BETHESDA, MD. – The Food and Drug Administration has designated stool for transplant as a biologic drug, necessitating that any gastroenterologist performing fecal microbiota transplants obtain an Investigational New Drug permit.
By designating stool for transplant as a biologic drug, anyone who performs fecal microbiota transplants (FMTs) – whether they perform a single transplant for one patient or recruit dozens for a study – needs to have an IND permit.
The announcement was made at a 2-day public workshop convened by the National Institutes of Health and the Food and Drug Administration to sift through some of the evidence surrounding FMTs.
The intent of the IND requirement, said Dr. Jay Slater, director of FDA’s Division of Bacterial, Parasitic, and Allergenic Products, is not to stamp out the care that patients can now receive, but to make sure it’s safe, effective, and data driven.
Courtesy of Dr. Lawrence Brandt
Dr. Lawrence Brandt is one of a handful of gastroenterologists in the U.S. who regularly perform fecal transplants.
"This is a low-tech procedure that already has a CPT code. A ‘how-to’ guide recently appeared online, and it walks you right through how to do the procedure. There are a very large number of people doing this off the grid. What we need are long-term controlled trials on this that will enhance our understanding of its safety and efficacy."
Although neither the biologic designation nor the IND requirement is brand new, they have not been well publicized, according to one of the innovators of FMT, Dr. Lawrence Brandt, of Albert Einstein Medical Center in New York.
"I am struck by the fact that FDA wants these INDs and yet FDA has never publicly set forth any message on it. So from this moment on, all of us who continue to do this without an IND are violating FDA’s policy," he said at the meeting.
One of the primary concerns now, according to Dr. Brandt, is a burgeoning public interest in FMTs, even to the point of do-it-yourself treatments. With online instructions for self-treatment, and a procedure that is rife with variations, regulators can no longer tacitly ignore the issue.
There’s no standardization of how the stool is prepared and filtered – it could be blended in a kitchen blender or by hand with a tongue depressor, or strained through gauze or a coffee filter, he said. Dosing is all over the place, listed as spoonfuls, grams, and milliliters. Different institutions screen donors in different ways. Some patients get a bowel prep, which can be mild or aggressive, and some don’t get one at all. Should the stool be fresh, and if so, how fresh? Is frozen okay? These are all issues that need to be examined from a safety and efficacy perspective and standardized.
Even the method of delivery varies. The transplant can be administered via nasogastric tube or colonoscope, or by enema. There’s no standardization of data collection either. Some large institutions keep records of everything from the first workup to the last visit. Doctors who perform transplants occasionally may not be as conscientious. And no one knows anything about the do-it-yourselfers, at home with a family member’s donation and a squeeze enema.
Dr. Brandt – and a number of clinicians at the meeting – agreed that answers must be found for all these questions. And they agree that well-conducted clinical trials are the best way to go forward.
Dr. Colleen Kelly, one of the gastroenterologists launching one of 22 currently recruiting studies on FMT, started doing the procedure 5 years ago. Her first patient was a 26-year-old medical student with recurrent bouts of a Clostridium difficile infection.
"I’d heard of [FMT], but never, ever thought of doing one," said Dr. Kelly, of Brown University Medical Center, Providence, R.I. "I thought it was something at the far fringes of medicine."
At her patient’s insistence, Dr. Kelly contacted Dr. Brandt and learned about his process for performing FMT. The following year, she performed 10 FMTs. She is now undertaking a study with Dr. Brandt to recruit about 48 patients with relapsing C. difficile to be randomized to FMT or to a sham treatment with their own stool. Patients who have clinical failure in the sham group will be offered FMT; patients in the active arm who fail on initial FMT will get another FMT from a different donor.
While most trials are examining the utility of FMT in patients with recurrent C. difficile, a few are investigating FMT for use in patients with Crohn’s disease and inflammatory bowel disease. Some clinicians and individual patients are now using FMTs for this condition outside a clinical trial, with no understanding of how a compromised intestinal mucosa might react to transplanted stool.