Tainted donations from stool bank reignite safety concerns about poop transplants
Last year, the death of an immuno-compromised elderly patient in a fecal microbiota transplantation (FMT) trial at the Massachusetts General Hospital — due to a stool donation that contained a rare type of E. coli bacteria — sent shivers across the field.
Now, another incident has come to light — this time emanating from the non-profit stool bank OpenBiome — in which tainted stool made six patients sick, four of whom were hospitalized. Two other FMT recipients whose transplants comprised OpenBiome’s product also died.
On Thursday, the FDA issued a safety alert about the potential risk of serious or life-threatening infections with the use of fecal microbiota for transplantation — after it had been notified that a company’s FMT product for treatment-resistant C. diff had caused E. coli infections in six patients.
Two patients who received FMT product that was prepared from stool from two different donors, developed EPEC (enteropathogenic E. coli) infections. The other four patients — who received FMT product that was prepared from stool from a single donor — contracted STEC (Shiga toxin-producing E. coli) infections. Both types of E. coli are pathogenic, cause diarrhea, and are associated with other symptoms such as fever, abdominal pain, and vomiting.
OpenBiome, in a separate press release, disclosed that the tainted stool had, in fact, come from three of its donors — and that it was immediately implementing changes to its screening program to ensure all FMT material is screened for these pathogens. All unused material from these three donors has been recalled and destroyed, the company added.
OpenBiome had been screening for STEC via an enzyme immunoassay, which had come up negative, but following the reports of the infection, the company tested the material using PCR testing that showed the presence of Shiga toxin production. OpenBiome has not previously screened donors for EPEC, it said, but follow-up PCR testing of the donor material also generated a positive EPEC signal.
OpenBiome is in the process of evaluating whether to use PCR testing for other pathogens, the non-profit company’s executive director Carolyn Edelstein told Endpoints News.
“It’s not obvious for every pathogen that we screen for that using the PCR method is not going to lead to different issues related to false positives as well as false negatives,” she cautioned.
In addition, it was also disclosed that two patients with underlying medical conditions had died following FMT procedures using stool from OpenBiome.
It is not clear if STEC infections contributed to these deaths, the FDA said initially on Thursday. Once the agency received additional data from OpenBiome, it concluded that the death of one patient — who received stool that was found not to be contaminated with STEC — was unrelated to the OpenBiome product. But with the death of the second patient, whose donated stool was not tested for STEC, the link was unclear, the FDA said. OpenBiome contended that the treating physician had determined that death was unrelated to STEC.
Designed to replenish gut microbes, FMT has shown high rates of efficacy in the treatment of recurrent C. difficile, a stubborn infection that has grown resistant to existing antibiotics and kills more than 29,000 Americans each year.
Pioneered in China, the intervention has gained traction in the United States. But the FDA considers it an investigational treatment with an unproven safety and efficacy profile — so far. In 2013, the US regulator implemented a policy of “enforcement discretion” in relation to FMT for treatment-refractory C. diff: While developers are working on advancing products under an IND, physicians can use FMT products after securing reasonable consent from patients.
FMT requires a stool sample to be screened, liquefied and delivered to the colon by nasal or rectal tube. Patients must either find their own donor, obtain viable stool from a licensed health care provider, or turn to a stool bank, such as OpenBiome. Fewer than 3% of the population qualify as healthy donors, according to the Fecal Transplant Foundation.
In 2016, citing safety concerns, the FDA advocated a revision to its policy on stool banks — fearing that using fecal matter from a limited number of donors could lead to, for instance, the transmission of infectious agents in scores of patients. But the draft guidance hasn’t yet been implemented.
Given the death in the MGH trial, and now the OpenBiome disclosure — the time has come for tighter FDA regulation, UK-based Microbiotica’s CEO Mike Romanos noted in an interview with Endpoints. “I think what this says is that we need standardized screening.”
Implications beyond FMT
Microbiome-based therapeutics is a fecund field for drug developers — big and small — capitalizing on science that suggests flushing ‘good’ gut bacteria into the system can treat a plethora of conditions — from C. diff infections to obesity — using different therapeutic modalities, some of which are designed to sidestep the “ick” factor associated with traditional stool transfer or FMT. Some companies, like Microbiotica, are going even further by working on isolating an “ideal mix” of microbic ecosystems derived from stool — but growing them separately once the cocktail of suitable bacteria has been sequenced and characterized.
A few years ago, the spectacular failure of Seres Therapeutics’ seminal Phase II trial testing its “crapsule” — donor-derived processed fecal material encapsulated in a pill — derailed the emerging field. “My hope is that this (OpenBiome situation) doesn’t read across to the whole microbiome field because I think the impact of Seres having an unsuccessful Phase II…affected the whole microbiome field,” Romanos said.
When Endpoints reached out to players in the microbiome therapeutics space, the disparities in screening protocols were apparent.
Seres, which is expected to unveil key trial data this year, pointed out in a statement that its manufacturing process douses samples in ethanol, which would inactivate potential pathogens such as STEC.
French microbiome player MaaT Pharma, which has a Phase II acute GvHD trial ongoing, said France’s National Agency of Drugs Safety recommends FMT donations be tested for STEC, using the PCR method, and that it also screens for EPEC among other pathogens using PCR testing, in an emailed statement to Endpoints.
A range of key trials from companies including Rebiotix and Finch Therapeutics — which was founded by members of the OpenBiome team — are expected to read out this year.