A paper today in Science calls for a better way to regulate an increasingly popular method of treating recurrent Clostridium difficile infection (CDI).
The method, known as fecal microbiota transplantation (FMT), involves the transfer of stool from a healthy donor—via colonoscopy, nasogastric tube, or enema—into the colon of a patient who has recurrent CDI to re-introduce healthy bacteria into the gut. While still an investigational treatment, FMT has produced strong results in several small clinical trials in recent years, with cure rates as high as 90%.
A growing number of physicians are turning to it as an alternative to antibiotics—which can contribute to re-infection by wiping out the beneficial gut bacteria that keep C difficile bacteria in check—and several medical societies have said it should be a standard of care for patients with multiply recurrent CDI.
But proponents of FMT are concerned that the unsettled regulatory landscape may be preventing the procedure from being more widely accessible.
The FDA approach
The position of the US Food and Drug Administration (FDA) on FMT has undergone several changes in recent years. Under the current rules, written in 2013, physicians are allowed to perform FMT using screened stool if recurrent CDI patients are not responding to standard treatment (antibiotics), as long as patients know the procedure is investigational and are aware of the risks. Unlike with other investigational drugs or procedures, the FDA doesn't require an investigational new drug (IND) application, which would require patients to enroll in a clinical trial. The FDA made that allowance only after patients and physicians complained that the IND requirement would limit access to the procedure.
Draft guidance issued in 2014 added a requirement that patients or their physicians know the stool donor, but that was also criticized. Another draft guidance from the FDA, published in March 2016 but not yet approved, would allow physicians to continue performing FMT without an IND as long as the stool isn't obtained from a stool bank and both the stool and stool donor are screened at the hospital under the direction of a physician. To continue using stool from stool banks, physicians and hospitals would have to enroll their patients in a clinical trial—a burdensome and time-consuming process.
The draft guidance has also come under fire from some patients and providers, who believe it creates more barriers to access for recurrent CDI patients who aren't responding to antibiotics. They've argued that stool banks are necessary because not all hospitals or laboratories, especially those in rural areas, have the facilities or training to do proper stool screening.
In addition, not all recurrent CDI patients may qualify for clinical trials. Some are concerned that the new rules, if approved, could give rise to patients attempting the procedure on their own, using stool from a friend or relative.
Carolyn Edelstein, executive director of Massachusetts-based OpenBiome, the country's first and largest stool bank, says the FDA's 2013 position truly opened the door for FMT to be widely available. Since October 2013, OpenBiome has sent out nearly 30,000 treatments for FMT in recurrent CDI patients.
But she's concerned that limiting access to those hospitals that have the administrative infrastructure to join a clinical trial would make it more difficult for patients to get FMT. "Ninety-seven to 98% of the country is within a 2-hour drive of one of our providers," Edelstein said in an interview. "When you've got chronic diarrhea, you really don't want to have to travel across the country to get treated."
The FDA's stance on the issue reflects some of the regulatory challenges presented by using fecal material for medical treatment. The agency considers stool more a drug than human tissue and argues that FMT hasn't been fully evaluated for safety and efficacy in controlled trials. The FDA's argument for the tightened rules is that stool from centralized stool banks, which are currently unregulated, could present safety concerns, including transmission of infectious diseases and other risks related to changes in the microbiome.
Balancing access and safety
To address these concerns, a group of lawyers, researchers, and physicians with the University of Maryland and the Veterans Affairs Maryland Health Care System have proposed an alternative regulatory system that they believe is similar to the FDA's approach but has advantages over the current system.
Under the first track of their three-track scheme, FMT for treatment of CDI would be regulated not as a drug but as the "practice of medicine" when performed by a physician with screened stool acquired from someone known to the physician or patient. In other words, physicians would be able to perform the procedure at their discretion, based on the scope of their practice. State medical boards would regulate the practice. FMT for any other condition would require an IND.
Under the second track, stool from stool banks could be used, but the stool banks would be regulated in the same way that human cell-tissue or blood banks are regulated. This would require annual registration with the FDA, and compliance with rules for donor screening and testing and "good manufacturing practices." In addition, stool banks would have to collect safety and outcomes data for every sample used and submit those data to the FDA.
Lead author Diane Hoffmann, JD, a professor of healthcare law at the University of Maryland, says that while she knows of no cases of patients dying or getting very sick from stool obtained from stool banks, more oversight of these facilities is needed.
"There are no requirements on stool banks in terms of how they get the stool, how they screen it or test donors and stool products, and there's no requirement for the kind of good manufacturing practices you would want," Hoffmann said in an interview. "These are the kind of things the FDA is concerned about when you're selling a product that's going to be a therapy for people.
"We think that would improve on the potential safety of the stool banks that are operating," she added.
The third track would require "modified stool-based products"—drugs containing beneficial bacteria cultured from stools—to be regulated as drugs or as biologics. Although there are no such products currently on the market, several companies are developing them, with mixed results from early-phase clinical trials.
Hoffman and her colleagues believe this strategy balances the desire for greater access to FMT with the need for more data on safety and effectiveness. But it also acknowledges that transplanted fecal material is not a typical drug and therefore might need a different regulatory pathway. And implementation would be relatively easy, they say.
OpenBiome's Edelstein, who was not involved in writing of the paper, called the approach compelling and said she thinks it's consistent with where OpenBiome thinks the regulatory emphasis should be on stool banks. Although OpenBiome already voluntarily provides the FDA with information on its screening and manufacturing process, tracks outcomes, and publishes safety and efficacy data, she agrees that there should be more oversight of stool banks.
"We have always supported the idea of finding the right regulatory mechanism for overseeing stool banks," she said. "I think it makes total sense that there should be regulations governing the safety of our process, from screening and selecting donors through manufacturing through storage and shipping."
CDI is a leading cause of diarrhea in hospital patients and one of the most common healthcare-associated infections. It's also difficult to cure. At least 20% of patients who get an initial CDI have a recurrent infection within 8 weeks, with the risk being as high as 50% to 60% after three or more infections. Recurrent CDI is also associated with higher morbidity and mortality.
Dec 15 Science policy forum