discretion for waiving certain IND requirements, provided that:

  • The licensed health care provider treating the patient obtains consent from the patient or his or her legally authorized representative for the use of FMT products. The consent should include, at a minimum, a statement that the use of FMT products to treat C. difficile is investigational and a discussion of its reasonably foreseeable risks;
  • The FMT product is not obtained from a stool bank; and
  • The stool donor and stool are qualified by screening and testing performed under the direction of the licensed health care provider for the purpose of providing the FMT product for treatment of the patient.

And FDA makes clear that an establishment that collects or prepares FMT products “solely under the direction of licensed health care providers for the purpose of treating their patients (e.g., a hospital laboratory) is not considered to be a stool bank under this guidance.”

Sachs co-authored her article with Carolyn Edelstein, director of policy and global partnerships at OpenBiome, a nonprofit stool bank that sells FMT capsules (recommended dose of 30 capsules plus a safety test capsule costs $535, or stool preparations for delivery by colonoscopy, enema, and EGD/naso-enteric tube are $385 each) after conducting first-in-human evaluations (N=4) and a randomized dose-finding study (N=17).

Edelstein told Focus that the draft “suggests that the FDA is seeking to set up a more tailored regulatory scheme, one that considers stool banking separately from small-scale directed donation. We are in favor of seeing stool banking receive more regulatory oversight. We plan to answer the agency’s request for comments on the elements of a regulatory framework that would lend this oversight to the practice of stool banking without unduly burdening the physicians and healthcare facilities using banked material, and by extension, unduly limiting access to the treatment for their patients.”

FDA also explains that there were “difficulties in interpretation” with previous draft guidance, particularly around the provision that the donor be known either to the patient or to the treating licensed health care provider, noting “the revised approach more accurately reflects our intent to mitigate risk, based on the number of patients exposed to a particular donor or manufacturing practice rather than the risk inherent from any one donor.”

But as new FMTs are likely to hit the market as orphan drugs, the bigger issue at play could be associated with cost. Sachs noted that any FDA-approved treatment, particularly since it’s an orphan product, could be expensive (upwards of thousands of dollars for treatment).

 

Source:

http://www.raps.org/Regulatory-Focus/News/2016/02/29/24428/Fecal-Transplants-to-Treat-C-difficile-FDA-Seeks-Comment-on-What-IND-Requirements-to-Waive/

Comparison Study Shows Efficacy in Frozen Fecal Product To Fresh For Fecal Microbiota Transplantation To Treat Recurrent C. diff. Infections

Frozen fecal microbiota transplantation showed efficacy comparable to fresh FMT for clinical resolution of diarrhea among adult patients with recurrent or refractory Clostridium difficile infection, according to results of a randomized trial published in JAMA.

Using frozen FMT would reduce costs associated with donor screening frequency, provide immediate availability of the treatment and enable delivery of the treatment to centers without on-site laboratory facilities,

the researchers wrote. “Previous studies have supported the use of frozen FMT for management of recurrent [C. difficile infection] but have not directly compared frozen with fresh FMT.”

Lee CH, et al. JAMA. 2016;doi:10.1001/jama.2015.18098

Malani PN, Rao K. JAMA. 2016;doi:10.1001/jama.2015.18100

Christine H. Lee, MD, from McMaster University in Canada, and colleagues, conducted a double-blind, noninferiority trial involving 232 adult patients with recurrent or refractory C. difficile infection (CDI) at six Canadian academic medical centers from July 2012 to September 2014. Patients were randomly assigned to receive frozen (n = 114) or fresh (n = 118) FMT via enema without bowel preparation, and if they showed no improvement by day 4, they received an additional FMT between days 5 and 8.

No recurrence of CDI-related diarrhea at 13 weeks and adverse events served as primary outcomes, and a 15% margin was set to confirm noninferiority.

In the per-protocol population (frozen, n = 91; fresh, n = 87), 83.5% of the frozen FMT group achieved clinical resolution compared with 85.1% of the fresh FMT group, a difference of – 1.6% (95% CI, – 10.5% to ∞; P = .01 for noninferiority). In the modified intention-to-treat population (frozen, n = 108; fresh, n = 111), 75% of the frozen FMT group achieved clinical resolution compared with 70.3% of the fresh FMT group, a difference of 4.7% (95% CI, – 5.2% to ∞; P < .001 for noninferiority). Adverse and serious adverse events were comparable between groups; the most common adverse events were transient diarrhea (70%), abdominal cramps (10%) or nausea (< 5%) during the 24 hours after FMT, and constipation (20%) and excess flatulence (25%) during follow-up, all mild to moderate in severity.

“Among adults with recurrent or refractory CDI, the use of frozen compared with fresh FMT did not result in worse proportion of clinical resolution of diarrhea,” the researchers concluded. “Given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting.”

These researchers have provided

“the best evidence to date supporting the use of frozen stool, with their finding that use of frozen stool for FMT resulted in a rate of clinical resolution of diarrhea that was no worse than that obtained with fresh stool for FMT and will likely expand the availability of FMT for patients with recurrent CDI,”

Preeti N. Malani, MD, MSJ, associate editor of JAMA, and Krishna Rao, MD, MS, both from the University of Michigan Health System, Ann Arbor, wrote in a related editorial. “The ability to use frozen stool eliminates many of the logistical burdens inherent to FMT, because stool collection and processing need not be tied to the procedure date and time.

This study also provides greater support for the practice of using centralized stool banks, which could further remove barriers to FMT by making available to clinicians safe, screened stool that can be shipped and stored frozen and thawed for use as needed. In theory, procedure costs may also be decreased, since comprehensive donor screening is expensive.” – by Adam Leitenberger

Disclosures: Lee reports she has participated in clinical trials for ViroPharma, Actelion, Cubist and Merck, and served as a member of the advisory boards for Rebiotix and Merck. Please see the study for a full list of all other researchers’ relevant financial disclosures. Malani and Rao report no relevant financial disclosures.dR

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http://www.healio.com/gastroenterology/infection/news/online/%7Bbac5a422-a30c-4501-8e35-05e9a346772a%7D/frozen-fmt-noninferior-to-fresh-fmt-for-treating-recurrent-c-difficile-infection