Tag Archives: Food and Drug Administration

FDA Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Reactions d/t Multi-drug Resistant Organisms

Important Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms

The Food and Drug Administration (FDA) is informing health care providers and patients of the potential risk of serious or life-threatening infections with the use of fecal microbiota for transplantation (FMT).  The agency is now aware of bacterial infections caused by multi-drug resistant organisms (MDROs) that have occurred due to transmission of a MDRO from use of investigational FMT.

Summary of the Issue

  • Two immunocompromised adults who received investigational FMT developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E.coli). One of the individuals died.
  • FMT used in these two individuals were prepared from stool obtained from the same donor.
  • The donor stool and resulting FMT used in these two individuals were not tested for ESBL-producing gram-negative organisms prior to use. After these adverse events occurred, stored preparations of FMT from this stool donor were tested and found to be positive for ESBL-producing E. coli identical to the organisms isolated from the two patients.

Information for Health Care Providers and Patients

In July 2013, FDA issued guidance stating that it intends to exercise enforcement discretion under limited conditions regarding the IND requirements for the use of FMT to treat Clostridium difficile (C. difficile) infection in patients who have not responded to standard therapies. The guidance states that FDA intends to exercise enforcement discretion provided that the treating physician obtains adequate consent for the use of FMT from the patient or his or her legally authorized representative. The consent should include, at a minimum, a statement that the use of FMT to treat C. difficile is investigational and a discussion of its potential risks. FDA is informing members of the medical and scientific communities and other interested persons of the potential risk of transmission of MDROs by FMT and the resultant serious adverse reactions that may occur.

Patients considering FMT to treat C. difficile infection should speak to their health care provider to understand the potential risks associated with the product’s use.

Additional Protections for Investigational Use of FMT

  • Because of these serious adverse reactions that occurred with investigational FMT, FDA has determined that the following protections are needed for any investigational use of FMT:
    • Donor screening with questions that specifically address risk factors for colonization with MDROs, and exclusion of individuals at higher risk of colonization with MDROs.
    • MDRO testing of donor stool and exclusion of stool that tests positive for MDRO. FDA scientists have determined the specific MDRO testing and frequency that should be implemented.

Reporting Adverse Event

FDA encourages all health care providers administering FMT products to report suspected adverse events to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

June 13, 2019


Researchers Find Key Role of Excess Calcium In the Gut In C. difficile infections (CDI)

New research shows, it can’t make this last, crucial move without enough of a humble nutrient: calcium.

And that new knowledge about Clostridium difficile (a bacterium also known as “C. diff“) may lead to better treatment for the most vulnerable patients.

The discovery, made in research laboratories at the University of Michigan Medical School and the U.S. Food and Drug Administration, is published in the online journal PLoS Pathogens.

It helps solve a key mystery about C. diff: What triggers it to germinate, or break its dormancy, from its hard spore form when it reaches the gut.

Though the findings were made in mice, not humans, the researchers say the crucial role of calcium may help explain another mystery: Why some hospital patients and nursing home residents have a much higher risk of contracting C. diff infections and the resulting diarrhea that carries its spores out of the body.

That group includes people whose guts are flooded with extra calcium because they’re taking certain medications or supplements, have low levels of Vitamin D in their blood or have gut diseases that keep them from absorbing calcium.

The new discovery shows that C. diff can recognize this extra calcium, along with a substance called bile salt produced in the liver, to trigger its awakening and the breaking of its shell.

Previous research had suggested it couldn’t do this without another key component, an amino acid called glycine. But the new findings show calcium and the bile salt called taurochlorate alone are enough. Mouse gut contents that were depleted of gut calcium had a 90 percent lower rate of C. diff spore germination.

“These spores are like armored seeds, and they can pass through the gut’s acidic environment intact,” says Philip Hanna, Ph.D., senior author of the new paper and a professor of microbiology and immunology at U-M. “Much of the spore’s own weight is made of calcium, but we’ve shown that calcium from the gut can work with bile salts to trigger the enzyme needed to activate the spore and start the germination process.”

Ironically, the researchers say, one way to use this new knowledge in human patients might be to add even more calcium to the system.

That could awaken all the dormant C. diff spores in a patient’s gut at once, and make them vulnerable to antibiotics that can only kill the germinated form. That could also prevent the transmission of more spores through diarrhea to the patient’s room. That could slow or stop the cycle of transmission that could threaten them or other patients in the future.

Hanna’s graduate student, Travis Kochan, made a key observation that led to the discovery. He noted that the fluid “growth medium” that the researchers typically grow C. diff in for their studies had calcium in it. He realized this could artificially alter the results of their experiments about what caused C. diff spores to germinate.

So, he used a chemical to remove the calcium while leaving all the other nutrients that                  keep C. diff growing. The result: no new spore germination happened in the calcium-free growth medium.

FDA’s Center for Biologics Evaluation and Research conducted further research in laboratory dishes and in the guts of mice. FDA’s Paul Carlson, Ph.D., a former U-M research fellow, and fellow FDA scientists in his laboratory found that C. diff spores that were mutated so that glycine couldn’t act on them could still germinate and colonize mice. This suggested that calcium, and not glycine, was critical for this process.

Both mutant and regular forms of the bacteria could still activate an enzyme inside the C. diff spore that led the bacteria to start dissolving their hard shell. This released the store of calcium that the spore had been harboring inside itself, and increases the local level of the nutrient even further.

“These spores don’t want to germinate in the wrong place,” says Kochan, whose grandfather suffered from a severe C. diff infection which ultimately led to his death. “C. diff spores have specialized to germinate in the gut environment, especially in the environment of the small intestine, where calcium and the bile salt injection from the liver comes in.”

Hanna notes that the bile salt connection to C. diff spore germination was first discovered at U-M in 1982 by a team led by Ken Wilson, M.D.

Calcium and the gut

Certain ailments and treatments cause defects in calcium absorption, but are also risk factors for C. diff infections. For example, patients with vitamin D deficiency are five times more likely to get C. diff.

Medications aimed at calming acid reflux – such as proton pump inhibitors – and steroids can increase the amount of calcium in the gut. A Vitamin D deficiency can keep the body from reabsorbing calcium through the gut wall, allowing it to build up.

And people with inflammatory bowel diseases such as Crohn’s and colitis also have a harder time absorbing calcium from food through their gut walls.

Older adults are also often counseled to take calcium supplements to compensate for lower calcium levels and protect their bones from fracturing.

Hanna cautions that the new findings should not cause any patients to stop taking their medications or doctor-recommended supplements, or to start taking new ones. But he hopes to work with clinicians at U-M and beyond to test the new knowledge in a clinical setting. Meanwhile, he and Kochan and their FDA and U-M colleagues will continue to study C. diff germination in mice and look for ways to block the enzymes crucial to spore germination.

 

To read the article in its entirety – please click on the following link to be re-directed:

http://www.news-medical.net/news/20170713/Scientists-reveal-key-role-of-excess-gut-calcium-in-C-diffc2a0infections.aspx?utm_source=dlvr.it&utm_medium=twitter

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

placeholder+image

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/