An FDA advisory board has recommended that the agency approve a fecal microbiota transfer (FMT) product for Clostridium difficile infections.
By a vote of 13 to 4 on Thursday, the Vaccines and Related Biologicals Advisory Committee (VRBPAC), declared RBX2660 to be effective in treating patients with recurrent diseases. C difference. infections that have failed first-line antimicrobial treatment. Security also landed in favor of the product, by a vote of 12 to 4 (there was one abstention).
RBX2660 is a microbiota suspension prepared from human stool, which is collected from pre-screened qualified donors and administered rectally by enema.
Committee members were not necessarily swayed by hard data, but rather by the strong need for treatment options in C.diff, which affects about half a million people in the United States each year, according to the CDC.
“It’s better than what we have,” said temporary VRBPAC voting member Clifford McDonald, MD, of the CDC in Atlanta, who voted in favor of the product.
No approved options are currently available for patients who have failed first-line antimicrobial therapy. The only further treatment is to give more antibiotics, which can lead to further recurrences and increased antibiotic resistance.
“I am sensitive to the unmet need for this condition,” said Dean Follmann, PhD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, who voted in favor of the product.
Other members have been influenced by the rigorous testing protocols established by developer Rebiotix.
We have a really “tortured” protocol to make sure we don’t transfer pathogens, said Paul Offit, MD, of Children’s Hospital of Philadelphia, who voted yes for safety and efficacy. “That’s the biggest advantage here.”
“The real goal here is to provide a standardized product and process for consistent efficacy and safety,” said Eric Rubin, MD, PhD, of Brigham and Women’s Hospital in Boston, who also voted yes.
Rebiotix’s application for approval included five studies in its clinical development program for the FMT product, all with at least 6 months of follow-up – a pair of phase III trials (one randomized) and three phase II trials.
The primary efficacy analysis for the randomized phase III trial used a Bayesian analysis that borrowed information from one of the phase II studies, due to recruitment issues that prevented two trials from being completed. placebo-controlled phase III.
The Phase III randomized trial providing primary support for RBX2660 — Study 2017-01 or PUNCH CD3 — enrolled 289 subjects with recurrence C difference. and assigned them in a 2:1 ratio to FMT treatment or placebo. The data combined with the previous trial demonstrated a success rate of 69% with RBX2660 (95% CI 0.63-0.76) versus 57% with placebo (95% CI 0.47-0, 67). Success was measured by the absence of C difference. diarrhea, which is three or more uniform stools in 24 consecutive hours or less for at least 2 consecutive days for 8 weeks.
But although the analysis met the threshold of success considered equivalent to a positive well-controlled trial, according to FDA staff, it did not meet the threshold of a statistically very convincing finding from a single trial that could actually replace positive evidence from two well-controlled trials.
The integrity of the efficacy data was the focus of heated debate, with agency staff noting that the results showed no statistically significant benefit for RBX2660, while the sponsor cited the difference as clinically significant.
It was also determined that the scan was not predefined. Charts, data, explanations spanning a dozen slides explained how data moved from one analysis to another.
“If you torture the data enough, it will confess to almost anything,” said Jay Portnoy, MD, of Children’s Mercy Hospital in Kansas City, who voted against the recommendation for approval.
Regarding safety, Portnoy was skeptical about dismissing 18 deaths (2.4%) in the study group, compared to none in the placebo group.
“We don’t know what changes in the gut microbiome do to your risk of having a heart attack or stroke or dying from some other reason,” he said.
Safety analyzes were derived from pooled data on 749 patients in the clinical program who received at least one dose of RBX2660 and 83 patients who received placebo.
Overall, treatment-emergent adverse events (TEAEs), reported in 69.6% in the pooled RBX2660 data set versus 60.2% in the placebo group, tended to be mild or moderate in nature. Common TEAEs included abdominal distension or bloating, rectal bleeding, irritation or pain, intense chills/chills, abdominal pain or cramps, increased diarrhea, constipation, nausea, vomiting and fever.
Serious TEAEs were recorded in 14.2% of RBX2660 patients and 7.2% of placebo patients.
Although the FDA is not required to follow the advice of its advisory committees, it generally does.