Months after the US Food and Drug Administration (FDA) announced it would reverse its prior regulatory strategy on fecal microbiota transplants (FMT), the agency has released a new draft guidance document meant to further clarify its regulatory stance on the issue.

Background

Fecal transplants are a relatively new innovation involving the transfer of either fecal matter or the bacteria found within fecal matter from a healthy patient to a sick one. Various published research has identified the procedure as being one that can fight off Clostridium difficile infections by introducing so-called "good bacteria" back into a person's body. The idea is to overload the gastrointestinal tract with enough of the good bacteria to overwhelm the C. diff, thereby ending the infection.

One device, known affectionately as either the "RoboGut" or the "RePoopulation Station," is essentially a small manufacturing facility that takes a selected 33 strains of healthy fecal microbiota which are then reproduced in a mixture for eventual transplantation during a colonoscopy procedure.

By standardizing the procedure, the researchers said they hoped to reduce the variability that now exists when FMTs are conducted and reduce the time between a patient having a need for the transplant and it occurring. At present, donors need to be found and screened, and patients aren't necessarily sure if they're getting the bacteria they need.

Uniform products would hypothetically allow for much higher assurances of quality, safety and efficacy - a problem FDA has been grappling with over the course of the last year.

FDA's Responses to Date

At first, FDA said in May 2013 it would require the products to be administered under an approved Investigational New Drug Application, which is required for biological products seeking FDA approval. More practically, they're also an application used to begin or continue clinical testing in humans, and are meant to show that a product meets baseline levels of safety.

FDA said a lack of regulation was potentially resulting in patients receiving dangerous therapies.

However, FMT advocates fought back against FDA, saying the new rules were onerous and costly, and would result in more patients resorting to do-it-yourself fecal transplants outside medical facilities.

That pushback resulted in FDA reversing its decision in less than a month. In a June 2013 announcement, FDA said it would institute a compromise of sorts, one built on a familiar concept known as "regulatory enforcement discretion."

FDA would maintain that it has the authority to regulate FMT products, but would allow more practitioners to conduct FMT procedures without an approved IND.

"Some health care providers have stated that applying IND requirements will make FMT unavailable and have suggested that an alternative regulatory approach is needed to ensure the widespread availability of FMT for individuals with C. difficile infection unresponsive to standard therapies," FDA explained. "The agency acknowledges these concerns and intends to exercise enforcement discretion regarding the IND requirements for the use of FMT to treat C. difficile infection not responding to standard therapies provided the treating physician obtains adequate informed consent from the patient or his or her legally authorized representative for the use of FMT products."

At the time, FDA said the policy was meant as a stopgap measure while it "develops appropriate policies for the study and use of FMT products under an IND."

"FDA intends to exercise this discretion on an interim basis while we further consider the matter," it added in a Federal Register posting announcing a finalized guidance document in July 2013.

New Guidance

Now FDA is out with an additional draft guidance document, one elaborating on the further considerations it hinted at in July 2013.

The guidance, Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies, again makes the case for an enforcement discretion based approach and states that further policies remain in the works.

The new guidance is meant to replace the July 2013 final guidance, FDA said, and reflect that FMT therapies will only be given leeway if they are intended for use in non-responsive cases of C. difficile.

FDA lays out a three-part approach in its guidance whereby it will not require an IND:

1. Informed consent is obtained from the patient or his or her legally authorized representative.
2. The FMT product is obtained from a donor known to either the patient or the licensed health care provider treating the patient.
3. The stool donor and stool are screened and tested for the specific purpose of providing the product to the specific patient.

Failure to meet any of those standards will require the use of an IND, FDA said. In addition, FDA's policy does not apply to any other uses of FMT beyond C. difficile. Some doctors have floated the idea that the FMT approach may also be useful for patients with Irritable Bowel Syndrome (IBD).

The July 2013 guidance was the same in principle, but lacked a clear delineation between what was and what was not acceptable under the enforcement discretion policy. FDA is still working on evaluating its enforcement policy, it said.

Comments on the draft guidance are due to FDA by 28 March 2014.

The stopgap measure may be intended to hold the fledgling therapeutic area over until approved therapies reach the market, the first of which may arrive soon. In late June 2013, FDA granted "fast track" status to Rebiotix's FMT suspension RBX2660, meaning the product could see an approval decision in early 2014 barring any delays.

Guidance

Federal Register